Top 10 cardiovascular therapies and

interventions for the next decade Prof.N.Sarrafzadega

nDR.M.Sadeghi

Chamran HospitalIsfahan,Dec.2014

Valentin Fuster, M.D., Ph.D., M.A.C.C

Director, Zena and Michael A. Wiener Cardiovascular Institute,Mount Sinai School of Medicine,US

• Valentín Fuster (Barcelona, 1943),

• 1st Marquess of Fuster, is a Spanish cardiologist .• The Only cardiologist to receive the two highest gold medal awards and all four

major research awards from the world's four major cardiovascular organizations: 1-Interamerican Society of Cardiology, (2005 and 2009), Scientific Award.

2-Gold Medal Award (ESC) 1992-2007. 3-Gold Medal Award and Distinguished Scientist (AHA). 4- Distinguished Scientist Award (ACC) 1993.

• In November 2012, Dr. Fuster received the highest honor given by the American Heart Association.

• Dr. Fuster has ranked among the Top Doctors in the US for the past 13 years and is considered in the top 1% of physicians in the United States by Castle-Connolly.

Top 10 cardiovascular therapies and interventions for the next decade

Valentin Fuster

-In this Perspectives article, I predict the 10 most-promising advances in cardiovascular therapies and interventions.

•- Our improved understanding of CVD might help us, during the next decade, to achieve a transition from treating complex disease to promoting global cardiovascular health

TOP1-Myocardial protection in STEMI

- One of the mechanisms in ischaemia reperfusion injury is opening of the mitochondrial permeability transition pore (mPTP) during the early stages of reperfusion in response to calcium overload, oxidative stress, inflammation, and restoration of physiological pH

•- Four strategies targeting this reperfusion injury phase (one of mechanical preconditioning, and three of early pharmacological

administration before PCI) will be discussed .

1 -Remote preconditioning, induced by four cycles of 5 min inflation and 5 min deflation of a blood pressure cuff placed on the upper arm .

increased myocardial salvage by 33% compared with no conditioning.

2 -Cyclosporin, a nonspecific blocker of the mPTP 40% reduction in the size of MI compared with placebo

3-IMMEDIATE trial tested the effect of GIK therapy administered by emergency medical services during transfer of >400 patients with ischaemia to hospital.

GIK administration for 12 h was not associated with an improvement in 30 day ‑survival, but was associated with a significantly reduced rate of the composite outcome

of cardiac arrest and in-hospital mortality .

4-The potential of β blockers to exert a cardioprotective effect by decreasing ‑reperfusion injury is currently being evaluated .

β1‑blocker metoprolol markedly reduced infarct size only when administered early (<6 h) and intravenously.It has been attributed to production of nitric oxide, perhaps counteracting the mPTP effect.

TOP2-Therapy for stable complex CAD• In the 1980s, CABG surgery was considered superior to optimal

medical therapy (OMT )• In the 1990s, this time favouring noninferiority of PCI over CABG

surgery. • In the 2000s sophisticated treatment algorithms have arisen that

incorporate overall anatomical complexity (SYNTAX Risk Score) intravascular-measured detection of ischaemia- using the fractional flow reserve (FFR) associated with each epicardial coronary stenosis. and- clinical aspects including left ventricular dysfunction,- global ischaemia, and- comorbidities (Clinical Risk Score).

• The SYNTAX score: can be used to assess coronary anatomy complexity from the perspective of potential intervention or surgery, patients with very complex or moderately complex anatomy (SYNTAX score >33 or 22–33, respectively) have improved outcomes when they undergo CABG surgery rather than PCI.Except in patients with LMC and intermediate SYNTAX who may benefit more from PCI.

• Measurement of the ischaemic FFR across each stenotic lesion is now advocated. (FFR ≤0.8).

• FREEDOM trial: studied 1,900 patients with multivessel CAD and diabetes mellitus; in these patients, CABG surgery was superior to PCI, independently of anatomical complexity or SYNTAX score. The rate of early stroke (<3 days after surgery) was increased. However,CABG surgery was more cost effective than PCI ‑in the long term

• COURAGE trial: Compared PCI plus OMT with OMT alone; no significant difference in the primary end point (all-cause mortality and nonfatal MI) during follow-up (median 4.6 years).

• BARI 2D :In patients with diabete support the use of OMT alone as a viable alternative to revascularization.

• FREEDOM, COURAGE, and BARI 2D trials only ~20% of patients with CAD and diabetes achieved treatment targets for blood pressure, lipid levels, and glycaemic control.

Prediction of Stable CAD • 1-The higher the complexity of CAD(stable), the better the outcomes with

CABG surgery compared with PCI.

• 2-Less complex CAD , FFR-guided PCI is reasonable strategy(only to quantify ischaemia across epicardial stenotic lesions ).

• CT, MRI, and PET technologies will increasingly be used to quantify both epicardial and microvascular ischaemia.

• 3-For uncomplicated CAD, initial OMT alone will be a prevalent strategy, especially in non symptomatic elderly individuals

• 1-Initialy,Wald and Law claimed that a polypill including six active components administered in every individual aged >55 years would reduce the incidence of cardiovascular disease (CVD) by >80%.

• 2-Polypill is suggested for primary prevention in individuals at high risk .

• 3-The use of a polypill for secondary prevention is aiming to increase adherence in a population with CVD.

• Polypill for secondary prevention is now being tested globally in high-income, middle-income, and low income‑ countries.

TOP3-Polypill to improve adherence

TOP4-Valvular intervention• Catheter-based therapies including balloon valvuloplasty of the pulmonary, mitral,

and aortic valves, have been in clinical use for >3 decades .

• EVEREST II trial: 279 patients with clinically significant chronic MR to either TMVR or open surgical repair. At 12 months, the composite end point (freedom from death, surgery for dysfunction,MR +3 to 4 was significantly less in TMVR(55% VS 73%).

• At 4 years, all-cause mortality was similar in both groups, but grade 3+ or 4+ residual MR occurred in 21% of the TMVR group compared with 9% in surgical one.

• The MitraClip® was approved in Europe in 2008, USA in 2013, but only for patients with degenerative MR who are at high surgical risk.

Devices in patients considered to be inoperable because of the high risk of surgical valve replacement.

• MitraClip® device in patients with mitral regurgitation has been reported.

• Three main concerns about TAVR need to be addressed:1- TAVR-associated stroke and silent brain infarcts should be reduced by procedural embolic protection devices/ clinical trials.

2-TAVR-related paravalvular aortic regurgitation (grade ≥2+),associated with increased mortality when with multiple comorbidities.

3- Whether the indications for TAVR can be expanded, for example to include patients with aortic stenosis at intermediate risk , or degenerated aortic bioprosthetic valves, and selected patients with aortic regurgitation.

TAVR/TAVI

•FIGURE 56-7 Newer valves currently in trials include• A, the Lotus (Boston Scientific Corp.) ;

• B, Direct Flow (Direct Flow Medical, Inc., Santa Rosa, Calif);

• C, CENTERA•(Edwards Lifesciences, Inc).

• D, Portico (St. Jude Medical, Inc.);• E, Engager (Medtronic, Inc.);

• F, JenaClip (JenaValve Technology, Inc., Wilmington, Del) ;

•G, Acurate (Symetis,•Inc., Ecublens, Switzerland); and

• H, Inovare valve (Braile Biomédica, Inc., Sao Jose do Rio Preta, Brazil).

TOP5-AF mechanisms and management

• Traditionally, developments in the field of AF have involved new pharmacological approaches to control the arrhythmia, and novel oral anticoagulant drugs to prevent stroke. (apixaban, dabigatran, edoxaban, and rivaroxaban) .

• The 2014 AHA/ACC/HRS67 and the 2013 ESC68 guidelines emphasize these dual approaches :

1-Early AF ablation procedures ‑ 2-Percutaneous left atrial appendix closure for stroke prevention.

• Our challenge is to know the mechanisms leading to AF and stroke— genetic, molecular, structural, and dynamic ,which might allow early prediction and management of AF.

• The familial or heritable nature of AF has now been established.

• Nine susceptibility regions on eight chromosomes implicate genes encoding transcription factors involved in cardiac-expressed ion channels and other signalling molecules in the pathogenesis of AF .

• Fibrotic atrial cardiomyopathy/ previous inflammatory insults,seen in a number of patients with AF, including lone AF.

• Therefore, etiology of some atrial cardiomyopathy might be similar to those that lead to ventricular dilated cardiomyopathies.

• Obesity, myocarditis, and fibrosis are important aetiologies of AF. • Systemic obesity is a risk factor for AF, but the underlying mechanism is

uncertain.

• An important mechanism of obesity-associated AF is the close link between periatrial epicardial adipose tissue volume and inflammation(CRP –IL).

• The association of epicardial adipose tissue with AF is independent of the presence of hypertension, diabetes, or left atrial enlargement.

• Weight reduction results in a substantial decrease in the burden and severity of AF symptoms.

• Left atrial contractile function using 2D echocardiography is an independent and important predictor of recurrent AF than left atrial volume.

• Independently of AF, left atrial total emptying fraction assessed using 3D transthoracic echocardiography, is strongly associated with MRI-detected subclinical brain infarcts.

• Finally, a large left atrial appendage orifice (measured using contrast-enhanced CT) is associated with slow left atrial appendage blood-flow velocity (assessed using transoesophageal echocardiography), and an increased predisposition to stroke.

• Patients with an irregular ‘cauliflower’ left atrial appendage morphology, imaged using contrast-enhanced CT or MRI, are much more likely to have an embolic event, even after controlling for comorbidities and CHADS2 score, than those with a smooth ‘chicken-wing’ morphology

Prediction1-Classic pharmacological approaches in AF to control heart rate or rhythm and coagulant state are under a slow transition towards mechanical approaches, such as early ablation procedures and percutaneous left atrial appendage closure.

2-Our understanding of mechanisms that lead to AF and stroke is insuffient.

3-Genetic,Molecular,structural and dynamic aspects need more study.

TOP6-Aggressive hypertension therapy

•Worldwid ~50% of patients with hypertension do not have their condition properly controlled.

•we can expect that even a small reduction in the population-wide average intake of dietary sodium will result in a major improvement in cardiovascular healthevents.(ideal sodium intake 1.5–2.3 g per day).

• SYMPLICITY HTN 3 trial:(535 patients with resistant ‑hypertension)underwent renal nerve denervation.

• SIMPLICITY HTN-3: whether sympathectomy was effective, control group are adherent medication.

• Therefore: selection of patients should be refined in the future.

Prediction

• 1-comprehensive data registries. • 2-sharing of performance metrics, regular blood-pressure

measurement.• 3-awareness of the benefits of pill combinations .• 4-Effort to reduce Sodium intake.

POLICY STATEMENT FROM THE WORLD HYPERTENSION LEAGUE

Standards for the Uniform Reporting of Hypertension in Adults UsingPopulation Survey Data: Recommendations From the World

Hypertension League Expert Committee

Marianne E. Gee, PhD; Norm Campbell, MD; Nizal Sarrafzadegan, MD ;Tazeen Jafar, MD, MPH; Tej K. Khalsa, MD; Birinder Mangat, MD; Neil Poulter, FRCP, FMedSci; Dorairaj

Prabhakaran, MD, DM, MSc, FRCP, FNASc; Sandor Sonkodi,MD, PhD, DSc; Paul K. Whelton, MB, MD, MSc; Mark Woodward, PhD; Xin-Hua Zhang, MD, PhD

The Journal of Clinical Hypertension, 2014

Three questions need to be addressed over the next few years .

• 1-What is the ideal blood pressure for individuals with specific diseases or in a particular ethnic group?

• 2-what community-driven strategies might succeed?

• 3-What is the role of salt in hypertension, and how urgent is the need for salt-reduction programmes?

• Finally, ~10% of patients with diagnosed hypertension have resistant hypertension;who will respond to renal nerve ablation?

TOP7-Cholesterol and diabetes• The general role of HDL cholesterol in promoting vascular health is

widely accepted, but the molecular mechanisms of this effect and the optimal HDL concentration in the blood are uncertain.

• The effects of artificially elevating the levels of HDL with cholesteryl ester transfer protein inhibitors, infusion of HDL mimetics, holoparticle HDL infusion, or infusion of delipidated HDL particles are controversial and under investigation.

• Statins remain the first-line therapy for lowering the LDL-cholesterol level and reducing atherosclerotic cardiovascular risk. (high-intensity statin therapy ).

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors on the surface of hepatocytes, thereby reducing LDL-cholesterol clearance .

• Three monoclonal antibodies against PCSK9 (alirocumab, bococizumab, and evolocumab) have all been shown to lower the LDL-cholesterol level dramatically in phase II clinical trials involving patients with or without familial hypercholesterolaemia, and when administered alone or in combination with a statin, with good safety and tolerability.

• Alirocumab in the ODYSSEY Outcomes trial (n = 18,000), bococizumab in the SPIRE 1‑ and SPIRE 2‑ trials (combined n = 18,300), and evolocumab in the FOURIER trial (n = 22,500;) with 5 year follow-up .‑

• Obesity and diabetes are closely associated, and their control is an increasing challenge.(In the global FREEDOM trial, COURAGE and BARI 2D trials).

• In the global FREEDOM trial of 1,900 patients with diabetes and CAD, the average BMI was 29.7 kg/m2, close to the definition of obesity (BMI >30 kg/m2), and other risk factors associated with the metabolic syndrome (such as hypertension and dyslipidaemia) were also prevalent.After 1 year of follow-up, only 8% of patients had reached an adequate risk-factor profile, including their level of glycated haemoglobin (HbA1c).

• Similar data were observed in patients with diabetes in the contemporary COURAGE and BARI 2D trials.

• The high prevalence of obesity and diabetes, as well as difficulties in controlling them by changes in lifestyle and the use of drugs, the potential application of bariatric surgery has been suggested by some clinicians.

• The randomized STAMPEDE trial, led by the Cleveland Clinic, OH, USA and involving 150 patients who were obese and had uncontrolled type 2 diabetes, was conducted.

• Intensive medical therapy plus bariatric surgery resulted in weight reduction and glycaemic control in significantly more patients than the use of medical therapy alone.

• This benefit in the bariatric surgery group extended to other risk factors involved in the metabolic syndrome (such as blood pressure and LDL-cholesterol level).

Prediction• 1-I predict that PCSK9 monoclonal antibodies, administered

subcutaneously every 2 weeks or every month, will be the solution in patients who are intolerant to, or experience adverse effects when taking, statins, and in those who do not achieve a target level of LDL cholesterol with statins.

• 2-For patients with familial hypercholesterolaemia, these antibodies

will become a panacea.

• 3-The ongoing investigational success of bariatric surgery might be useful in combatting the high prevalence of obesity and diabetes and lead to a reduction in clinical events in these patients.

TOP-8:Heart–brain interaction

• The US National Alzheimer’s Coordinating Center database of 5,715 autopsy cases with neuropathological and cerebrovascular evaluation documented that patients with Alzheimer disease have a high prevalence of moderate-to-severe arteriosclerosis in the Circle of Willis and smaller arteries, as well as a high prevalence of large and multiple microinfarcts.

• A high prevalence of MRI-silent brain infarcts, presumably as a result of microemboli in the small vessels, has been observed in patients with AF, after TAVR and other cardiac procedures, and in those with left ventricular dysfunction.

• In the largest and longest prospective study, involving 3,381 adults (aged 18–30 years at baseline) in four cities in the USA and with 25 years of follow-up, cognitive function was assessed at year 25 (2010–2011) with the most-sophisticated technology:

1-Cumulative exposure to cardiovascular risk factors was associated with impaired cognition. 2-Education and a healthy lifestyle are important factors for reducing the risk of late-life dementia.• On the basis of information from neurovascular imaging,

psychological testing, and neuropathology, strong evidence exists of a relationship between cardiovascular risk factors, CVD, cerebrovascular disease, and dementia.

• In 2009, the Nobel Prize in Physiology or Medicine was awarded to Blackburn, Greider, and Szostak for their discovery of how chromosomes are protected by telomeres and the enzyme telomerase during DNA replication.

• The shortening of telomere length and subsequent vulnerability or senescence probably explains part of the molecular process of ageing.

• The documented association between ageing and various cardiovascular risk factors, particularly obesity, lack of exercise, and cigarette smoking are associated with oxidative stress, which can contribute to telomere shortening .

Prediction

•However, modifiable social and behavioural factors will increase survival and quality of life among older people only when achieved early in life, preferably during childhood.

TOP- 9:Promoting cardiovascular health• CVD and associated Non-communicable diseases were

once considered a problem faced by only wealthy, industrialized nations .

• Ageing of populations, globalization, and rapid urbanization are changing disease patterns around the world.

• The move of major funding agencies, such as the Gates Foundation, which have traditionally been restricted to infectious diseases, to provide financial backing to tobacco-cessation programmes worldwide is a trend that I predict will grow over the next decade.

TOP10:Cell and gene therapy• The fields of cell and gene therapy for CVD have evolved over the past

few decades.

• AGENT clinical trials, Grines and colleagues infused an adenoviral construct containing the human fibroblast growth factor 4 gene (Ad5FGF 4‑ ) into the coronary arteries of patients with chronic stable angina, with the aim of stimulating angiogenesis and reducing cardiac ischaemia.

• AGENT I and AGENT II showed positive results, but the definitive phase III double-blind, placebo-controlled, randomized, studies (AGENT III and AGENT IV) were negative and, in fact, were not completed

• SERCA2a gene therapy being trialled in the CUPID studies, in which investigators have incorporated a refined gene-delivery vector (adeno-associated virus type 1) coupled with a well-validated upstream target that is central to calcium handling in cardiomyocytes.

• Three studies conducted by investigators in the NIH-sponsored

Cardiovascular Cell Therapy Research Network in the USA yielded negative findings using bone-marrow-derived mononuclear cell populations.

• Second-generation cell therapies efficacy in early-phase clinical cardiovascular studies for c kit+ cells‑ , mesenchymal stem cells, and cardiosphere-derived cells.

Prediction

• I predict the emergence of ‘third-generation’ cell therapy approaches those that involve delivering targeted biologic agents to stimulate endogenous cardiovascular stem or progenitor cell populations in situ rather than administering or injecting cells themselves .

THNANK YOU FOR YOUR ATTENTION