Thyroid Disease and the HeartIrwin Klein, MD

Professor of Medicine and Cell BiologyNYU School of Medicine

Disclosures

Dr Klein has no conflicts to disclose

In 1786, Caleb Hillier Parry described a woman with goiter and palpitations, whose "each systole shook the whole thorax".

He was the first to suggest "the notion of some connexion (sic) between the malady of the heart and the bronchocoele" (Parry CH, 1815, Crutwell, Bath).

Cardiovascular Symptoms of Hyperthyroidism

• Palpitations• Atrial Fibrillation• Exercise Intolerance• Systolic Hypertension• Angina• Peripheral Edema• Congestive Heart Failure

Cardiovascular Symptoms of Hyperthyroidism

• Palpitations• Atrial Fibrillation• Exercise Intolerance• Systolic Hypertension• Angina• Peripheral Edema• Congestive Heart Failure

Thyroid Hormone and the Cardiovascular System

Thyroid hormone mediated changes may occur via

• Direct effects on the heart• Effects on the peripheral

circulation and then indirectly on the heart

Sites of Action of ThyroidHormone on the Heart andCardiovascular System

Klein and Danzi, In: The Thyroid 2012

Klein I et al. NEJM. 2001;344:501.

SVR (dyne•s•cm-5)

Heart rate (bpm)

% EF

IVRT (msec)

Cardiac output(L/min)

Blood volume(% normal)

1500-1700

72-84

60%

60-80

5.8

100

Normal

2100-2700

60-80

<60%

>80

<4.5

84.5

Hypothyroid

700-1200

88-130

>60%

25-40

>7.0

105.5

Hyper-

Cardiovascular ChangesWith Thyroid Disease

Klein I et al. NEJM. 2001;344:501.

Cellular Mechanisms of Thyroid Hormone Action on the Heart

Klein I et al. NEJM. 2001;344:501.

Thyroid Hormone Responsive Cardiac Genes

Myosin heavy chain-

SR Calcium ATPase (SERCA2)

1 Adrenergic receptor

GTP binding protein Gs

Na+ / K+ – ATPase

Voltage-gated K+ channels(Kv 1.5, 4.2, 4.3)

Positive Regulation

MHC-

Phospholamban

Adenylyl cyclases V, VI

T3 Receptor 1

Na+ / Ca2+ exchanger (NCX)

Negative Regulation

Left Ventricular Diastolic Function in Hyperthyroidism

IUntreated Graves

IIIEuthyroid

IIBeta- Blockade

Control HyperthyroidI II III

Heart Rate (bpm) 73 95 81 70

Diastolic Filling (ms) 225 173 201 216

Diastolic Compliance 156 97 122 148

Relaxation Time 58 33 34 52

70

60

50

40

30

20

Control Hyperthyroid Propranolol Euthyroid(N = 10) (N = 9)

Isovolumic Relaxation TimesIS

OVO

LUM

IC R

ELA

XATI

ON

TIM

E (m

sec)

Mechanisms of Heart Failure inPatients with Thyrotoxicosis

1) Exacerbation of underlying heart disease

2) Rate related left ventricular dysfunction

3) Right ventricular overload- Pulmonary Hypertension

Treatment of the Thyrotoxic Cardiac Patient

1) Beta-adrenergic Blockade2) Radioiodine3) Antithyroid Drugs4) Calcium Channel Blockers5) Anticoagulation

Changes in Subclinical Hyperthyroidism

1) Sinus Tachycardia2) Unexplained Weight Loss3) Atrial Fibrillation4) Cardiac Hypertrophy5) Enhanced Cardiac Contractility6) Skeletal Muscle Weakness

Hypothyroidism and the Heart

• Hypertension• Elevated Cholesterol• Long Q-T Syndrome• Serum CK• Coagulopathy• Response to Treatment

Initial Laboratory Data and Response to Thyroid Hormone Replacement Therapy

Patient THR Rx Cholesterol CK LDHmg/dl U/L U/L

1. Before 322 943 512 During 157 52 125

2. Before 265 2650 760 During 124 67 123

Reference Range <200 <90 <220

DIASTOLIC FUNCTION AND THYROID DISEASE

OH SCH C H H+P E

Isov

olum

ic R

elax

atio

n Ti

me

(mse

c)

0

20

40

60

80

100

120

Klein I. In: Braunwald’s Heart Disease. 8th ed., 2007

Cardiovascular Risk Associated with Hypothyroidism

Hypercholesterolemia ++

Diastolic hypertension +

Left ventricular diastolic dysfunction ++

Impaired endothelial mediated vasodilatation ++

Hypercoagulable state +

Elevated serum homocysteine +

Elevated C-reactive protein –

Risk Factor Response to Treatment

Danzi and Klein, Current Hypertension Reports 2003

ASCVD and Hypothyroidism

1,503 patients

400 (at Risk)

90 Clinical ASCVD

55 Patients with angina before Rx

35 Onset of angina after Rx

Keating, et al. Prog CV Disease 1961.

Effect of treatment

ASCVD and Hypothyroidism

Keating, et al. Prog CV Disease 1961.

Patients with angina before Rx

55

21 (clinically improved)

25(no change)

9 (worse)

Effect of treatment

ASCVD and HypothyroidismEffect of treatment

Keating, et al. Prog CV Disease 1961.

Onset of angina after Rx

35

6 (1st month)

6 (1st year)

23 (>1 year)

Subclinical Hypothyroidism• Definition:

– TSH 5–20 – Normal free T4

• Synonyms:– Compensated hypothyroidism– Decreased thyroid reserve– Mild hypothyroidism/mild thyroid

failure

Biondi B, et al. JECM. 1999;84:2064-2067; Taddei et al. JCEM 2003

FS (%)

CO (mL)

SVR (dyn/sec•cm-5)

IVRT (ms)

EDRF (%)

Control

Changes in Cardiovascular Function in Mild Hypothyroidism

Pre Post

36 +/- 4

5223 +/- 960

1460 +/- 340

84 +/- 8

503%

36 +/- 4

5300 +/- 1260

1470 +/- 370

94 +/- 13

358%

39 +/- 7

5806 +/- 1760

1361 +/- 383

77 +/- 15

446%

Hypothyroid

Risk of MI and Atherosclerosis

Hak AE, et al. Ann Int Med. 2000;132:270-278.

0

0.5

1

1.5

2

2.5

3

3.5

Myocardial Infarction Aortic Atherosclerosis

1.0 1.0

2.3

1.7

3.1

1.9

Euthyroid

Subclinical hypothyroid

Subclinical hypothyroid and antibodiesOddsRatio

Carotid intima-media thickness in subclinical hypothyroidism and the

response to treatment

Kim, et al. Endocrine J. 2009; 56:753.

• 2809 females from the General Practitioner Research Data Base in the UK were analyzed with regard to subclinical hypothyroidism and its treatment.

• 50% of the overall population was treated with L-T4.• When compared to non-treated patients, L-T4 treatment

led to a significant decrease in cardiovascular morbidity and mortality.

Conclusion: L-T4 treatment had the beneficial effect to reduce cardiovascular events and all cause mortality in adults with subclinical hypothyroidism.

Crowley et al. NEJM. 1967.

Thank you for your attention

Questions?