clinical journal of hypertension - hsindia.orghsindia.org/images/journal/2018/jan_march_2018.pdf ·...

ClinicalJournal of Hypertension

EDITOR-IN-CHIEF

Dr. Siddharth N. Shah

JANUARY-MARCH 2018 VOL. NO. 2 ISSUE NO. 3Mumbai Published on 15th of January, 2018

Price : Rs. 20

RNI No. MAHENG 14164

www.hsindia.org

OFFICIAL PUBLICATION OF

Editorial Board

Editor-in-Chief

Siddharth N. Shah

Associate Editors

Falguni Parikh § Shashank R. Joshi § N.R. Rau § G.S. Wander

Assistant Editors

Nihar P. Mehta § Dilip Kirpalani

Editorial Board

M.M. Bahadur § Amal K. Banerjee § R.K. Bansal § A.M. Bhagwati § Aspi R. Billimoria Shekhar Chakraborty § R. Chandnui § R.R. Chaudhary § M. Chenniappan Pritam Gupta § R.K. Jha § Ashok Kirpalani § Girish Mathur § Y.P. Munjal

A. Muruganathan § K.K. Pareek § Jyotirmoy Paul § P.K. Sashidharan N.P. Singh § R.K. Singhal § B.B. Thakur § Mangesh Tiwaskar § Trupti Trivedi § Agam Vora

Ex-Officio

Hon. Secretary General

B.R. Bansode

Printed, Published and Edited by Dr. Siddharth N. Shah on behalf of Hypertension Society India, Printed at Shree Abhyudaya Printers, Unit No. 210, 2nd Floor, Shah & Nahar Indl. Estate, Sitaram Jadhav Marg, Sun Mill Compound, Lower Parel, Mumbai 400 013 and Published from Hypertension Society India. Plot No. 534-A, Bombay Mutual Terrace, Sandhurst Bridge, 3rd Floor, Flat No.12, S.V.P. Road, Grant Road, Mumbai 400 007.

Editor : Dr. Siddharth N. Shah

3

Vol. 2 • Issue No. 3 • January-March 2018

Official Publication of Hypertension Society IndiaEditor-in-Chief: Siddharth N. Shah

clinical

Journal of Hypertension

EDITORIAL Hypertension and Pregnancy Siddharth N Shah ............................................................................................................. 5

ORIGINAL ARTICLE Role of Serum Uric Acid as a Prognostic Marker in Acute Coronary Syndrome: A Hospital Based Study Chandra Prakash Thakur, Kallol Bhattacharjee, Dwijen Das ............................... 10

To Study the Clinical Profile and Electrocardiographic Criteria in Patients with Left Ventricular Hypertrophy and Coorelate them with Echocardiographic Findings Suraj A Kodak, Vikram Vikhe, Prakash Shende, Koushik Chavalla ..................... 17

REVIEw ARTICLEResistant Hypertension: Management Guidelines Ashok K Taneja, Akshat Taneja ................................................................................. 24

Hyponatremia Associated with Diuretics Rahul Chhabria, Kaustubh A Vaidya ......................................................................... 32

Non-Pharmacological Management of Hypertension - Beyond Controversy Bhupendra Chaudhary, Rajeev Aggarwala, Puneet Bhasin ................................... 35

CASE REPORT Robotic Adrenalectomy: An Emerging Option in the Treatment of Pheochromocytoma Ameya Tirodkar, Nihar Mehta, AB Mehta ............................................................... 41

HSICON 2018 ............................................................................................................ 46

Contents

4 Clinical Journal of Hypertension | January-March 2018 | Vol. No. 2 | Issue No. 3

Governing Body

Hon. PatronsAspi R. Billimoria (Mumbai) • N.R. Rau (Udupi)

President Executive Chairman P. K. Sasidharan (Calicut) Siddharth N. Shah (Mumbai)

President - Elect Past President Ashok Kirpalani (Mumbai) Shashank R. Joshi (Mumbai)

Vice PresidentsR. Chandni (Calicut) • R.R. Chaudhary (Patna)

Secretary General Jt. Secretaries B.R. Bansode (Mumbai) Santosh B. Salagre (Mumbai) • Anita Jaiswal – Ektate (Mumbai)

TreasurerAshit M. Bhagwati (Mumbai)

Chairman: Research CommitteeGurpreet S. Wander (Ludhiana)

Editor : Clinical Journal of HypertensionSiddharth N. Shah (Mumbai)

Chairman: Epidemiology CommitteeA. Muruganathan (Tirupur)

MembersD.P. Singh (Bhagalpur) • Dilip Kirpalani (Mumbai) • Nihar P. Mehta (Mumbai)

Shibendu Ghosh (Kolkata) • K.G. Sajeeth Kumar (Kozhikode) • R.K. Jha (Indore) • P.K. Sinha (Gaya)


1Editor-in-Chief: Clinical Journal of Hypertension; Hon. Physician and Diabetologist, Bhatia Hospital, Saifee Hospital, S.L. Raheja Hospital, Mumbai; Executive Editor: JAPI

Hypertension and Pregnancy

Siddharth N Shah1

EDITORIAL

of throwing light on certain pathogenic mechanisms.2 Far from being an inert organ, the placenta dynamically interacts with the mother and the fetus all through its growth. Emerging from the interactions and recip-rocal influences between these three players, the materno-placento-fetal physiology is a complex process, and a determining one for the life of the future adult.Arterial hypertension in women is one of the principal causes of morbidity and involves 15% of pregnant women.3 However, the risk scores and the strategies for cardiovascular risk reduction, used in clinical practice in adults, does not apply to young women who are in the procreating age. Hypertensive disorder in pregnancy shows signs of vascular disease and remodeling which entirely mimic atherosclerosis and which are similar to the

IntroductIonThe theory of fetal programming has taught us that the occurrence of chronic and cardiovas-cular diseases at an adult age would already, in part, be determined and influenced by intra-uterine life.1 Placenta is considered as a simple anatomical waste. In the present-day context, once delivery is carried out, the placenta does not present any clinical significance and is only analysed in some cases (suspicion of infection, delay in growth...). However, on integrating the genetic and epigenetic factors, pre-existing maternal diseases and environ-mental factors, the placenta depicts changes via intra-uterine life, holding the potential

abstract• Hypertensive disorders involve 15% of pregnancies and are increasing due to late

pregnancies and excess weight, which makes it a public health problem.• Chronic arterial hypertension increases the risk of preeclampsia, intra-uterine growth

retardation and placental detachment.• Prophylacticdosesofaspirinmustbeenvisaged fromthe first trimesterofpregnancy in

patients at risk.


lesions observed in the coronaries and the great vessels.4 Being the first indicator of arterial damage due to hypertension, the study of placental vascularisation offers a survey of future vascular health of the woman and an opportunity for an early implementation of risk reduction measures.It is estimated that hypertensive disorders complicate 15% of pregnancies. This number is expected to rise with pregnancies occurring at a later age and the observed increase in the BMI in the general population.5

Complicated pregnancies of chronic arterial hypertension are strained with an increased risk of preeclampsia, intra-uterine growth retardation (IUGR) and placental detachment.5 Indeed, the rate of preeclampsia in hypertensive patients varies between 25-50%, according to the duration of progress of hypertension, personal history of preeclampsia in an earlier pregnancy and the presence of diastolic arterial hypertension between 100-110 mmHg.5 The risk of low birth weight is more than double and perinatal mortality is three to four times greater than that of the general population.The risk of placental detachment is also

doubled in case of chronic arterial hyper-tension, and this association is much stronger in case of preeclampsia added on to a concom-itant IUGR.6 These three conditions are linked to a placental ischemic disease, which makes one suppose a common pathophysiological mechanism in association with an abnormality of placental vascularisation and exacerbated in case of chronic arterial hypertension.6

During its nine months of intra-uterine life, the fetus depends entirely on the placenta for its development and its protection. This transitory organ has an extraordinary capacity of assuming the function of several organs, whilst ensuring the transport of respi-ratory gases and nutrients, the elimination of metabolic waste, the synthesis of growth and pregnancy hormones, which guarantee immune interactions between the mother and the fetus.7 Thus, a healthy and functional vascularisation is essential to fetal growth and to a good progress of the pregnancy.In its normal development, the placenta puts into place a uteroplacental circulation which comprises a maternal circulation and a fetal circulation (Figure 1). The two blood networks develop in parallel, without however ever coming into contact.8 A part of the embryonic tissue, called the trophoblast and initially made up of cytotrophoblast and syncytiotrophoblast, is responsible for the process of implantation in the endometrium and the development of the placenta. The cells of the trophoblast are organised in placental villosities with the fetal capillary network in their center. On the maternal side, the spiral arteries, emerging from uterine circulation, are subjected to lysis activity of the syncytio-trophoblast, and are transformed into lacunae of maternal blood which flows between these villosities, the inter-villous space.8

In this encounter, a fundamental stage of devel-opment of placental vascularisation consists of the migration of a sub-population of cells of the trophoblast in the endometrium, leading to an essential physiological remodeling of the spiral arteries. The latter will lose their smooth muscle bed which will be replaced by

Fig. 1: Normal placental development


fibrous tissue.8,9 This significant modification releases the arteries of their tonus control through neuro-hormonal mediators, which enable an increase in the blood flow towards the placenta and configures it as an organ with low resistance.8,9 The abnormal invasion of the trophoblast and the incomplete remodeling of the spiral arteries are partly at the origin of placental dysfunctions and abnormalities of fetal development (Figure 2).9

Chronic arterial hypertension is traditionally a silent disease, whose first signs of attack of the organ are sometimes only detectable after several years of progression. However, some abnormalities of utero-placental circu-lation are already evident in hypertensive patients within a few weeks of pregnancy itself. Investigation of the uterine arteries by Doppler enables the detection of the first signs of vascular insufficiency, by revealing a raised resistance index or protodiastolic incisures (notch). The isolated presence of a uterine notch in the second trimester is difficult to interpret, since it can occur in a physiological situation or disappear in the third trimester. The predictive value of the parameters of the uterine Doppler combined with other markers, have especially been studied in the preeclampsia. Paticularly in the case of chronic arterial hypertension, the anomalies of uterine Doppler in the second trimester in hypertensive patients are often associated with the augmentation of preeclampsia, IUGR, low birth weight. This requires a close clinical

and echographic follow-up throughout the pregnancy.10

On macroscopic examination of placenta, signs of circulatory insufficiency could already be present in the form of a hypot-rophic placenta, placental infarction and placental detachment.11 On histological examination, maternal vasculopathy as well as ischemic and inflammatory modifications of the placenta have been described. Among the lesions observed, one could count an incomplete remodeling of the spiral arteries, with retention of the muscular bed, and acute atherosis, a fibrinoid necrosis, placental infarction and a chronic villitis of indeter-minate origin.11-13

acute atherosis and lack of remodeling of spiral arteriesAcute atherosis, described in spiral arteries of hypertensive pregnancies, makes a reference to its similarity with the first stages of devel-opment of atherosclerotic lesions observed in the coronary arteries and other big vessels.4 Acute atherosis is characterised by the sub-endothelial accumulation of lipid-laden spumous cells, a fibrinoid vascular necrosis and a perivascular lymphocytic infiltrate.4 In good preeclampsia studies, the presence of acute placental atherosis has been described in the case of chronic arterial hypertension, disseminated erythematous lupus, anti-phospholipids antibody syndrome, diabetes, IUGR and even in normal pregnancy.4

Fig. 2: Acute atherosclerosis in pre-eclampsia


or having presented with more than one episode of preeclampsia).16

The association between the abnormalities of placental vascularisation and future vascular health of the mother and child and the establishment of a cardiovascular risk score taking into consideration the histological aspects seems promising, in order to target women who could benefit from strategies for risk reduction, specially for a subsequent pregnancy.

conclusIonChronic arterial hypertension could affect the physiological development of utero-placental circulation and is associated with an increased risk of ischemic placental diseases. Placental pathology enables the detection of atheromatous changes in arterial vascu-larisation whose clinical significance ought to be specified. As in any other target organ of hypertension, pregnancy should have its place in the decision on a preventive strategy.

references1. Barker DJ, Erksson JG, Forsen T, Osmond C. Fetal

origins of adult disease: Strength of effects andbiological basis. Int J Epidemiol 2002; 31:1235-9.

2. Redline RW. Placental pathology: A systematic approach with clinical correlations. Placenta 2008; 29 (Suppl. A):586-91.

3. Alexander RW, Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response:Anewperspective.Hypertension 1995; 25:155-61.

4. Staff AC, Dechend R, Redman CW. Review:Preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: Two new hypotheses. Placenta 2013; 34:(Suppl.):573-8.

5. Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol 2002; 100:369-77.

6. Ananth E, Peltier MR, Kinzler WL, Smulian JC, Vintzileos AM. Chronic hypertension and risk ofplacental abruption: Is the associationmodified byischemic placental disease? Am J Obstet Gynecol 2007; 197:273.el-7.

7. Burton GJ, Fowden AL. The placenta: A multifaceted

The causes and consequences of acute atherosis of the placenta are not well known. They could be the reflection of an increased inflammatory state, found in all the above-mentioned diseases, and a disturbed lipid metabolism.4 These acute atheromatous changes induce a narrowing of the arterial lumen, and facilitate vascular occlusion, thrombi, thus reducing the blood flow and contributing to placental dysfunction and to delayed growth of the fetus.4,14 The incomplete remodeling of the maternal spiral arteries are not however limited to acute atherosis. Arteries have too much of vasoreactivity, due to the retention of smooth musculature, leading to lesion of the hypoxia-reoxygenation type and could be responsible for oxidative stress.14 A high speed maternal blood flow disturbs the network of fetal villosities and thus contributes to throm-botic events and accumulation of fibrin.14

The preliminary results of a Netherlands cohort study concerning the correlation between placental vascular abnormalities and post-partum maternal cardiovascular risk markers were published this year.15 Considering the glycemic and lipid profiles which were carried out on the first day after-delivery in patients with preeclampsia or IUGR, and comparing them with normal pregnancies, the authors suggest an associ-ation between higher levels of triglycerides and LDL cholesterol and the presence of acute placental lesions of atherosis. The future work announced by this team will consolidate this first observation.

PreventIon and PersPectIvesAt the present moment, the prevention of obstetrical complications linked to chronic arterial hypertension rests on the admin-istration of prophylactic doses of aspirin from the first trimester. Nevertheless, in the absence of strong evidence, the American College of Obstetricians and Gynecologists remains cautious and suggests that aspirin be reserved for hypertensive patients with high risk of obstetrical complications (women with a history of early preeclampsia, prematurity


transient organ. Philo Trans R Soc London B Biol Sci 2015; 370:20140066.

8. www.Embryology.ch.9. Seifer DB, Samuels P, Kniss DA. The physiologic

basis of gynecology and obstetrics. Philadelphia: LippincottWilliams&Wilkinsedition,2001.

10. Ghidini A, Locatelli A. Monitoring of fetal well-being: Role of uterine artery doppler. Sein Perinatol 2008; 32:258-62.

11. Faye Peterson OM, Heller DS, Joshi W. Handbook of placental pathology, second edition. CRC Press, Taylor&FrancisGroup,2006.

12. Maloney KF, Heller D, Baergen RN. Types of maternal hypertensive disease and their association with pathologic lesions and clinical factors. Fetal Pediatr Pathol 2012; 31:319-23.

13. Sheppard BL, Bonnar J. An ultrastructural study of utero-placental spiral arteries in hypertensive and normotensive pregnancy and fetal growth retardation. Br J Obstet Gynaecol 1981; 88:695-705.

14. Gabbe SG, Niebyl JR, Simpson JL et al. Normal and problem pregnancies, sixth edition. Elsevier Saunders, 2012.

15. Veerbecek JH, Brouwers L, Koster MP et al. Spiral artery remodeling and maternal cardiovascular risk: The spiral artery remodeling (spar) study. J Hypertens 2016; 34:1570-7.

16. American College of Obstetricians and Gynecologists, Task Force on Hypertension in P. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol 2013; 122:1122-31.


1Post Graduate Trainee, 2Associate Professor, DepartmentofMedicine,SilcharMedicalCollege&Hospital, Silchar, Assam

Role of Serum Uric Acid as a Prognostic Marker in Acute Coronary Syndrome: A Hospital Based Study

Chandra Prakash Thakur1, Kallol Bhattacharjee2, Dwijen Das2

Original Article

abstractBackground: Coronary artery disease remains the dominating cause of death in the world. Despite understanding & controlling the known risk factors for coronary artery disease, itremains the worldwide epidemic. This raises the possibility of the presence of unknown or underestimated risk factors. The role of uric acid as a prognostic factor in patients with acute coronary syndrome is controversial. The aim of the present study is to estimate serum uric acid levels in acute coronary syndrome and its correlation with Killip’s classification of heart failure&inhospitalmortality.Methods: A total of 100 patients with acute coronary syndrome meeting the inclusion and exclusion criteria, with an equal number of age and sex matched controls were selected for study during the period 1st July 2016 - 30th June 2017. Serum uric acid level was estimated on day 0 and 7 of acute coronary syndrome.Results and observations: A statistically significant higher level of serum uric acid concen-tration in patients of acute coronary syndrome (5.80±1.53) was observed on the day of admission as compared to controls (3.8±0.85). There was no statistically significant difference observed in relation with diabetes and hypertensive status and gender. Higher serum uric acid (>7mg/dl) level along with higher Killip’s class (III, IV) was associated with higher mortality and major adverse cardiac events.Conclusion: Patients with elevated serum uric acid levels belonged to higher Killip’s classi-fication and were associated with higher in hospital mortality. Hence serum uric acid can be used as a short term prognostic marker in patients with acute coronary syndrome.

IntroductIonCardiovascular disease is responsible for

30% of all deaths in the world. Although the mortality for this condition has gradually declined over the last decades in western countries, it still causes about one-third of all deaths in people older than 35 years. About 80% of the global burden of cardiovascular


disease occurs in low and middle income countries. In India cardiovascular diseases (CVD) have become the leading cause of mortality.1 CVD affects Indians at least a decade earlier and in their most productive midlife years when compared to the people of European ancestry. India carries a significant portion of this global burden. In addition, case fatality attributable to CVD in low-income countries, including India, and appears to be much higher than in middle and high income countries.2 Reasons for the high propensity to develop CVD, the high case fatality, and the high premature mortality include biological mechanisms, social determinants, and their interactions.3

Until now various bio-markers have been studied in patients of acute coronary syndrome (ACS). However, no single marker gives definite prognostic information during the course of the disease. While there is no doubt that multiple factors play different roles in the development of acute coronary syndrome, recent studies have revealed the potential role of hyperuricemia as a novel prognostic marker. Uric acid is the final product of purine metabolism in humans, and its level is determined by dietary intake, rate of cell turn-over in the body, and renal excretion. Adenosine synthesized locally by vascular smooth muscle in cardiac tissue is rapidly degraded by the endothelium to uric acid, which undergoes rapid efflux to the vascular lumen due to low intracellular pH and negative membrane potential.4 Under ischemic conditions the activity of xanthine oxidase and uric acid synthesis are increased in vivo, and therefore we can consider elevated serum uric acid as a marker of underlying tissue ischaemia.5 Epidemiological studies have recently shown that uric acid may be a risk factor for cardiovascular diseases and a negative prognostic marker for mortality in subjects with heart failure and coronary artery disease.The aim of the present study was to note levels of serum uric acid in acute coronary syndrome, to correlate serum uric acid levels with Killip

class and to observe any relationship between serum uric acid level and mortality following acute coronary syndrome.

MaterIals and MeHodsThe present study was a single centered observational prospective study conducted from July 2016 to June 2017 for a period of one year in the Department of General Medicine atSilcharMedicalCollege&Hospital,Silchar.A total of 100 patients with acute coronary syndrome meeting the inclusion and exclusion criteria, with an equal number of age and sex matched controls were selected for the study. All patients who were of age greater than 18 years and diagnosed as ACS with at least 2 of the following criteria: a) Presence of typical symptoms like chest pain, palpitation etc on admission b) ECG changes consistent with acute MI in at least 2 contiguous leads c) Elevation of the cardiac enzymes (Troponin T&I,CK-MB)wereconsideredforstudy.Allthe patients diagnosed with ACS presented within 12 hours. All acute STEMI patients who presented within 12 hours of onset, and were eligible for fibrinolytic therapy received fibrinolytic therapy using intravenous strep-tokinase with the dose of 1.5 million units, and given over 30 to 60 minutes. Patients diagnosed with gout and with other recog-nized risk factors known to increase serum uric acid levels like renal failure, multiple myeloma, leukemia, lymphoma, hemolytic anemia, psoriasis, hypoparathyroidism, chronic alcoholism and patients taking drugs that are known to raise serum uric acid levels like diuretics, chemotherapeutic agents, nicotinic acid, ACE inhibitors like Losartan, salicylates, ethambutol and pyrizinamide were excluded from the study.A detailed history and physical examination with special reference to Killip class was carried out. All patients underwent routine investigations including complete hemogram, renal function tests, liver function tests, ECG, chest x-ray and echocardiography. Patients were followed up till hospital stay i.e. 7 days. Serum uric acid level was measured on day 1 &7ofACS.


A detailed statistical analysis was carried out. Basal serum uric acid levels were compared with controls with unpaired ‘t’ test. The levels of serum uric acid on day 1 and 7 were compared by paired ‘t’ test. Uric acid levels and Killip class was compared with coeffi-cient of correlation. The study was approved by the Ethics committee of the hospital.

results and observatIonsIn the present study, 100 patients with ACS with an equal number of age and sex matched healthy controls were studied. The age of the cases varied from 36 to 85 years, the mean age being 58.13±10.08 years. Maximum number of cases (36%) was in the age group of 50-59 years. Majority of the cases were male (68%) and the male: female ratio was 2.12: 1. In the present study, the highest numbers of patients were non smoker (67%), and only 33% of patients were smoker. Out of 100 cases, only 7 had family history of IHD as against 2 in the control group. Obesity was found in only 24% of the patients and 36% were overweight. Echocardiogram showed mild LV dysfunction in 32 patients, moderate LV dysfunction in 38 patients, severe in 18 patients and normal LV function in 12 patients. Only 43% of the patients were hypertensive. Type 2 Diabetes mellitus was found in 47% of the patients.

In the present study, majority of the cases were having STEMI (80%), followed by NSTEMI (15%) and Unstable Angina (5%). In the present study the most common presenting symptom was chest pain (92%) followed by increased sweating (52%), nausea and vomiting (28%). Four patients presented with altered mental status. Mean serum uric acid levels on day 1 was 5.80±1.53 and on day 7 was 4.93±1.26.There is a significant reduction of uric acid levels on Day 7 on comparing with day 0 (P = 0.034). The mean serum uric acid level of controls on day 1 was 3.8±0.85. The baseline characteristics of both the groups are shown in Table 1.There was no statistically significant difference in serum uric acid levels when compared with established risk factors like sex, hypertension, diabetes mellitus and smoking in patients with ACS (Table 2).Serum uric acid level on the day of admission was positively correlated with Troponin T

Table 1: Comparison of cases and controlsVariables Cases Controls P valueAge (years) 58.13±10.08 58.16±10.18Sex (M:F) 68:32 68:32Smokers (%) 33 14 0.02BMI≥25(%) 60 54 0.83Serum uric acid on day 1

5.80±1.53 3.8±0.85 0.001

Table 2: Comparison of serum uric acid levels in cases with established risk factorsParameters P ValueHypertension Yes (43) No (57) 0.183

(NS)Serum Uric Acid 6.03 5.62Diabetes Melllitus Yes (47) No (54) 0.191

(NS)Serum Uric Acid 5.07 5.35Smoking Habit Yes (33) No (67) 0.35

(NS)Serum Uric Acid 5.31 5.25Sex Male (68) Female (32) 0.375

(NS)Serum Uric Acid 5.28 5.25

Fig. 1: Scatter plot depicting relation between uric acid and troponin t (cTnI)

Fig. 2: Scatter plot depicting relation between uric acid and CK-MB level

0

2

4

6

8

10

12

0 0.5 1 1.5

URIC

ACI

D

cTnI LEVEL

URI ACID

Linear (URI ACID)

0

2

4

6

8

10

12

0 20 40 60 80 100UR

IC A

CID

CK-MB

URIC ACID

Linear (URIC ACID)


levels (Pearson correlation 0.807, P value <0.00001) and CK-MB levels (Pearson corre-lation 0.768, P value <0.00001) (Figures 1, 2).Negative correlation was found between the serum uric acid level on the day of admission and ejection fraction obtained (Pearson corre-lation -0.827, P value <0.00001) (Figure 3).On day of admission out of 100 patients, 18 patients had serum uric acid >7 mg/dl, in which 14 patients were in Killip class IV and 2 each in class II and III (P value <0.0001) (Table 3). Out of the 22 patients who died, 17 had serum uric acid level > 7.0 mg/dl and 5 patients had serum uric acid < 7 mg/dl. Of these 22

patients, 12 died on the day of admission and 10 patients died over next 7 days. Out of 22 patients who died 14 patients were in Killip class IV (Table 4, 5, 6).

dIscussIonElevated SUA levels have been associated with an increased risk for Cardio-vascular disease. The potential mechanisms by which SUA may directly cause cardiovascular risk include enhanced platelet aggregation and inflammatory activation of the endothelium.6 Previous studies have shown that serum uric acid increases in cardiac failure.5 In a study done in Japan in 2005 by Kojima et al7 it was shown that serum uric acid levels correlate with Killip classification. Combination of Killip class and serum uric acid level after AMI is a good predictor of mortality in patients who have AMI.Present study was conducted in 100 patients of ACS, who presented to hospital with in 12 hrs of onset of symptoms. All the patients with acute STEMI were thrombolysed in our study. One hundred age and sex matched healthy controls were also evaluated for comparison of uric acid levels. Out of 100 patients, 80 had STEMI, while 15 patients were of NSTEMI and 5 patients had unstable angina (UA). In the present study, mean age of cases was 58.13±10.08 years and of controls were 58.16±10.18 years. According to study by MY Nadkar et al8 the mean age of patients was

Fig. 3: Scatter plot depicting relation between uric acid and ejection fraction (%)

0

2

4

6

8

10

12

0 20 40 60 80

URIC

ACI

D

EJECTION FRACTION (%)

URIC ACID

Linear (URIC ACID)

Table 3: Correlation of serum uric acid level with killip classification on day 1Killip Classification

Serum Uric Acid <7 mg/

dl

Serum Uric Acid >7 mg/

dl

Total P Value

I 47 0 47

0.0001II 15 02 17III 17 02 19IV 03 14 17Total 82 18 100

Table 4: Correlation of serum uric acid level with killip classification on day 7Killip Classification

Serum Uric Acid <7 mg/

dl

Serum Uric Acid>7 mg/

dl

Total P Value

I 44 00 44

0.05II 16 00 16III 09 03 12IV 02 04 06Total 71 07 78

Table 5: Correlation between serum uric acid level and mortalityMortality Uric Acid

< 7 mg/dlUric Acid > 7 mg/dl

Total P Value

DAY 1 2 10 12 0.05DAY 7 3 7 10TOTAL 5 17 22Table 6: Correlation between Killips class and mortalityVariable Killip

Class IKillip Class

II

Killip Class

III

Killip Class

IV

Total P Value

Day 1 1 0 3 8 12 0.05Day 7 0 1 3 6 10Total 1 1 6 14 22


58.29±11.31 years and the mean age in control group was 56.84±8.98 years. Similar findings were also observed in the study conducted by LS Patil et al9 and Gandiah P et al10.There was a statistically significant higher level of serum uric acid concentration in patients with ACS on day of admission as compared to controls (P=<0.00001). This finding of the present study correlated with studies done by Gandiah P et al,10 MY Nadkar et al,8 Shirish Agrawal et al.11

In the present study there was no significant difference in uric acid levels between male and female patients (P=0.375). Similar finding was observed by, Gandiah P et al10 and M Y Nadkar et al.8 However in the study by Kojima S et al7 males had higher uric acid level as compared to females.There was no significant difference in uric acid levels between hypertensive and non hypertensive patients (P=0.183). This finding of the present study correlated well with the studies by LS Patil et al,9 MY Nadkar et al,8 Qureshi et al.12 In contrast to finding of present series Harris P et al13 and Kojima S et al7 noted that serum uric acid level was significantly correlated with hypertension. In another study by Chen L et al14 serum uric acid was significantly associated with hyper-tension in patients aged <40 years.There was no significant difference in uric acid levels between diabetic and non diabetic patients (P= 0.1910). This finding was in concordance with the study by LS Patil et al,9 M Y Nadkar et al8 and Toumilheto et al15 in which there was no significant association between serum uric acid and diabetic status. However this finding is in contrast to other study by Safi et al16and Harris P et al13 where hyperuricemia was significantly associated with type 2 diabetes mellitus. There was no significant difference in uric acid levels between smokers and non smokers which was similar to the study by Qureshi et al.12

Serum uric acid level on the day of admission was correlated with Troponin T value a strong positive correlation was obtained (Pearson

correlation 0.807, P value <0.00001), that is, as the value of one increases the other also increases. Hasic et al17 in their study found the similar positive correlation. In the study of Lippi et al18 significantly higher SUA levels in patients with Troponin T values above decisional threshold was revealed.Serum uric acid level on the day of admission was correlated with CK-MB value a strong positive correlation was obtained (Pearson correlation 0.768, P value <0.00001). Similarly Amrut A Dambal et al19 and Harris P et al13

also found statistically significant positive correlation between CK-MB and uric acid on day of admission.In the present study when serum uric acid level on the day of admission was correlated with ejection fraction (%) a strong negative correlation was obtained (Pearson correlation -0.827, P value <0.00001). Chen L et al14 showed a significantly lower LVEF in patients with high serum uric acid. Yoshiro et al20 and PinelliM et al21 clarified in his study that high UA levels reduced LVEF independently of the severity of Ischemic heart disease (IHD). In contrast Nozari Y et al22 there was no correlation between uric acid and LVEF (Correlation coefficient= -0.111, P=0.129).In the present study, out of 100 patients, 18 patients had serum uric acid >7 mg/dl, in which 14 patients were in Killip class IV and 2 each in class II and III (P value <0.0001, highly significant). Thus patients of Killip class IV had higher levels of uric acid as compared to other Killip classes. In a study done in Japan in 2005 by Kojima S et al7 it was shown that serum uric acid levels correlate with Killip classification. MY Nadkar et al8 also found that there was a positive correlation between serum uric acid level and Killip class on day of admission. Similar findings were also observed by LS Patil et al9 and Gandiah P et al10

In the present study, there was significant relation between uric acid level and in-hospital mortality. High serum uric acid levels on admission were strongly associated with increased mortality. In the present study


out of 100 cases, 22 patients (22%) died. More than half of the patients (12) died on the day of admission and 10 patients died over next 7 days. Out of the 22 patients who died, 17 had serum uric acid level more than 7.0 mg/dl and 5 patients had serum uric acid less than 7.0 mg/dl. Bickel C et al23 reported that one mg/dl increase in serum uric acid levels was associated with a 26% increase in mortality. Siniša Carl et al24 and MY Nadkar et al8 concluded in their study that serum uric acid level after acute myocardial infarction is a good predictor of mortality. Out of 12 patients died on the day of admission (day 1), 8 patients were in Killip class IV, 3 patients in Killip class III and 1 patient in Killip class I. Over next 7 days another 10 patients died, out of which 6 were in Killip class IV, 3 in Killip class III and 1 in Killip class II. In the study by MY Nadkar et al8 83% of patients who died were in higher class i.e. class III and IV at time of admission. Similar observations were found in the study by by L S Patil et al9 and Gandiah P et al.10

conclusIonIt is concluded from the present study that serum uric acid levels were higher in patients of ACS as compared to healthy controls. Patients with elevated serum uric acid levels belonged to higher Killip’s classification and had higher mortality. It can be inferred from this study that serum uric acid can be regarded as an inexpensive independent risk factor and prognostic marker of short term mortality in patients with ACS.Although, conduction of this study in a sole institution with paucity of time and resource highlighted the role of serum uric acid in influencing the course of ACS, a more elaborate multi centric study would have been desirable to precisely establish the role of serum uric acid in ACS. It is hoped that the present study will encourage new studies related to the above subject with a broader spectrum and for longer durations.

references1. Srinath Reddy K, Shah B, Varghese C, Ramadoss A.

Responding to the threat of chronic diseases in India. Lancet 2005; 366:1744–1749.

2. Xavier D, Pais P, Devereaux PJ, Xie C, Prabhakaran D, Yusuf S et al; CREATE registry investigators. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Lancet 2008; 371:1435–1442.

3. Lopez A, Mathis D, Ezzati M, Jamesan D, Mcurray C. Global and regional burden of disease and risk factors. The Lancet 2006; 367:1747-57.

4. Kroll K, Bukowski TR, Schwartz LM, KnoepflerD,Bassingthwaighte JB. Capillary endothelial transport of uric acid in guinea pig heart. Am J Physiol 1992; 2H420-31

5. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and haemodynamic staging. Circulation 2003; 1991-97.

6. “Systemic Hypertension: Mechanism and Diagnosis.” Elsevier Saunders 37:962.

7. Kojima S, Sakamoto T, Ishihara M, et al. Prognostic usefulness of serum uric acid after acute myocardial infarction (Japanese Acute Coronary Syndrome Study). Am J Cardiol 2005; 96:489-95.

8. Nadkar MY, Jain VI. Serum Uric Acid in Acute Myocardial Infarction. Journal Assoc Physicians India 2008; 56:759-762.

9. Patil LS, et al. Study of serum uric acid levels in acute ST elevation myocardial infarction patients and its correlationwithKillip’sclassificationofheartfailure.International Journal of Biomedical and Advance Research 2015; 6:673-677.

10. Gandiah P, Venkateshwarlu N, et al. Serum Uric acid Estimation in Acute Myocardial Infarction - A Prognostic Indicator. International Journal of Recent Trends in Science and Technology 2013; 9:199-204.

11. Agrawal S, Aundhkar SC, Patange A, et. al. Evaluate the role of serum uric acid in acute myocardial infarction as a prognostic marker. Int J Health Sci Res 2014; 4:120-128.

12. Qureshi AE, Hameed S, Noeman A. Relationship of serum uric acid level and angiographic severity of coronary artery disease in male patients with acute coronary syndrome. Pak J Med Sci 2013; 29:1137-1141.

13. Harris P, Feroz P Jenner, Sunil Kumar. Serum uric acid as a marker of left ventricular failure in acute myocardial infarction. IOSR Journal of Dental and Medical Sciences (IOSR-JDMS) 2015; 14:102-109.

14. Chen L, Li XL, Qiao W, Ying Z, Qin YL, Wang Y, et al.


Serum uric acid in patients with acute ST-elevation myocardial infarction. World J Emerg Med 2012; 3:359.

15. Tuomilheto J, Zimmet P, Evawolf. Plasma Uric acid level and its association with Diabetes Mellitus and some Biologic Parameters in a Biracial Population of FIJI. Am J Epidemiol 1988; 127:3213.

16. Safi AJ, Mahmood R, Khan MA and Haq A.Association or serum uric acid with type-II diabetes mellitus. J Postgrad Med Inst 2004; 18:59-63.

17. Sabaheta Hasic et al. Serum Uric Acid Could Differentiate Acute Myocardial Infarction andUnstable Angina Pectoris in Hyperuricemic Acute Coronary Syndrome Patients. Med Arch 2017; 71: 115-118.

18. Lippi G, Montagnana M, Franchini M, Guidi GC, Targher G. Uric acid concentration in patient with acute coronary syndrome. Intern Emerg Med 2008; 3:409-11.

19. Amrut AD, Ambal, et al. Serum uric acid in myocardial infarction- A comparative study. International Journal of Clinical Biochemistry and Research 2016; 3:227-230

20. Yoshiro Tanaka, et al. Close linkage between serum uric acid and cardiac dysfunction in patients with ischemic heart disease according to covariance structure analysis. Sci Rep 2017; 7:2519.

21. Pinelli M, et al. Serum uric acid levels correlate with left ventricular ejection fraction and systolic pulmonary artery pressure in patients with heart failure. Recenti Prog Med 2007; 98:619-23.

22. Nozari Y, et al. Correlation between the serum levels of uric acid and HS-CRP with the occurrence of early systolic failure of left ventricle following acute myocardial infarction. Acta Med Iran 2011; 49:531-5.

23. Bickel C, Rupprecht HJ, Blankenberg S, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002; 89:12-7.

24. Sinisa Car, Vladimir Trkulja. Higher Serum Uric Acid on Admission is Associated with Higher Short-term Mortality and Poorer Long-term Survival after Myocardial Infarction: Retrospective Prognostic Study. Croat Med J 2009; 50:559-66.


1Junior Resident-3, 2Professor, 3Associate Professor, 4JuniorResident-2,Dr.D.Y.PatilMedicalCollege&Hospital,Pune,Maharashtra

To Study the Clinical Profile and Electrocardiographic Criteria in Patients with Left Ventricular Hypertrophy and Coorelate them with Echocardiographic Findings

Suraj A Kodak1 , Vikram Vikhe2 , Prakash Shende3, Koushik Chavalla4

Original Article

abstractLeft ventricular hypertrophy is an important complication of long standing hypertension and valvular heart diseases and is proven to be associated with target organ damage. Left ventricular hypertrophy refers to be an increase in the size of the myocardial fibres in the main cardiac pumping chamber. Such hypertrophy is usually the response to the chronic volume or pressure overload. Hypertension is the leading causes of left ventricular hypertrophy followed by aortic stenosis, aortic regurgitation and mitral regurgitation. The present study is done to compare various electrocardiographic criteria’s for left ventricular hypertrophy using echocardiography as gold standard.Materials and Methods: The present study included 110 patients with history and clinical profile suggestive of cardiac morbidities such as hypertension, aortic stenosis, aortic regurgi-tation, and mitral regurgitation having the evidence of left ventricular hypertrophy in echocar-diography and as well as fulfilling the criteria’s of electrocardiography. Electrocardiographic criteria’s used for diagnosis of left ventricular hypertrophy were Sokolov-Lyon index, Romhilt-Estes scoring system, Total QRS voltage criteria. Diagnostic validity tests such as specificity, sensitivity and Kappa’s measure of agreement were performed.Results: Using Sokolov-Lyon index criteria could diagnose left ventricular hypertrophy in 29 (38%) of patients with 82% specificity. Using Romhilt-Estes scoring system electrocardiog-raphy could diagnose left ventricular hypertrophy in 43 (56%) of patients with 79% specificity. Using Total QRS voltage criteria electrocardiograph could diagnose left ventricular hyper-trophy in 46 (60%) patients with 91% specificity. The present study found sensitivity 38% for


IntroductIonLeft ventricular hypertrophy is the condition that severely affects the morbidity and mortality from cardiovascular diseases including myocardial infarction, congestive cardiac failure, and stroke. In developing countries like India the prevalence of left ventricular hypertrophy is increasing.1 Left ventricular hypertrophy is no longer to be considered as an adaptive process that compensates the pressure imposed on the heart, but has been considered as an independent and significant risk factor for sudden death, acute myocardial infarction, and congestive cardiac failure.2

The increase in the left ventricular mass represents the final pathway towards the adverse effects on the cardiovascular system leading to the serious complications.3 The electrocardiographic assessment of cardiac dimensions has lost its prominence in the favour of imaging techniques that provide a multi-dimensional display of the heart but secondary ST-T changes due to left ventricular hypertrophy which are uniquely determined from the electrocardiography and are known to increase the risk of cardiovas-cular morbidity and mortality.4

Today two dimensional echocardiogram still demands considerably more time, lack of technical skill of the operator and complexity of processing than routine 12-lead electrocar-diograph. Electrocardiographic criteria used in left ventricular hypertrophy are

1. Sokolow-Lyon index:5 In 1949, Sokolow and Lyon pointed out that the presence of ventricular hypertrophy in adult is suggested when the sum of S wave in VI and R wave in V5 or V6 totals more than 35 mm.

2. Romhilt and Estes scoring system for left ventricular hypertrophy:6 Romhilt and Estes in 1968 developed a point scoring system. A score of five or more points on ECG is diagnostic of left ventricular hypertrophy. A score of 4 points indicates that there is probably left ventricular hypertrophy.

3. Total QRS voltage criteria:7 The total QRS voltage is obtained by adding the QRS amplitude in each lead in a 12-lead electro-cardiogram. The amplitude of the QRS complex is measured from the peak of the R wave to the dip of the S wave according to the method of Siegel and Roberts. The total QRS voltage of 174 mm is taken as normal. Any value 175 mm or more will be taken as significant indicating left ventricular hypertrophy. Considering the magnitude of left ventricular hypertrophy study designed to co-relate between three different electrocardiographic criteria’s of left ventricular hypertrophy using echocardiography as gold standard.

MaterIals and MetHodsThe present study included 110 patients with history and clinical profile suggestive of cardiac morbidities such as hypertension, aortic stenosis, aortic regurgitation, and

Sokolov-Lyon index, 56% sensitivity for Romhilt-Estes point score system and 60% sensitivity and 91% specificity for Total QRS voltage criteria.Conclusion: The sensitivity for Total QRS criteria was 60% to 38% for Sokolov-Lyon criteria. The different electrocardiographic criteria used for the diagnosis of left ventricular hyper-trophy, Total QRS voltage criteria showed better sensitivity compared to other criterias. So for the diagnosis of left ventricular hypertrophy, the role of electrocardiographic criteria is of limited value and thus echocardiography is the choice for the diagnosis of left ventricular hypertrophy.Key words: Electrocardiography, Echocardiography, Sokolov-Lyon index, Romhilt-Estes score system, Total QRS voltage criteria


mitral regurgitation having the evidence of left ventricular hypertrophy in echocardiog-raphy and as well as fulfilling the criteria’s of electrocardiography. This study was cross sectional analytical study. Institute Ethics Committee approvals will be obtained before start of the study. The electrocardiographic variables recorded were Voltage of R, S or Q waves in all the leads, ST-T changes, Axis, Duration of QRS complexes in limb leads, Intrinsicoid deflexion in V5, V6, ‘P’ terminale in VI (Tables 1, 2).The study group: comprised of patients who have echocardiographic evidence of left ventricular hypertrophy.The control group: comprised of patients who

had no echocardiographic evidence of left ventricular hypertrophy.Electrocardiographic criteria’s used in this study are:I. Sokolov - Lyon Index5: S in VI, + R in V 5

or V 6 > 35 mmII. Romhilt - Estes point score system6 (Table

1)III. Total QRS voltage criteria7: The total QRS

voltage was obtained by adding the QRS amplitude in each lead in a 12-lead electro-cardiogram. The amplitude of the QRS complex was measured from the peak of the R wave to the dip of the S and Q-wave, whichever was greater, according to the method of Siegel and Roberts. A total QRS voltage of 174 mm was taken as normal. Any value 175 mm or above was taken as significant indicating left ventricular hypertrophy. These three criteria are most widely used and hence present study was done on these three criteria.

After obtaining results of electrocardiogram and echocardiography diagnostic validity tests (specificity and sensitivity) and Kappa measure of agreement were performed (Table 3).

resultsIn this study 110 patients were enrolled. Out of 110 patients 67 were male and 43 were female. Among the study subjects 64 were hypertensive, 13 patients were having mitral regurgitation (MR), 8 were suffering from aortic regurgitation (AR), 10 had aortic stenosis (AS) and 15 were having combined lesions (MR, AR, AS and AR).

Table 1: Electrocardiographic Variables1 R or S in limb leads

S in V1, V2, or V3R in V4, V5, or V6

20 mm or more25 mm or more 3 points25 mm or more

2 ST-T changes(without digitalis)(with digitalis)

3 points(1 points)

3 ‘P’ terminal force in V1 or more than 0.04 sec.

3 points

4 Left axis deviation of -15° or more

2 points

5 QRS interval 0.09 sec. or more

1 point

6 IntrinsicoiddeflectioninV5, V60.04 sec. or more

1 point

Total 13 Points4 points: Probable left ventricular hypertrophy; 5 points ormore:Definiteleftventricularhypertrophy.

Table 2: Reference Limits and Partition Values of Left Ventricular Mass (gm)8

Women MenLinear methodReference Range 67-162 88-224Mild 163-186 225-258Moderate 187-210 259-292Severe >211 >2932D methodReference Range 66-150 96-200Mild 151-171 201-227Moderate 172-182 228-254Severe >183 >255

Table 3: Interpretation of ResultsEchocardiogram

+ -

Electrocardiogram

+ A (true +ve)

B (false +ve) A + B

-

C (false –ve)

D (true –ve) C +D

A + C B + D


The patients were divided into two groups, the study group and the control group. Clinical profile of the patients with left ventricular hypertrophy included the shifting of apical impulse in 50 patients, chest pain (unstable angina) in 6 patients, palpitations in 37 patients, shortness of breath (exertional dyspnoea) in 7 patients, and headache was only seen in 10 patients who were having hypertension (Table 4). The study group patients had echocar-diographic evidence of left ventricular hypertrophy i.e., the average of septal and posterior wall thickness > 1.2 cm. This study group comprised of 76 patients out of which 48 were males and 28 females. The control group patients had no echocardiographic evidence of left ventricular hypertrophy i.e., the average of sums of septal and posterior wall thickness was < 1.1 cm. The control group consisted of 34 patients out of whom 19 were males and 15 females. Using Sokolov-Lyon index criteria could diagnose left ventricular hypertrophy in 29 (38%) of patients with 82% specificity. Using Romhilt-Estes scoring system electro-cardiography could diagnose left ventricular hypertrophy in 43 (56%) of patients with 79% specificity. Using Total QRS voltage criteria electrocardiograph could diagnose left ventricular hypertrophy in 46 (60%) patients with 91% specificity.

The present study found sensitivity 38% for Sokolov-Lyon index, 56% sensitivity for Romhilt-Estes point score system and 60% sensitivity and 91% specificity for Total QRS voltage criteria (Table 5).

sokolov - lyon IndexThe sensitivity shown by Sokolov-Lyon index is 38%, with specificity of 83% .The diagnostic accuracy being 51%. But the Kappa’s measure of agreement is 0.14 which suggests that there is poor measure of agreement between electrocardiography and echocardiography in diagnosing left ventricular hypertrophy.

roMHIlt - estes PoInt score systeMThe study shows a better sensitivity compared to Sokolov-Lyon index (Table 6). The study showed 49% sensitivity when 5 points were used and 56% sensitivity when 4 points were used, whereas the diagnostic accuracy being 63% by using 4 point score and 59% by using 5 point score Kappa measure of agreement is 0.29 suggesting a poor measure of agreement between echocardiogram and electrocar-diogram in diagnosing left ventricular hyper-trophy.

total Qrs voltage crIterIa This study showed the highest sensitivity of 60% as compared to the other electrocardio-

Table 4: Signs and Symptoms Wise Breakup of Patients in the Study and Control GroupDisease Shifted apical impulse Chest pain Palpitations Exertional dyspnoea HeadacheHypertension 31 1 22 0 10Aortic stenosis 3 1 4 2 0Aortic regurgitation 3 1 3 1 0Mitral regurgitation 5 1 6 1 0Combined valvular heart diseases 8 2 2 3 0Total 50 6 37 7 10

Table 5: Single table analysis of Sokolov-Lyon Index

Echo TotalPositive Negative

ECGPositive 29 6 35Negative 48 27 75Total 77 33 110

Table 6: Single table analysis of Romhilt-Estes Scoring

Echo

TotalPositive Negative



Table 7: Single Table Analysis of Total QRS voltage

EchoTotalPositive Negative


Table 8 : Sensitivity, Specificity, Accuracy, Positive Predictive value, Negative Predictive Value and Kappa Measure of agreement of Different Electrocardiographic Criteria for Left Ventricular Hypertrophy

Sr. No. ECG criteria Sensitivity % Specificity % Accuracy % PPV % NPV % Kappa measure of agreement

1 S.L. Criteria 38 82 51 83 36 0.14

2 R.E point score 4 point 56 79 63 86 43 0.295 point 49 82 59 86 41 0.24

3 Total QRS 60 92 69 94 49 0.47

graphic criteria used which was used for this study. The Kappa measure of agreement is 0.4 which suggests that there is a fair measure of agreement between electrocardiogram and echo diagnosing left ventricular hypertrophy.

dIscussIonThe present study was conducted with an aim to study the clinical profile and electro-cardiography criteria in patients with for the patients with left ventricular hypertrophy and then co-relating them with two dimen-sional echocardiography. As two dimensional echocardiography being the gold standard to diagnose left ventricular hypertrophy we compared three important electrocardio-graphic criteria for diagnosing left ventricular hypertrophy.The electrocardiographic (ECG) diagnostics of left ventricular hypertrophy (LVH) currently is based primarily on the QRS voltage criteria. However, increased QRS voltage in the setting of actual anatomical left ventricular hyper-trophy (LVH) is not a consistent finding, as reflected in a wide range of both sensitivities and specificities of ECG criteria for LVH.9,10 Nevertheless, ECG criteria for LVH have been shown to be a strong independent predictor of cardiovascular morbidity and mortality in patients with essential hypertension and in the general population.11,12

Sokolov - Lyon criteria5 is the oldest, simplest and quickest method for the diagnosis of left ventricular hypertrophy which was described in 1949 by Sokolow M and Lyon TP.14 The Kappa measure of agreement was found to be 0.14 by Sokolow Lyon criteria, suggesting that there was a poor measure of agreement between electrocardiography and echocardiography in diagnosing left ventricular hypertrophy. The present study found sensitivity 38% and specificity 82% of Sokolov-Lyon index. Reichek et al13 reported sensitivity 21% and specificity 95%. Murphy et al14 reported sensitivity 60% and specificity 80%. Jaggy et al15 reported sensitivity 61% and specificity 68%. Martin et al16 reported sensitivity 31% and specificity 75%. Romhilt and Estes point score system6 involves complicated data acquisition for scoring. In the present study Kappa measure of agreement is 0.24 suggesting a poor measure of agreement between echocardiogram and electrocardiogram in diagnosing left ventricular hypertrophy. However, a better sensitivity compared to Sokolov-Lyon index was found. The present study found sensi-tivity 49% and specificity 82% by Romhilt and Estes point score system. Reichek et al13 reported sensitivity 50% and specificity 95%. Kansal et al17 reported sensitivity 57% and specificity 81%. Murphy et al14 reported sensi-tivity 60% and specificity 90%. Hameed et.al18 reported sensitivity 35% and specificity 90%.Total QRS voltage criteria7 with the normal upper limit for total QRS amplitude of 175 mm was first determined by Roberts and Day19 and later validated by Odom et al.20,21 Odom et al20 found that the upper limit of 175 mm yielded specificity of 100% for diagnosing LVH in


subjects with heart weight less than 400 g.21 Compared to Sokolov-Lyon and Romhilt-Estes criteria the total QRS criteria showed better sensitivity, specificity, accuracy and a fair Kappa measure of agreement. The Kappa measure of agreement was found to be 0.40 which suggests that there is a fair measure of agreement between electrocardiogram and echo diagnosing left ventricular hypertrophy (Tables 7, 8, 9, 10). The present study found sensitivity 60% and specificity 91% by total QRS voltage criteria. Odom et al20 reported sensitivity 70% and specificity 90%. Jaggy et al15 reported sensitivity 42% and specificity 78%. Martin et al16 reported sensitivity 30% and specificity 86%.

conclusIon Hypertension is one of the leading causes of left ventricular hypertrophy. The other causes of left ventricular hypertrophy are aortic stenosis, aortic regurgitation, and mitral regurgitation. In this study, 60% were patients of hypertension, 12% patients were of aortic stenosis and combined valvular diseases (MR, AR,AS&AR).The sensitivity was in the range of 60% for total QRS voltage criteria to 38% for Sokolov Lyon criteria. Among the different criteria used Total QRS criteria showed better sensi-tivity compared to others. In the evaluation of patients for left ventricular hypertrophy, the role of electrocardiography with all the commonly used criteria is of limited value and

echocardiography is the method of choice. Electrocardiogram showed a better sensitivity in detecting left ventricular hypertrophy only when it is severe.

references1. Friedman AJ, et al. Accuracy of M-mode

echocardiographic measurements of left ventricle. Am J Cardiol 1982; 99:716-720.

2. Devereux RB. Does increased blood pressure cause left ventricular hypertrophy or vice versa? Ann Intern Med 2000; 112:57-8.

3. Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart Journal 2001; 141:334-341.

4. Martinova E, et al. Automated Computer Analysis in Diagnosis of left ventricular hypertrophy by electrocardiography. Journal of Electrocardiology 2007; 40:S41–S42.

5. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949; 37:161.

6. Romhilt D, Estes EH Jr. A Point score system for the ECG diagnosis of Left ventricular hypertrophy. Am Heart J 1968; 75:752.

7. Miruis DM, Goldberger AL. Electrocardiography. Chapter-5 in Heart disease - text book of cardiovascular medicine, 6th Edn., Edt. Braunwald, Zipes,Libby,W.B.Saunders&Company,2001;pageno.82-106.

8. Lang RM, Bierig M, Devereux RB, et al, Chamber Quantification Writing Group; American Societyof Echocardiography’s Guidelines and Standards Committee.J Am Soc Echocardiogr 2005; 18:1440.

9. Hancock EW, Deal BJ, Mirvis DM, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part V:

Table 9: Table Showing Sensitivity of Various ECG Criteria according to Disease

S.L. Index R.E. Point System

Total QRS Voltage Criteria

Hypertension 40% 53% 55%Mitral Regurgittion 29% 29% 43%

Aortic Regurgitation 40% 80% 80%

Aortic Stenosis 33% 56% 68%

Combined Valvular Heart Diseases

33% 79% 79%

Table 10 : Table Showing Diagnostic Accuracy of Various ECG Criteria According to Disease

S.L. Index R.E. Point System

Total QRS Voltage Criteria

Hypertension 53% 63% 66%Mitral Regurgittion 54% 54% 69%

Aortic Regurgitation 50% 75% 88%

Aortic Stenosis 30% 50% 60%Combined Valvular Heart Diseases

53% 73% 80%


electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement fromthe American Heart Association Electrocardiography and Arrhythmias Committee, Council on ClinicalCardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am CollCardiol 2009; 53:992-1002.

10. Rautaharju PM, LaCroix AZ, Savage DD, et al. Electrocardiographic estimate of left ventricular mass versus radiographic cardiac size and the risk of cardiovascular disease mortality in the epidemiologicalfollow-upstudyofthefirstNationalHealth and Nutrition Examination Survey. Am J Cardiol 1988; 62:59-66.

11. Kannel WB, Gordon T, Castelli WP, Margolis JR. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease: the Framingham Study. Ann Intern Med 1970; 72:813- 22.

12. Lorenz JN, Kranias EG. Regulatory effects ofphospholamban on cardiac function in intact mice. Am J Physiol 1997; 273:H2826–H2831.

13. Reichek N, Devereux RB. Left ventricular hypertrophy: relationship of anatomic, echocardiographic and electrocardiographic findings. Circulation 1981; 63:1391-8.

14. Murphy ML, Thenabadu PN, de Soyza N, Meade J, Doherty JE, Baker BJ. Sensitivity of electrocardiographic criteria for left ventricular hypertrophy according to type of cardiac disease. Am J Cardiol 1985; 55:545-9.

15. Jaggy C, Perret F, Bovet P, van Melle G, Zerkiebel N, Madeleine G, et al. Performance of classic

electrocardiographic criteria for left ventricular hypertrophy in an African population. Hypertension 2000; 36:54-61.

16. Martin TC, Bhaskar YG, Umesh KV. Sensitivity and specificityoftheelectrocardiograminpredictingthepresence of increased left ventricular mass index on the echocardiogram in Afro-Caribbean hypertensive patients. West Indian Med J 2007; 56:134-8.

17. Kansal S, Roitman DI, Sheffield LT.A quantitativerelationship of electrocardiographic criteria of left ventricular hypertrophy with echocardiographic left ventricular mass: a multivariate approach. Clin Cardiol 1983; 6:456-63.

18. Hameed W, Razi MS, Khan MA, Hussain MM, Aziz S, Aslam SHM. Electrocardigraphic Diagnosis of Left Ventricular Hypertrophy: Comparison with Echocardiography. Pak J Physiol 2005; 1:1-2.

19. Roberts WC, Day PJ. Electrocardiographic observations in clinically isolated, pure, chronic, severe aortic regurgitation: Analysis of 30 necropsy patients aged 19 - 65 years. The American Journal of Cardiology 1985; 55:432-438.

20. Odom H, Davis JL, Dinh H, Baker BJ, Roberts WC, Murphy ML. QRS voltage measurements in autopsied men free of cardiopulmonary disease: a basis for evaluating total QRS voltage as an index of left ventricular hypertrophy. Am J Cardiol 1986; 58:801-4.

21. Kumar D, Bajaj R, Chhabra L, Spodick DH. Refinement of total 12-lead QRS voltage criteriafor diagnosing left ventricular hypertrophy. World Journal of Cardiovascular Diseases 2013; 3:210-214.


1Sr. Consultant Diabeto-Cardiologist, 2Jr. Resident, Tanjena Heart-Diabetes Centre, New Colony, Gurgaon 122001, Haryana

Resistant Hypertension: Management Guidelines

Ashok K Taneja1, Akshat Taneja2

REVIEW ARTICLE

IntroductIonResistant hypertension defined as blood pressure that remains above the target level in spite of concurrent use of three antihy-pertensive agents of different classes. Out of three classes one class must be a diuretic. Identifying resistant hypertension is of paramount importance as there is tremendous increaseinmorbidity&mortality.Moreover,it identifies patients having reversible causes of hypertension and/or patients may benefit from special diagnostic and therapeutic procedures. Patients whose blood pressure is controlled with four or more medications should be considered to have resistant hyper-tension.1 Points to remember is :a. One of the three agents should be a

diuretic.b. All agents should be prescribed at optimal

doses (ie, 50 percent or more of the maximum recommended antihypertensive dose)

c. Although patients with resistant hyper-tension may have elevations in both systolic and diastolic pressures, isolated systolic hypertension is common.

d. Resistant hypertension is not synonymous with uncontrolled hypertension, since

resistant hypertension is not the only cause of uncontrolled hypertension.

e. Other causes include inadequate treatment regimens and pseudo resistance or inappropriate BP measurements.2

terminologiesa. Apparent Resistant hypertension b. Pseudoresistant hypertension c. True resistant hypertensiona. Apparent resistant hypertension: Patients

have uncontrolled clinic blood pressure (ie, greater than or equal to 140/90 mmHg) despite being prescribed three or more antihypertensive medications, or require prescriptions of four or more drugs to control their blood pressure. There is apparent lack of control on > or =3 medica-tions.

b. Pseudoresistant Hypertension: Pseudo resistance refers to poorly controlled hypertension that appears resistant to treatment but is actually attributable to other factors. The five most common causes of pseudo resistance are:

1. Inaccurate measurement of blood pressure

2. Poor adherence to antihypertensive therapy


3. Suboptimal antihypertensive therapy

4. Poor adherence to lifestyle and dietary approaches

5. White coat hypertension: Also called isolated clinic or office hypertension. It refers to patients who have office readings that average more than 140/90 mmHg and reliable out of office readings that average less than 140/90 mmHg. The office BP is usually taken by a nurse or technician rather by a physician. Clue to the diagnosis is patients with white coat hypertension have less severe target organ damage and appear to be at less cardiovas-cular risk, compared to those patients with persistent hypertension during ambulatory monitoring.

c. True resistant hypertension Patients with true resistant hypertension

are those who have uncontrolled clinic blood pressure despite being compliant with an antihypertensive regimen that includes three or more drugs (including a diuretic, and each at optimal doses) and who also have uncontrolled blood pressure confirmed by 24-hour ambulatory blood pressure monitoring. It represents higher riskofmorbidity&mortality.3

Prevalence The true prevalence of resistant hypertension is not known. A major problem is that not all patients with uncontrolled hypertension have resistant hypertension as defined above; many are uncontrolled because of poor adherence or inadequate treatment regimens. Pooled analysis shows prevalence rates of 10.1% and 7.9% for uncontrolled resistant hypertension among individuals treated for hypertension and all hypertensive individuals, respec-tively. Whereas, data from North America and Europe with a combined sample size of >600,000 hypertensive participants, the prevalence of resistant hypertension is 14.8% of treated patients and 12.5% of all hyperten-sives. Framingham Heart Study reported only

48% of treated participants were controlled to <140/90 mm Hg and less than 40% of elderly participants (>75 years of age). Among higher- risk populations and in patients with diabetes mellitus or chronic kidney disease (CKD), with application of the lower goal blood pressures as recommended in JNC 7 for, the proportion of uncontrolled patients is even higher. Of NHANES participants with chronic kidney disease, only 37% were controlled to <130/80 mm Hg3 and only 25% of participants with diabetes were controlled to <130/85 mm Hg.4

etIologyA. Primary causes B. Secondary causes C. Factors contributing to resistant hyper-

tensionA. Primary causes:- • Olderage;especially>75years

• High baseline blood pressure andchronicity of uncontrolled hyper-tension

• Target organ damage (left ventricularhypertrophy, chronic kidney disease)

• Diabetes

• Obesity

• Atheroscleroticvasculardisease

• Aorticstiffening

• Sex(women)

• Ethnicity(black)

• Excessivedietarysaltintake.

B. Secondary causes: • Primaryhyperaldosteronism

• Renalarterystenosis

• Renalparenchymaldisease

• Obstructivesleepapnoea

• Phaeochromocytoma


• Thyroiddiseases

• Cushing’ssyndrome

• Coarctationoftheaorta

• Intracranialtumours

C. Factors contributing to resistant hyper-tension:

i. Lifestyle factors:-

• Obesity

• Excessalcoholintake

• Excessdietarysodium

• Cocaineandamphetaminesmisuse

ii. Drug related causes:

• Non-steroidal anti-inflammatorydrugs

• Contraceptive hormones—Combinedoral contraceptives are more often associated with elevated blood pressure, whereas menopausal hormone therapy has minimal effects.

• Adrenalsteroidhormones

• Sympathomimeticagents(nasaldecon-gestants, diet pills)

• Erythropoeitin,cyclosporin,andtacro-limus use

• Liquorice (suppresses themetabolismof cortisol)

• Herbal supplements (ephedra, bitterorange, etc)

iii. Volume overload:

• Progressiverenalinsufficiency

• Highsaltintake

• Inadequatediuretictherapy.

Treatment of resistant Hypertension is a diagnosis of exclusion requiring a systematic approachtoEvaluation&management.6,8

evaluatIon A. Medical history: The medical history should

document age of onset, duration, severity, and progression of the hypertension. Particular emphasis should be given to concurrent medication use (including herbal and over-the-counter medica-tions).mention must be made regarding the response to prior medications used.Patient adherence to the treatment must be established. The patient should also be questioned about possible manifestations of secondary causes of hypertension, such as Renal artery stenosis, Co-arctation of aorta, Pheochromocytoma and Cushing’s syndrome.

B. Physical examination — The physicalexamination should include careful measurement of the blood pressure, detailed cardio-vascular exam including peripheral pulses and murmurs in carotids/subclavian/femoral or abdominal aorta. Detailed fundoscopic examination looking for retinopathy must be done. Diminished femoral pulses and/or a discrepancy between arm and thigh blood pressures which may suggest aortic coarctation or significant aortoiliac disease should be carefully noted.6

C. Investigations • Ureaandelectrolytes.KFT

• Estimate glomerular filtration rate,24-hr creatinine clearance.

• Plasmaglucose

• Plasmareninoraldosteronelevels

• 24 hour urinary metanephrines ornormetanephrines (for phaeochromo-cytoma) and sodium excretion to check salt sentivity.

• Urine analysis—microalbuminuriaand macroalbuminuria, haematuria, VMA (R/O Pheochromocytoma).

• Electrocardiography: Look for LVH


and pre-existing ischemic heart disease or arrhythmias.

• Screening for primary aldosteronismbegins with a paired, morning measurement of the plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to PAC/PRA ratio.

• Non-invasiveimaging—Mostpatientswith resistant hypertension should undergo noninvasive imaging for renal artery stenosis, atherosclerotic disease in other vascular beds, coronary artery disease, cerebrovascular disease. Get a whole abdomen USG done to rule out structural renal disease, Aortic aneurysm etc.

• E choca rd iog raphy :T rans tho ra c i c(TTE) & Transesophageal (TEE).Look for LV mass (LVH);systolic &diastolic functions, any structural disorder of heart including aorta.Particular attention should be paid to co aarctation of aorta. Look carefully peripheral arteries to rule out any stenosis.

• CTScan/MRI:wheresecondarycausesare suspected.

• Renal imaging: including CT renalangiogram to rule out renal artery stenosis or mass or structural renal/adrenal disease.

• ConfirmAccuracyofBPmeasurementby 24 hr ABPM (ambulatory BP measurement) to check for Pseudo Resistance and White Coat effect.

• RenalBiopsy:Arenalbiopsyisrequiredfor undiagnosed glomerulonephritis.6

ManageMent1. Confirm accuracy of BP measurement2 Non-Pharmacological3. Pharmacological4. Device Therapy

1. Confirm Accuracy of Measurment: Utilize correct BP measurement technique and rule out white coat hypertension.Tips for obtaining accurate BP in your clinic/office:-

• Allow the patient to sit quietly orrelaxed for at least 5 min.

• Removeclothingthatconstrictsupperarm.

• Averageof3orminimum2readings1minute apart. If different in both arms, take the higher value.

• Cuffsh’beofappropriatesize.covering80% of arm circumferance.

• Nicotine intake, smoking, caffeineintake sh’be avoided before taking BP.

• Automated Bp apparatus may haveadvantage,but calibration necessary.

• HomeBPmeasurement is agood toolbut take average of 4-5 reading to minimze error.

• To confirmwhite coat effect comparehome/office BP readings and do ambulatory BP Measurements (ABPM).5

2. Non-pharmacologic intervention : A vast epidemiological data suggests an apparent relationship between resistant hypertension and lifestyle choices and habits. For example, observational studies have shown that people with raised blood pressure tend also to have low dietary calcium, higher sodium intake, salt resistant, dyslipidemic, dysglycemic and obesity. The role of diet, exercise, alcohol, caffeine, potassium and magnesium supplements, sodium (table) salt and use of rock salt have been widely studied and all have shown beneficial effects. The music therapy, yoga,meditation& relax-ation therapies have shown good benefits in lowering calcitrant BP. However, there are certain life style barriers to control BP which are:-


A. Interrfering substances

B. Dietary salt Intake

C. Alcohol consumption

D. Obesity

A. Interfering substances: Certain drugs may elevate BP or may inhibit the effects of antihypertensives, e.g.

• NSAIDS&Cox2inhibitors.

• Sympathomimeticdrugs likeephedra,phenyleepherins, amphetamines etc.

• Herbalsupplements

• Anabolicsteroids

• Appetitesuppresants

• Erythropoitin

• OralContraceptives.

If possible, discontinue the offending drug or modify it.

B. Dietary Salt Intake: First ascertain whether patient is salt senisitive or salt resistant. Excessive dietary Salt ingestion is a risk factor for devel-oping resistant BP. Calculate urinary sodium excretion, if it is >150 mmol/day, patient need to reduce salt intake to urinary excretion6 of<100mmol/day. Practically it amounts to 2.4mg per day i.e.half tea spoon fill in 24 hrs.No table salt or snacks to be used. Elderly/blacks/Indians & patients with CKDare very salt sensitive. Instead of using table salt,add lemon or soup toppings to salads or cut fruits.8

C. Alcohol intake: More than 3-4 drinks (120ml) per day also contributes to resistance. Moderate alcohol consumption i.e. Men=60-70ml/day; Women=30-40ml/day (of 42% proof i.e. whisky, rum, vodka) or less should be ensured. For 12 % proofs like wine or beer-more than 1 pint should not be allowed.7

D. Obesity is associated with more severe hypertension & resistance.Thetarget should be reduction of weight by increasing physical exercise and adopting high fibre- protein diet e.g DASH, Mediterranean etc.

3. Pharmacotherapy The choice of agents should be individu-

alized and may depend upon consideration of prior benefit, history of adverse events, financial limitations and the presence of concomitant diseases such as chronic kidney disease or diabetes.However as per JNC7&subsequentlyby8 thebroadguidelines are:-

A. The triple combination of an ACE inhibitor or ARB, a long-acting dihydropyridine calcium channel blocker (usually amlodipine), and a long-acting thiazide diuretic (preferably chlorthalidone) is often effective and generally well tolerated. (A+C+D).

B. If the patient is still hypertensive, additional medications are added sequentially. Other possible agents that may be used include:

i. Beta blockers preferably with vaso-dilator properties (labetalol, carvedilol, ornebivolol)orcombinedbeta&alphablockers (Prazocin)

ii. Centrally acting agents (clonidine or guanfacine).

iii. Direct vasodilators (hydralazine or minoxidil).

If beta blockers are used, a vasodilating beta blocker, such as labetalol, carvedilol or nebivolol, may provide more antihy-pertensive benefit with fewer side effects compared to traditional beta blockers, particularly when high doses are used.6,8

iv. Direct Renin Inhibitors: Aliskiren, the only available direct renin inhibitor, is at least as effective as ARBs in reducing end target organ damage but has not


been directly tested in resistant hyper-tension.

v. Endothelin receptor antagonists are a new family of antihypertensive medications that are currently being evaluated.

a. Darusentan has demonstrated significant dose-dependent reductions in both systolic and diastolic blood pressures and has been positively evaluated in resistant hypertension.

b. Atrasentan is another highly selective endothelin receptor antagonist that has shown positive results in blood pressure reduction for 72 patients

vi. Omapatrilat- is medication that combines inhibitors of vasoconstrictive mediators with drugs that potentiate vasodilating mediators by inhibiting their breakdown by neutral endopep-tidases (NEPs) {OCTAVE trial}.9

4. Device therapy : In the pathophysiology of hypertension the role of activity of sympa-

thetic nervous system (SNS) is amply established. In resistant Hypertension, there is increased SNS activity with inhibition of Parasympathetic nervous system(PSNS)causingtachycardia&vaso-constriction. On the other hand,subdued SNS activity with increased parasym-pathetic activity results in bradycardia & vaso-dilatation. Thus, understandingof this pathophysiology has allowed the exploration of (physical) sympathectomy to treat human hypertension in the middle of last century. Nonselective crude surgical lumbar sympathectomy gave significant relief from severe hyper-tension but unfortunately increased the incidence of bothersome side-effects such as symptomatic postural hypertension. Hence, the procedure did not find a place in the therapy of hypertension and was abandoned. In the last decade, techno-logical and safety advances have led to the refined techniques to selectively ablate renal sympathetic activity, so-called renal denervation (RDN) therapy Similarly, baroreceptor activation therapy (BAT) has

Fig. 1 : Radiofrequency ablation of the renal sympathetic nerves

Fig. 3 : Electrical stimulus on median nerve

Fig. 2 : Activation of baroreceptors reflex Fig. 4 : Median nerve modulation


also been developed simultaneously as a method of sympathetic deactivation to treat hypertension.9 Following techniques have recently been evaluated:

A. Percutaneous transluminal radiofre-quency sympathetic denervation of the renal arteries (RDN).

B. Carotid Baroreflex Activation Therapy (BAT).

C. Median Nerve Modulation.

D. Central Arterio-venous Coupler Therapy (CAVCT)

A. RDN: In the last decade this procedure has gained recognition.Many devices have been developed to cause selective RDN. A catheter is inserted in the renal arteries which delivers thermal injury to disrupt the local afferent and efferent nerve fibers. Radiofrequency ablation is the preferred mode of energy. symplicity HTN-3 trial11 showed promising results. Radiofrequency ablation of the renal sympathetic nerves should be reserved for patients who meet all of the following criteria.10,11 Figure 1.

• Resistanthypertension

• Pseudoresistanthypertensionhasbeenexcluded (eg, white coat effect, non- adherence to Optimal dose & type oftreatment etc).

• Identifiable secondary causes ofresistant hypertension, such as primary aldosteronism, have been excluded.

• Renalfunctionispreserved(estimatedglomerular filtration rate greater than or equal to 45 mL/min/1.73 m).

• The renal artery anatomy is eligible(i.e, there are no accessory renal arteries and no renal artery stenosis or renal artery revascularization)

B. Carotid Baroreceptor Stimulation Therapy (BTA): Activation of barore-

ceptors results in decrease in the SNS activity via central mechanism (Figure 2). Affarent reflexes originating from the carotid body inhibit the cardiovas-cular efferents from the brain resulting a sympathetic deactivation which leads to vaso-dilatation (reduced systemic vascular resistance) and bradycardia. Long-term observations with baroreflex activation therapy (BAT) are not yet available but the short term results are encouraging.10,11 A device (Rheos BAT system),similar to pacemaker,is implanted which electri-cally stimulates carotid baroreceptors. The results evaluated at 3 months BAT device showed an office BP reduction of 21/12 mm Hg and ABP was reduced by 6/4 mm Hg. At 2 years followup,the office BP was reduced by 33/22 mm Hg and ABP was reduced by 24/13 mm Hg.12

C. Median Nerve Modulation (MNM): Median nerve modulation is done by a small coin which gently stimulates the median nerve. The Ecoin is implanted under the forearm skin to activate the median nerve. The low powered electrical stimulus, communicates with the multiple pathways in the brain which control the blood pressure (Figure 3). The procedure takes only 20 minutes to perform in the office setting. Ecoin showed a significant improvement in the office and ABP levels.15 SBP fell 10.31 ± 20.93 mm Hg and ABP fell by 4.68 ± 11.05 mm Hg (Figure 4) at 6 months. No significant procedure related adverse effects were noted.13

D. Central Arterio-venous Coupler Therapy (CAVCT): In resistant hyper-tension increased peripheral vascular resistance (due to arterial wall thickening) is the hall mark. A new technique—the Rox coupler creates asmall A-V fistula (AVF) between the iliac artery and vein with a controlled shunt flow creating a low resistance


vascular bed and the system vascular resistance table. A large study of 80 persons (40 patients & 40 controls)showed that at 6 months the AVF group showed a significant reduction in office BP and ABP levels. Figure 4 The novel technique was shown to be effective but a third of AVF patients developed ipsilateral venous stenosis which resolved after stenting or venoplasty. This unique promising procedure awaits further testing and additional research.14

references1. Sheppard JP, Martin U, McManus RJ. Diagnosis and

management of resistant hypertension. BMJ Heart 2015; 103:16.

2. Calhoun D, Jones D, Textor S, Goff D, Murphy T,Toto R, White A, Cushman W, White W, Sica D, Ferninand K, Giles T, Falkner B, Carey R. Resistant Hypertension. Diagnosis, Evaluation, and Treatment: A Scientific Statement from the American HeartAssociation. Hypertension 2008; 51:1403-1419.

3. Apparentandtrueresistanthypertension:definition,prevalence and outcomes. J Hum Hypertens 2014; 28:463-8. Epub 2014

4. The ALLHAT Officers and Coordinators for theALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to PreventHeartAttack Trial (ALLHAT). JAMA 2002; 288:2981–2997.

5. Hermida RC, Ayala DE, Calvo C, López JE, Mojón A,FontaoMJ,SolerR,FernándezJR.Effectsoftime

of day of treatment on ambulatory blood pressure pattern of patients with resistant hypertension.Hypertension 2005; 46:1053–1059.

6. Laragh J. Laragh’s lessons in pathophysiology and clinical pearls for treating hypertension. Am J Hypertens 2001; 14:491–503.

7. Wildman RP, Gu D, Muntner P, Huang G, Chen J, Duan X, He J. Alcohol intake and hypertension subtypes in Chinese men. J Hypertens 2005; 23:737–743.

8. Bansal N, Tendler BE, White WB, Mansoor GA. Blood pressure control in the hypertension clinic. Am J Hypertens 2003; 16:878–880.

9. Ram CVS, Wali M. Therapies for Resistant Hyertension: A Status Update; CSI update, chapter 9;2017

10. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension:a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373:1275-81.

11. Symplicity HTN-2 Investigators: Renal sympathetic denervation in patients with treatment-Resistant hypertension (The SYMPLICITY HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376:1903-9.

12. Doumas M, Faselis C, Kokkinos P, et al. Carotid baroreceptor stimulation: a promising approach for the management of resistant hypertension and heart failure. Curr Vasc Pharmacol 2014; 12:30-7.

13. Webster M, Valle M, Blake J, et al. Median nerve modulation: a novel approach to resistant hypertension. J Am Coll Cardiol Intv 2016; 9(4_S):S54.

14.Korsheed S, EldehniMT, John SG, et al. Effects ofarteriovenous fistula formation on arterial stiffnessand cardiovascular performance and function. Nephrol Dial Transplant 2011; 26:3296-302.


1Full Time Consultant Cardiologist, 2Hon. Cardiologist, Jaslok Hospital and Research Centre, Mumbai, Maharashtra

Hyponatremia Associated with Diuretics

Rahul Chhabria1, Kaustubh A Vaidya2

Review Article

IntroductIonThiazide type diuretics are the first line drug for the treatment of hypertension. However, its use is limited by potential complica-tions of hyponatremia especially in elderly population. Hyponatremia is an occasional but severe cases can lead to severe symptoms and rarely death. Practically all the cases of severe diuretic induced hyponatremia are due to a thiazide-type diuretic.1-7 A loop diuretic is much less likely to induce this problem unless the diuretic has induced volume depletion8 or water intake is very high (since loop diuretics partially impair urinary diluting capacity).

IncIdence The exact incidence is uncertain.19-21 One of the 10 years of retrospective cohort study on 2613 patients showed a incidence of hyponatremia (defined as serum sodium of 130 meg/l or less) was 30% in patients who received thiazide uretic (66 of 220 patients). In comparison to these incidence was 18% (422 of 2393 patients) in patients who received alternate therapy. The highest incidence occurred in the first three months after the initiation of thiazide diuretic but the risk continued to remain for 10 years of follow up period. The median time to diagnosis of hyponatremia was 1.7 years,

hence it is important to regularly monitor these patients. The incidence also increases with increasing age. This study showed a slightly higher incidence (37 vs 24%) in patients greater than 60 years. However, this difference was not statistically significant. This association has also been shown in various other studies. Each 10-year increment of age was associated with a twofold increase in risk, and every 5 kg increment in body mass decreased the odds ratio by 27 percent.1-5,12,22,23

PatHogenesIs Lower incidence of hyponatremia with loop diuretics is probably because of the different mechanism of action as compared to the thiazide type diuretics. Loop diuretics act by interfering with accumu-lation of Nacl in the medulla. Although the loop diuretic can increase ADH levels by inducing volume depletion, responsiveness to ADH is reduced because of the impairment in the medullary gradient.9 As a result, water retention and the development of hypona-tremia will be limited, unless distal delivery is very low or water intake is very high.The thiazides, in comparison, act in the cortex in the distal tubule; as a result, they do not interfere with medullary function or with ADH-induced water retention. In addition, in vitro data indicate that thiazides increase


Hyponatremia Associated with Diuretics

Rahul Chhabria1, Kaustubh A Vaidya2

water permeability and water reabsorption in the inner medullary collecting duct, an effect that is independent of ADH.10 In addition to water retention, the combination of increased sodium and potassium excretion (due to the diuretic) and enhanced water reabsorption (due to ADH) can result in the excretion of urine with a sodium plus potassium concen-tration higher than that of the plasma.3 Loss of this fluid can directly promote the devel-opment of hyponatremia independent of the degree of water intake. To summarize, various mechanisms which can lead to diuretic induced hyponatremia are:1. Volume depletion can stimulate the

release of ADH, leading to the production of a concentrated urine.1,3,8

2. Enhanced ADH release may be a secondary event induced by nausea and other neuro-logic symptoms.

3. Thiazide diuretics may be associated with water retention that is independent of ADH.10

4. Patients treated with diuretics may have a reduced glomerular filtration rate, which is a common contributor to hyponatremia in older adults

5. Decreased dietary protein intake, due to dietary preferences or acute illness, may limit electrolyte-free water excretion and predispose to hyponatremia in patients treated to thiazides.

In most patients, the combination of sodium plus potassium loss and water retention accounts for essentially all of the fall in the plasma sodium concentration.2,4 However, there are patients in whom this does not appear to be the case, raising the possibility that the hyponatremia is due in part to osmotic inactivation of sodium in the cells or perhaps bone.16 How or if this actually occurs is not clear. A similar hypothesis was proposed in the syndrome of inappropriate ADH and then seemingly excluded by careful balance studies.17,18

clInIcal ManIfestatIons The clinical manifestations of diuretic-induced hyponatremia are similar to those of other causes of hyponatremia. The hypona-tremia typically begins soon after the onset of thiazide therapy and corrects over a period of days to two weeks after the cessation of therapy.2,3 Most patients do not exhibit signs of volume depletion.2,6

Diuretic-induced hyponatremia is rarely, if ever, associated with cerebral edema severe enough to cause herniation of the brain. This was illustrated in a series of 223 patients hospitalized for symptomatic hyponatremia due to thiazide diuretics; the mean plasma sodium was 115 meq/L.6 The major symptoms were malaise, lethargy, dizzy spells, and vomiting, all of which are well described manifestations of severe hyponatremia. There was only a 1 percent incidence of seizures and no cases of herniation.6

The older literature includes reports of brain damage in outpatients with thiazide-induced hyponatremia.3,7 However, at the time of these studies, the consequences of overly rapid correction were unknown. The reported patients were all treated with hypertonic saline, increasing the plasma sodium concen-tration by more than 25 meq/L in 48 hours, a rate of correction now known to be associated with osmotic demyelination in the brain.

treatMent Treatment of diuretic-induced hyponatremia consists of discontinuing the diuretic and administering either isotonic saline or, if the hyponatremia is severe or symptomatic, hypertonic saline. There is a potential risk of overly rapid correction of the hyponatremia with either regimen. Once the diuretic has been cleared and the patient becomes euvolemic, antidiuretic hormone (ADH) release will be appropriately suppressed, resulting in the excretion of a dilute urine, which can lead to rapid excretion of the excess water. Thus, patients with moderate to severe hypona-tremia must be monitored carefully during


treatment to minimize the risk of osmotic demyelination.1

PreventIon There is no proven way to identify patients at risk of developing hyponatremia after diuretic therapy, making prevention difficult. A regular cose follow up of the patient for serum sodium levels should be done especially in elderly individuals and patients with less body weight. Also, patient and family should be thought about the signs and symptoms of the disease for an eaely diagnosis and prompt treatment. A thiazide diuretic should generally not be used in patients who have had a previous episode of hyponatremia.

references 1. Sonnenblick M, Friedlander Y, Rosin AJ. Diuretic-

induced severe hyponatremia. Review and analysis of 129 reported patients. Chest 1993; 103:601.

2. Friedman E, Shadel M, Halkin H, Farfel Z. Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis. Ann Intern Med 1989; 110:24.

3. Ashraf N, Locksley R, ArieffAI. Thiazide-inducedhyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70:1163.

4. Fichman MP, Vorherr H, Kleeman CR, Telfer N. Diuretic-induced hyponatremia. Ann Intern Med 1971; 75:853.

5. Chow KM, Szeto CC, Wong TY, et al. Risk factors for thiazide-induced hyponatraemia. QJM 2003; 96:911.

6. Chow KM, Kwan BC, Szeto CC. Clinical studies of thiazide-induced hyponatremia. J Natl Med Assoc 2004; 96:1305.

7. Mozes B, Pines A, Werner D, et al. Thiazide-induced hyponatremia: an unusual neurologic course. South Med J 1986; 79:629.

8. Sonnenblick M, Rosin AJ. Significance of themeasurement of uric acid fractional clearance in diuretic induced hyponatraemia. Postgrad Med J 1986; 62:449.

9. Szatalowicz VL, Miller PD, Lacher JW, et al. Comparative effect of diuretics on renal waterexcretion in hyponatraemic oedematous disorders. Clin Sci (Lond) 1982; 62:235.

10. César KR, Magaldi AJ. Thiazide induces water absorption in the inner medullary collecting duct of normal and Brattleboro rats.Am J Physiol 1999; 277:F756.

11. Maronde RF, Milgrom M, Vlachakis ND, Chan L. Response of thiazide-induced hypokalemia to amiloride. JAMA 1983; 249:237.

12. Sharabi Y, Illan R, Kamari Y, et al. Diuretic induced hyponatraemia in elderly hypertensive women. J Hum Hypertens 2002; 16:631.

13. Frenkel NJ, Vogt L, De Rooij SE, et al. Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2. J Hypertens 2015; 33:627.

14. Clark BA, Shannon RP, Rosa RM, Epstein FH. Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol 1994; 5:1106.

15. DecauxG,SchlesserM,CoffernilsM,etal.Uricacid,anion gap and urea concentration in the diagnostic approach to hyponatremia. Clin Nephrol 1994; 42:102.

16. Johnson JE, Wright LF. Thiazide-induced hyponatremia. South Med J 1983; 76:1363.

17. Cooke CR, Turin MD, Walker WG. The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation. Medicine (Baltimore) 1979; 58:240.

18. Verbalis JG. Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis. Am J Physiol 1994; 267:R1617.

19. Leung AA, Wright A, Pazo V, et al. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med 2011; 124:1064.

20. Clayton JA, Rodgers S, Blakey J, et al. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Pharmacol 2006; 61:87.

21. Rodenburg EM, Hoorn EJ, Ruiter R, et al. Thiazide-associated hyponatremia: a population-based study. Am J Kidney Dis 2013; 62:67.

22. Gross P, Palm C. Thiazides: do they kill? Nephrol Dial Transplant 2005; 20:2299.

23. Huang CC, Chung CM, Hung SI, et al. Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia. Medicine (Baltimore) 2015; 94:e1422.


1Head,Deptt.ofNeurosciences,2Senior Consultant Cardiologist,Head,Deptt.ofCardiology,3Senior ConsultantPhysician&Internist,JaswantRaiSpecialityHospital,Meerut,UttarPradesh

Non-Pharmacological Management of Hypertension - Beyond Controversy

Bhupendra Chaudhary1, Rajeev Aggarwala2, Puneet Bhasin3

Review Article

abstractTraditional approaches to control the epidemic of blood pressure-related atherosclerotic cardiovascular disease (ASCVD) have largely focused on drug therapy in persons with hyper-tension. Still, non-pharmacologic therapy, also termed lifestyle modification, has an important and expanding role that complements drug therapy. Specifically, non-pharmacologic therapies can serve as initial therapy in Stage 1 hypertensive patients, facilitate medication step down or withdrawal in patients with well-controlled hypertension, prevent hypertension in high-risk populations, and reduce blood pressure in normotensive individuals and thereby lower their risk of ASCVD.It particularly refers to life-style modifications i.e. therapeutic lifestyle changes (TLC) which include reducing dietary sodium, exercise for at least 30 min per day, five days per week; to have Dietary Approach to stop Hypertension (DASH) diet protocol and to achieve a weight loss goal of 4.5 kg or more by non-pharmacological measures such as increased physical activity, reduced salt intake, reduced fat intake, alcohol abstinence, smoking cessation, behavioural changes, yoga, meditation etc.In fact, when we talk about controlling of hypertension, lifestyle modifications is always the first step of foremost importance.

government officials, and the general public is to develop and implement effective clinical and public health strategies that lead to desirable lifestyle modifications.High blood pressure is an independent risk factor for cardiac as well as cerebro-vascular diseases. At the cut off of 140/90 mmHg, 28 to 44% of the world population has hypertension, with ethnic variations. The lifetime risk of developing hypertension is estimated to be

IntroductIonNon-pharmacologic approaches have enormous potential as a means to reduce blood pressure and control hypertension, thereby preventing the occurrence of ASCVD. The current challenge to health care providers,


90%. Indeed, blood pressure is a continued process and any increase above optimal levels, confer additional independent risk of coronary heart disease, stroke, congestive heart failure, end-stage renal disease, peripheral vascular disease and others.All over the globe, hypertension is poorly controlled. About one third of patients have achieved the National High Blood Pressure Education Programme goal of 140/90 mmHg or lower. The mainstay of hypertension is pharmacotherapy. However, the non-pharma-cological aspects are important, but often overlooked. Although, some lifestyle modifi-cations may seem to have only minimal blood pressure lowering effect, these should not be discounted, but rather should be given top priority.A reduction of systolic blood pressure of 5 mmHg has been associated with 14% reduction in mortality caused by stroke, 9% in mortality caused by heart disease and 7% in all cause mortality. In addition, a weight loss 4.5 kg, a realistic goal for most individuals who are overweight, can reduce or prevent hypertension. Multiple mechanisms appear to contribute to BP reduction by dietary inter-vention (reduced weight and sodium, alcohol abstinence and increased calcium, potassium and magnesium). For exercise, these include improvements in arterial endothelial function and compliance, left ventricular structure as well as function and perhaps vascular blood supply with increased cardiorespiratory endurance. The available evidence is exces-sively in support of TLC (therapeutic lifestyle changes) for management of elevated BP and for the primary prevention of hypertension.While antihypertensive agents have been used, it is imperative that reduction of blood pressure to optimal levels and prevention of age-related increase in BP be pursued actively. There has been increasing emphasis on the prevention and treatment of hypertension by non-pharmacological means, termed lifestyle modifications. Lifestyle modifications that effectively lower BP are reduced sodium intake, increased physical activity, weight

loss, smoking cessation, alcohol abstinence in alcoholics and the Dietary Approaches to Stop Hypertension (DASH) diet eating plan.

strongly recoMMended lIfestyle ModIfIcatIons

sodium reductionThere is a strong & consistent evidencethat reducing sodium intake reduces blood pressure. Dietary salt (sodium chloride) intake has a linear association with blood pressure. Reduced sodium intake to approxi-mately 2 gm/day can prevent hypertension, can facilitate blood pressure control in elderly patients on medication and can potentially prevent cardiovascular events in overweight individuals.In a Trial of Non-pharmacologic intervention in the Elderly (TONE) study, patients were randomized to a low sodium diet (5 gm of sodium chloride or 2 gm of sodium), a usual care (i.e. no study related counselling in lifestyle change). The intervention group had a 2.8 mmHg more reduction in systolic blood pressure than the control group. A study done later on, assessed the impact on blood pressure of three levels of daily sodium intake i.e. 3.6, 2.0 and 1.2 gm per day, representing a typical American diet. Results demonstrated a graded blood pressure response, with a corre-lation between greater reduction in blood pressure with lower sodium consumption. The message is as follows :• Reduce salt intake to (5 gm of sodium

chloride or 2.0 gm of sodium/day).• Reduce amount of salt in food prepara-

tions.• Avoidfoodshavinghighsaltcontent.

Some foods with a high sodium content• Potatochips,saltedcrackers/biscuits• Fastfoods,tomatojuice(canned)• Commerciallypreparedsoupsandstews• Pastriesorcakes,processedcheeseIt should be noted that in the elderly (and


in Black patients), sodium restriction may be more effective than in Whites and young people.A lower sodium level of 1,500 mg a day or less is appropriate for people 51 years of age or older and individuals of any age, who have high blood pressure, diabetes or chronic kidney disease. Tips for decreasing sodium in diet :• Trace how much salt is to be in daily diet

: To keep a food diary to estimate how much sodium is in food and drinks on daily basis.

• To read food labels : To choose low-sodium alternatives of the foods and beverages purchased daily.

• To eat fewer processed foods : To avoid potato chips, frozen dinners and processed lunch.

• To avoid extra salt : To add spices, rather than salt, to add more flavour to your foods.

• To go slow : If it is not possible to reduce the sodium drastically, it may be done gradually.

exercIse/Increased PHysIcal actIvItyAerobic exercise has positive effects on blood pressure, whether or not a person has hyper-tension. It reduces, on an average, systolic blood pressure by 4.0 mmHg and diastolic blood pressure by 3.0 mmHg. Additional benefits of aerobic exercise are increased insulin sensitivity and increasing high density lipoprotein cholesterol (HDLC) level.Since low-calorie diets are challenging, one must also increase energy expenditure with aerobic exercise to have a decent chance for successful weight reduction, which will help in achieving the goal blood pressure. Physicians should help patients find an activity that they enjoy, because enjoyment will increase their adherence. Patients may listen to music while walking, which may help to maintain interest level. If one has pre-hypertension (systolic

blood pressure between 120 and 139, diastolic BP between 80 and 89), exercise can help avoid developing full blown hypertension. Regular physical exercise can bring blood pressure down to safer levels.Avoid being a ‘Weekend Warrior’. It is not a good strategy to limit all exercise on the weekends to make up for weekday inactivity. Those sudden bursts of activity could actually be harmful.Recommendation : Brisk walking for 30 minutes per day, ideally on most days of the week but at least on five days per week. Most health benefits occur with at least 150 minutes per week of moderate-intensity physical activity, such as brisk walking. Some physical activity is better than none, and more activity results in greater benefits. Health benefits of exercise include reduced rates of all-cause mortality, coronary heart disease, hyper-tension, stroke, type 2 diabetes, metabolic syndrome, colon cancer, breast cancer and depression.A programme can be structured, so that someone could burn upto 200 extra calories or more a day, over and above the basic calories used for sedentary living etc.

WeIgHt lossWeight loss is an important lifestyle modifi-cation in reducing blood pressure. A reduction of 5 kg can help reduce blood pressure or prevent hypertension. A reduction of 10 kg may produce a reduction in systolic blood pressure of 5 to 20 mmHg. Weight reduction is more effective than a low salt diet in young adults. However, in middle aged and elderly subjects, there is a significant additive effect of weight reduction and salt restriction on lowering blood pressure.Besides shedding kilos, one should also keep an eye on one’s waistline. Carrying too much weight around the waist, one can have greater risk of high blood pressure, in general.• Menareatrisk,iftheirwaistmeasurement

is greater than 102 cm (40 inches).


• Women are at risk, if theirwaist circum-ference is greater than 88 cm (35 inches).

• Asian men are at risk, if their waistmeasurement is greater than 90 cm.

• Asian women are at risk, if their waistmeasurement is greater than 80 cm.

alcoHol consuMPtIonIn view of bad effects of alcohol as well as because of availability of other health benefit programmes, alcohol consumption is not recommended at all for non-drinkers or drinkers.As part of a comprehensive lifestyle program, alcohol consumption should be limited to two drinks per day (about 1 oz or 30 ml of ethenol) for most men and 1 drink per day women and lighter weight men. If somebody does not normally drink alcohol, the physician should not advocate drinking, as a way to lower blood pressure. There are more potential harms than any benefit to drinking alcohol. Drinking more than the suggested amounts should be cut back.

dIetary ModIfIcatIon and suPPleMentatIonThe Dietary Approaches to Stop Hypertension (DASH) Eating Plan study showed that an even lower intake of sodium further reduces BP in both normotensives and hypertensives. However, palatability concerns are important and the fact should be kept in mind that other nutrients intake would suffer, whilst trying to stick to such an intensive regimen (5 gm of salt/day).The DASH eating plan outlines a diet rich in fruits and vegetables, high in low fat dairy products, potassium, magnesium as well as calcium and low in saturated fats. This can produce a mean reduction of 6 mmHg in systolic blood pressure and 3 mmHg in diastolic blood pressure.Premier Trial : In this trial, the impact of comprehensive lifestyle changes on blood pressure was assessed. Participants in the lifestyle changes had a greater reduction in

blood pressure than those in the usual care group and this was further enhanced with addition of the DASH eating plan.Garlic is commonly used as a dietary supplement to lower blood pressure. Data from two randomized controlled trials comparing the use of garlic vs. placebo in patients with hypertension showed that garlic may have some blood pressure-lowering effect. However, compared with dietary changes, reduced sodium intake, and physical activity, there is insufficient evidence to support the use of garlic in reducing morbidity or mortality associated with cardiovascular events.Cocoa has a small but statistically significant blood pressure-lowering effect (average of 2 to 3 mm Hg) in adults with hypertension, but there is no evidence that it improves patient-oriented outcomes in the long term.Although vitamin C, coenzyme Q10, omega-3 fatty acids, and magnesium have been used for lowering blood pressure, there is no evidence to support their use in the management of hypertension due to lack of data on well-designed randomized controlled trials.

sodIuM, PotassIuM & blood PressureSodium (Na) and potassium (K) fluctuate antagonistically. A decrease in potassium leads to sodium retention, whereas an increase in potassium leads to sodium excretion, thereby promoting diuresis and natriuresis.In persons with essential hypertension, a diet low in potassium results in a systolic increase of 7 mmHg because of increased sodium retention. Increased potassium resulted in a reduction of 2.42 mmHg in systolic blood pressure and a drop of 1.57 mmHg in diastolic blood pressure. However, current recom-mendations are to obtain adequate potassium intake through a healthy diet.

sMokIng cessatIonCigarette smoking causes 4 mmHg increase in systolic blood pressure and 3 mmHg increase


in diastolic blood pressure. Compared with placebo, nicotine released during cigarette smoking increases sympathetic nervous activity which in turn increases myocardial oxygen demand through increased blood pressure, heart rate and myocardial contrac-tility.Hypertensive patients, those who smoke have increased risk of total, ischemic as well as hemorrhagic stroke and this rise is related to the number of cigarettes smoked. Smoking cessation should be part of any comprehensive lifestyle modification plan to reduce the risk of high blood pressure and cardiovascular disease.

yoga, MedItatIon & otHer relaxatIon tenHnIQuesYoga and meditation include a variety of techniques, such as repetition of a word or phrase (mantra) and careful attention to the process of breathing, to achieve a state of inner calm, detachment and focus. Transcendental meditation may even reduce blood pressure modestly and also reduces mortality in patients with hypertension. Meditation may have other benefits and does not appear to be harmful, except in patients with psychosis. Biofeedback techniques have been proven effective and may be considered in clinical practice to lower blood pressure.The mechanism by which relaxation techniques lower blood pressure is unclear. One theory suggests that they may help lower the stress and physiologic arousal produced by the autonomic nervous system, thereby reducing blood pressure.

clInIcal focus• Lifestylemodifications have definite role

in all categories of hypertension and is especially advised in pre-hypertensive stage.

• Lifestylemodificationsshouldbethefirst-line of therapeutic approach in all patients with mild hypertension.

• Regular exercise, sodium restriction,

weight loss measures etc. should be strictly adhered to by hypertensives to maintain a better quality of life.

• Therapeutic lifestyle modificationsminimize the cost of pharmacological intervention and the untoward effects of various drugs.

• Daily exercise, as per recommendation,is always better than weekend vigorous exercise, which may actually be harmful.

• Dietary modification, as per DASHprotocol, is ideal and may be gradually attained.

• Alcohol can never be recommended andshould not be initiated in non-drinkers.

• Meditation helps in achieving the goalBP and at the same time helps in having physical and mental well-being.

• Pharmacological intervention in a timelyfashion is desirable in all patients having BP, who are not optimally controlled with therapeutic lifestyle modifications.

suMMaryNon-pharmacologic measures should be part of routine management of hypertension. It is emphasized that simple advice from physi-cians can have positive influence on patient’s motivation to make positive lifestyle changes.Lifestyle recommendations’ should not be given as lip service but instituted with adequate behavioural and expert support and reinforced periodically. Because long-term compliance with lifestyle measures is low and the BP response highly variable, patients undergoing non-pharmacological treatment should be followed up closely to start drug treatment when needed and in a timely fashion.Non-pharmacologic approaches to reduce BP have enormous potential as a means for preventing hypertension and controlling BP, thereby reducing the occurrence of ASCVD. Now, the greatest challenge is developing and implementing strategies that lead to a reduced salt intake, reduced weight,


increased physical activity, moderate alcohol intake among those who drink, and an overall healthy dietary pattern.

references1. Rouse IL, Beilin LJ, Armstrong BK. Vandongen R.

Bloodpressure-lowering effect of avegetariandiet;Controlled diet in normotensive subjects. Lancet 1983; 1:5-10.

2. MargettsBM,BeilinLJ,VandongenR,ArmstrongBK.Vegetarian diet in mild hypertension: A randomised controlled trial. Br Med J 1986; 293:1468-1471.

3. Morris MC, Sacks FM. Dietary fats and blood pressure. In Textbook of Hypertension (Ed. Swales J), p.605-618 Oxford, UK: Blackwell, 1994.

4. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among U.S. adults: The National Health and Nutrition Examination Surveys, 1960to 1991. J Am Med Assoc 1994; 272:206-211.

5. CappuccioFP,ElliottP,AllenderP,PryerJ,FollmanDA, Cutler JA: Epidemiologic association between dietary calcium intake and blood pressure: A meta-analysis of published data. Am J Epidemiol 1995; 142:935-945.

6. Allender PS, Cutler JA, Follmann D, Cappuccio FP, PryerJ,ElliottP.Dietarycalciumandbloodpressure:A meta-analysis of randomized clinical trials. Ann Intern Med 1996; 124:825-831.

7. JNC VI - Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National CommitteeonthePrevention,Detection,Evaluation,and Treatment of High Blood Pressure. Arch Intern Med 1997; 157:2413-2446.

8. NHLB1. Clinical guidelines on the identification,evaluation, and treatment of overweight and obesity in adults—the evidence report. J Obes Res 1998; 6:51S-209S.

9. Svetkey LP, Simons-Morton D, Vollmer WM, Appel LJ, Conlin PR, Ryan DH, Ard J, Kennedy BM. for the DASH Research Group: Effects of dietary patternson blood pressure: Subgroup analysis of the dietary approaches to stop hypertension (DASH) randomized clinical trial. Arch Intern Med 1999; 159:285-293.


1Cardiology Registrar, 2Consultant Cardiologist, 3DirectorofCardiology,JaslokHospital&ResearchCentre (JHRC), Mumbai

Robotic Adrenalectomy : An Emerging option in the treatment of Pheochromocytoma

Ameya Tirodkar1, Nihar Mehta2, AB Mehta3

CASE REPORT

abstractPheochromocytoma is a rare catecholamine secreting tumor originating usually from adrenal medulla and produces signs and symptoms due to excessive catecholamine secretion from tumour. A 50 year old lady, hypertensive since 20 years was admitted at our center with recent history of three episodes of accelerated hypertension in the last two months; despite being on three anti hypertensive drugs. Clinical suspicion of pheochromocytoma was confirmed with transabdominalUSG,CT scan of abdomen&by 24 hour urinary catecholamine level.Afterthree weeks of pre-operative preparation with labetalol and propanolol, she was re-admitted for Adrenalectomy. Robot assisted Adrenalectomy was performed using the da Vinci Robotic system. Patient had an uneventful perioperative course and was discharged on day 3 of the procedure.Pheochromocytoma is a rare cause of hypertension. Adrenlectomy offers complete cure from this condition. Intraoperative handling the tumour and excision is technically challenging. Robotic Surgery provides an efficient alternative to conventional Laproscopic adrenalectomy, minimizing the overall complications of the procedure.

are rare neoplasms, probably occurring in less than 0.2 percent of the patients with hypertension.1,2 We present a case of adrenal pheochromocytoma in a 52 year aged female patient presenting with paroxysmal attacks of hypertension who was treated successfully by Robotic Adrenalectomy.

case rePortA 52 years female was admitted with complaints of paroxysmal attacks of dizziness and headache for last 6 months. She required 3

IntroductIonPheochromocytoma is a rare tumor originating from catecholamine secreting chromaffin cells that are derived from the ectodermic neural system and mostly situated within the adrenal medulla.1 It is estimated that the annual incidence of pheochromocytoma is approximately 0.8 per 100,000 person-years.2 Catecholamine-secreting tumors


Fig. 1: CT Abdomen with contrast showing Right Adrenal mass

Fig. 2: Hypodense lesion seen in medial limb of Right Adrenal gland

anti-hypertensive medications, Telmisartan 40 mg, Nebivolol 5 mg and Amlodipine 10mg for her blood pressure control. She was admitted in emergency with Hypertensive crisis at an outside hospital. She was diagnosed to have hypertensive left ventricular failure for which she required treatment with i.v. Nitroglycerine and ICU stay for few days. Patient was stabi-lized and discharged with increased doses of anti hypertensive medicines to optimize her blood pressure. Recurrent hospitalizations and labile blood pressure with headaches had increased morbidity in the last 6 months for which she had frequent consultations at different centers with no relief.On physical examination patient had a Pulse of 70/min, Blood Pressure of 160/90mm hg. Complete blood count, Random Blood Sugar, Blood urea, Chest X-rays and ECG reports were within normal limit.Thyroid,chest and cardiovascular system examination were unremarkable. There was no abdominal bruit or lower extremity oedema. Serum creatinine, Serum Potassium and other electrolytes were normal. Plasma Renin levels were within normal levels.Apart from the routine investigations, Plasma Metanephrine level were slightly raised 73.2 pg/ml (normal <65 pg/ml). Her 24 hours Urine metanephrine levels were normal.

She underwent a CT Scan of Abdomen with contrast which revealed a 14 mm x 8 mm well defined enhancing lesion in the medial limb of the right adrenal with Hounsfield unit (HU) of – 3 units (Figures 1, 2).In view of her clinical and laboratory findings, it was decided to prepare the patient for elective Right Adrenalectomy. She was started on Tablet Prazosin 2.5 mg 12 hourly and gradually stepped up to 5 mg 12 hourly. Tab Labetalol was added to the treatment regimen for the next 3 weeks. She underwent Robotic right Adrenalectomy under General Anaesthesia. Patient had minor intra operative Blood pressure fluctuations during the procedure. She tolerated the procedure well. Her blood pressure normalized to 110/70 mm hg on first post operative day.Her post operative course was uneventful. Her blood pressure medications requirement had decreased and patient was discharged on third post operative day with Tablet prazosin 2.5 mg and Tablet Labetelol 25 mg once a day.The excised Adrenal gland mass was sent for Histopathology analysis which showed hyperplasia of Adrenal Medulla with oncolytic changes (Figure 3). Immunohistochemistry study of the sample demonstrated all cells of Medulla to be strongly positive for


Chromogranin and Synaptophysis, which are markers of Neuroendocrine tumours (Figures 4, 5).The patient had clinical improvement with decrease in the dosage of her anti hypertensive medications. There were no further episode of paroxysmal headaches on following up of the patient for 6 months.

dIscussIonPheochromocytomas are rare neuroendocrine tumors originating from chromaffin tissue. They are found in 0.2-0.6 % of subjects with hypertension.3-5 The cost-effectiveness of diagnostic workup of pheochromocytoma is markedly restricted by low specificity of clinical symptoms together with symptoms overlapping within a wide variety of other conditions, including idiopathic hyper-

tension, hyperthyroidism, heart failure, migraines, and anxiety.The most common sign of pheochromocytoma is hypertension, found in approximately 95% of patients and related to catecholamine excess.6-7 Upto two-thirds of patients with hypertension who have pheochromocytoma, may have parox-ysmal elevation of blood pressure. Our patient had underlying essential hypertension with paroxysms of accelerated hypertension.The clinical manifestations of a pheochromo-cytoma result from excessive catecholamine secretion by the tumor. The first step in the diagnosis is the biochemical confirmation of catecholamine excess. Plasma metanephrine testing has the highest sensitivity (96%) for detecting a pheochromocytoma, but it has a lower specificity.8 In comparison, 24 hour urinary catecholamines and metanephrines have a sensitivity of 87.5% and a specificity of 99.7%.9 In our case plasma metanephrine levels were high. The biochemical diagnosis is then followed by the localization of the pheochromocytoma and / or metastases. Computed Tomography (CT) scanning with contrast or Magnetic Resonance Imaging (MRI) is carried out to locate and determine the size of the tumour. In this case a 14 mm x 8 mm mass was detected in the medial limb of the Right Adrenal

Fig. 3: Zona Fasciculata cells showing oncolytic cells.

Fig. 4: Synaptophysis positive Medulla cells.

Fig. 5: Strongly chromogranin positive Medulla cells.


gland. Surgical resection of the tumour is the treatment of choice and usually results in cure of hypertension. It is also important to remember that tumor manipulations during surgery may be associated with the release of tremendous amounts of catecholamines into circulation, which might be capable of overpowering thepharmacological blockade. In order to control hypertension levels prior to an operation, even in preoperative normotensive patients, it is recommended that patients undergo preoperative pharma-cological treatment. Careful preoperative preparation requires combined alpha and beta blockade to control blood pressure and to prevent intraoperative hypertensive crisis. Alpha-adrenergic blockade, in particular, is required to control blood pressure and prevent a hypertensive crisis. Our patient was put on labetalol and prazosin prior to the Robotic Adrenalectomy surgery.Robotic Adrenalectomy is found to be at par with Laproscopic Adrenlectomy in terms of success rates, complications and conversion to open resection. In addition, current use of this modality is limited by higher cost, which precludes its routine use. However it provides potential advantages of a shorter hospital stay, less blood loss, and lower occurrence of postoperative complications.13

It is challenging to maintain normal haemody-namics during Pheochromocytoma resection, in the face of catecholamine surges (especially at laryngoscopy, peritoneal insufflation, surgical stimulation, and tumor handling) followed by the opposite scenario following tumor ligation. It requires aggressively utilizing potent, short acting, intravenous, anti-hypertensive agents – sodium nitro-pruside and nitroglycerin - to control sudden changes in blood pressure during surgery. If adequately primed for the surgery, the chances of wide blood pressure fluctuations are minimized. Our patient underwent Robotic excision of the Right Adrenal Gland and with 3 days of post operative stay in the hospital. On three months of post surgery follow up, patient was

weaned off her hypertension medications and had no further episode of accelerated hyper-tension.

conclusIonPheochromocytoma is an important cause of Secondary Hyertension, which has a definite surgical cure.In addition to being a great mimicker; pheochromocytoma represents one of the most challenging diagnosis. This case emphasizes the importance of appropriate preoperative conditioning of the patient to minimize the intraoperative haemodynamic instability. Robot assisted adrenalectomy is a novel surgical approach the post operative stay, and minimize complications and morbidity in such patients.

references1. Neumann HP. Pheocromocytoma. In: Fauci AS et al,

editors. Harrisons Principles of Internal medicine. 17th edition. New York: Mcgraw-Hill medical; 2008.

2. Beard CM, Sheps SG, Kurland LT, et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo ClinProc 1983; 58:802.

3. Omura M, Saito J, Yamaguchi K, et al. Prospective Study on the Prevalence of Secondary Hypertension among Hypertensive Patients Visiting a General Outpatient Clinic in Japan. Hypertens Res 2004; 27:193–202.

4. Ariton M, Juan CS, AvRuskin TW. Pheochromocytoma: Clinical observations from a Brooklyn tertiary hospital. Endocrine Practice 2000; 6:249–252.

5. Manger WM. The Protean Manifestations of Pheochromocytoma. HormMetab Res 2009; 41:658–663.

6. Calhoun DA, Jones D, Textor S, et al. Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific Statement From the American HeartAssociation Professional Education Committeeof the Council for High Blood Pressure Research. Hypertension 2008; 51:1403–1419.

7. Guérin M, Guillemot J, Thouënnon E, et al. Granins and their derived peptides in normal and tumoralchromaffin tissue: Implications for thediagnosis and prognosis of pheochromocytoma. Regulatory Peptides. 2010.

8. Kudva YC, Sawka AM, Young WF jr. Clinical review 164: Thelaboratory diagnosis of adrenal


pheochromocytoma: Mayo Clinic experience. J ClinEndocrinolMetab 2003; 88:4533-9.

9. De jong WH, Eisenhofer G, Post WJ, Muskiet FA, de Vries EG, Kema IP. Dietary influences onplasma and urinary metanephrines: Implications for diagnosis of catecholamine producing tumour. JClinEndocrinolMetab 2009; 94:2841-2849.

10. Bravo EL, Tagle R. Pheochromocytoma: State-of-the-Art and Future Prospects. EndocrRev 2003; 24:539–553.

11. Ross E, Prichard B, Kaufman L, et al. Preoperative and operative management of patients with phaeochromocytoma. Br Med J 1967; 1:191–198.

12. Desmonts JM, Marty J. Anaesthetic management of patients with phaeochromocytoma. Br J Anaesth 1984; 56:781–789.

13. Brandao L F, Autorina R, Eur Urol 2014; 65:1154 61.doi:10.1016/j.eururo.2013.09.021. Epub 2013 Sep 20


27th National Annual Conference ofHypertension Society of India

HSICON 201831st August - 2nd September 2018 • Thiruvananthapuram (Trivandrum)

Hypertensi

on Society ofIndia

Organising Chairman

Dr. P. K. Sasidharane-mail: [email protected]

Organising Secretary

Dr. R. ChandniMobile: 9447202748

e-mail: [email protected]

clinical journal of hypertension - hsindia.orghsindia.org/images/journal/2018/jan_march_2018.pdf ·...

Documents