Congestive Heart Failure 2009 Where are we today

David M. Strasser MD FACC

October 7, 2009

Overview
DEFINITION NATURAL HISTORY EITOLOGY Medications Pharmacogenomics Stem Cell Resynchronization Devices

CHF DEFINITION
A clinical syndrome in which heart disease reduces cardiac output, increases venous pressures, and is accompanied by molecular abnormalities that cause progressive deterioration of the failing heart and premature myocardial cell death.

Outcomes of Acutely Decompensated Heart Failure

Median length of hospital stay: 6 days1 Hospital readmissions:
2% within 2 days1 20% at 30 days1 50% at 6 months1

Mortality:
11.6% at 30 days2 33.1% at 12 months2 50% at 5 years1
1. Aghababian RV. Rev Cardiovasc Med. 2006;3(suppl 4):S3S9. 2. Jong P et al. Arch Intern Med. 2002;162:16891694.

ACC/AHA CHF GUIDELINES 2009 Stage

Patient Description
HTN CAD DM
Family hx cardiomyopathy

A B C D

High risk for developing HF Asymptomatic HF Symptomatic HF

Previous MI LVSD Asymptomatic valvular disease Known structural heart disease SOB and fatigue Reduced exercise tolerance Marked symptoms at rest despite maximal therapy

Refractory endstage HF

Evolution in Concept of CHF Pathophysiology

1990s focus on long-term structural alterations of the myocardium and vasculature and the effects of various mediators Concept of left ventricular damage leads to remodeling the change in LV geometry such that it dilates, hypertrophies, and becomes more spherical Various neurohormonal factors are now thought to contribute to cardiac architecture and lead to progression of remodeling

CHF NEUROHORMONAL DISEASE

Angiotensin II

Norepinephrine

Hypertrophy, apoptosis, ischemia, arrhythmias, remodeling, fibrosis

Circulating Hormone Type Factors

Activation of RAS and SNS leads to
abnormalities in regional blood flow renal retention of sodium pulmonary congestion structural changes in heart and vasculature that mediates progression of LV remodeling

SNS activation seems early RAS activated upon symptom onset

Heart Failure Pathophysiology

Myocardial Injury Fall in LV Performance Activation of RAAS, SNS, ET, and Others

Myocardial Toxicity

ANP BNP

Peripheral Vasoconstriction Hemodynamic Alterations

Morbidity and Mortality

Remodeling and Progressive Worsening of LV Function

Heart Failure Symptoms

Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2S6.

Underlying Causes
Valvular Disease (congenital or
acquired)

Cardiomyopathies Specific heart muscle disease

infections collagen vascular disease granulomatous diseases metabolic toxins hypersensitivity physical agents genetic, neuromuscular or inherited diseases hematologic diseases fibroplastic diseases infiltrative

Hypertension Coronary artery disease High-Output Failure Syndromes Pericardial Disease Pulmonary Vascular Disease and Obliterative hypertension Incessant Intractable Tachyarrhythmia Bradycardia and Heart Block Congenital Heart Disease Cardiac Rejection in Transplant Patients Abnormal Coronary Microvasculature Trauma

Partial List of Potentially Reversible Causes of CHF and Cardiomyopathy

Alcohol Atrial myxoma Bradyarrhythmia Cardiac tramsplant rejection Carnitine deficiency Congenital heart disease Constrictive pericarditis Coronary artery disease Dilated cardiomyopathy associated with renal disease, treatable with renal transplantation High output states
anemia atrioventricular fistula Beriberi thyrotoxicosis

Hypertensive heart disease Hypertrophic cardiomyopaty Hypocalcemia Hypophosphatemia Infective endocarditis Iron overload Myocarditis Pericardial tamponade Pulmonary emboli Sardoidosis Selenium deficiency Tachyarrhythmias Thyroid disorders Toxin exposure Valvular heart disease Ventricular aneurysm

CHF DIAGNOSIS
Clinical Exam 1C Echocardiography 1C CXR 1C 12 Lead EKG 1C Basic Labs 1C BNP / Pro BNP 2a A

Medications

Angiotensin I

Angiotensin II Aldosterone ACE AT receptor inhibitor antagonist Vasopeptidase inhibitor

Kinins Spironolactone Hypertrophy Apoptosis

Vasodilator peptides

Metoprolol

Carvedilol

1-receptor blockade -receptor suppression Endothelin suppression Antioxidant effects a1- and 2-receptor blockade

Sympathic antagonism

Core Measure Metrics Heart Failure

Rate Of ACE-I / ARB Use for LVSD Aug 2009 CYTD 2009 Joint Comm 2008 Best Practice 92.9% 96.3% 89.3% 92.6%

Pharmacogenomics
The development of a single drug costs an average of $500 million Only 30 percent of approved drugs even recover these costs Pharmaceutical industry is under growing pressure to streamline and optimize the identification of novel therapeutics. In addressing this need, pharmacogenomic profiling has the potential not only to increase the efficiency and speed with which new medicines are developed, but also to improve diagnostics for drugs already in the market. As a result, there is a growing awareness among pharmaceutical and biotechnology companies about the benefits of using pharmacogenomics in the selection of compounds with a favorable safety and efficacy profile.

Pharmacogenomics
Over the past several years, a series of intriguing observations has arisen with regard to the role genetic variations (polymorphisms) in signaling pathways that contribute to disease progression in the failing heart. Investigating the idea that small variations in the human genome may determine how well a patient with heart failure responds to the standard pharmaceutical therapy. Single nucleotide polymorphisms involved in pharmacodynamics, pharmacokinetics or processes specific to each drug could be predictors of this response. These observations have given rise to the hope that information regarding genetic polymorphisms might be harnessed to develop personalized therapeutic strategies for patients with heart failure

Pharmacogenomics Table 1 Effect of Gene Polymorphisms on the

Pharmacological Treatment of Heart Failure
Gene Polymorphism
Arginine (Arg) to glycine (Gly) switch at codon 389 (Arg389Gly)

Functional Impact
Arg389 allele has 3x greater adenylyl cyclase activity in response to agonist than the Gly389 variant

Impact on Pharmacological Therapy

Arg389Arg genotype better tolerated during the initiation of beta-blocker and had greatest improvement in LVEF with betablockers, and improved mortality with bucindolol in BEST Ser49Ser genotype requires higher doses of diuretics during beta-blocker up-titration

ADBR1

ADBR1

Serine (Ser) to glycine (Gly) switch at codon 49 (Ser49Gly) Glycine (Gly) to arginine (Arg) switch at codon 16 (Gly16Arg) Glutamine (Gln) to glutamic acid (Glu) switch at codon 27 Deletion mutation of aa 322-325 (2CDel322-325)

Ser49 allele has decreased agonist-promoted downregulation and decreased adrenergic coupling Gly16 allele has greater agonistpromoted down-regulation

ADBR2

No reported interactions with beta-blockers

ADBR2

Glu27 allele is resistant to receptor down-regulation Loss of function mutation leading to decreased NE uptake

Glu27 homozygotes have improved LVEF with carvedilol compared with Glu27 carriers

Increased likelihood of developing HF in patients with the beta1-AR Arg389 polymorphism; effect on drug responsiveness in HF not known BEST = Beta-blocker Evaluation of Survival Trial; HF = heart failure; LVEF = left ventricular ejection fraction; NE = norepinephrine.

ADRA2C

Pharmacogenomics
A-HeFT Trial BiDil Hydralazine Nitrate African American 1000 for 18 month EF 28% Class III or greater Benefit in addition to B-Blocker 75% and Ace-I/ARB 80% 33% reduction CHF symptoms 46% reduction mortality

When you dont get the results you were hoping for.

Non-Phamacologic Therapies in the Management of HF

Cardiac resynchronization Implantable Cardioverter Defibrillator Left Ventricular Assist Devices Implantable fluid monitors Implantable hemodynamic monitors Cardiac transplantation LV reconstruction Gene therapy

Sudden Death & CHF

ELECTROPHYSIOLOGY IN CHF
BASIC THEORY: In CHF, the heart function is already impaired Any change in the electrical process usually causes a change in the mechanical function In approximately 30% CHF patients, an abnormality in the heart's electrical conducting system (called an "intraventricular conduction delay" or bundle branch block) causes the two ventricles to beat in an asynchronous fashion. That is, instead of beating simultaneously, the two ventricles beat slightly out of phase. This asynchrony greatly reduces the efficiency of the ventricles in patients with heart failure, whose hearts are already damaged. This may ultimately worsen overall cardiac functioning

Patients With Reduced Left Ventricular Ejection Fraction

I IIa IIb III

Resynchronization Therapy
Patients with LVEF less than or equal to 35%, sinus rhythm, and NYHA functional class III /IV symptoms despite recommended, optimal medical therapy and who have cardiac dyssynchrony, which is currently defined as a QRS duration greater than or equal to 0.12 seconds, should receive cardiac resynchronization therapy, with or without an ICD, unless contraindicated.
Clarified Rec

Cardiac Resynchronization Therapy

Resynchronization refers to altering this abnormal conduction to mimic the normal process Allowing synchronous contraction of both the LV and RV Pacing leads are placed in the RA, RV and the coronary sinus (LV)

Cardiac Resynchronization Therapy

Clinical Trials: PATH CHF Ventak CHF PAC MAN MIRACLE** MUSTIC VECTOR CHF MIRACLE ICD CARE HF **

AP X-ray. LV lead in mid-lateral vein.

Cardiac Resynchronization Therapy

MIRACLE: Multicenter InSync RAndomized CLinical Evaluation

Purpose:To compare the effect of CRT vs. no CRT on QOL and functional capacity in pts with CHF and ventricular dysynchrony To assess the safety of CRT using the Medtronic InSync System in pts with CHF Protocol 44 Centers /532 patients Randomized, double-blind parallel controlled study Diagnosed with CHF, NYHA class III or IV QRS 130 msec LVEF 35 No indication for ICD

6 minute hall walk

CRT: MIRACLE Trial Results

P=0.032 P=0.004 P=0.033

350 Meters
Control N=116

300

CRT N=121

250

Base1 line Month

3 Months

6 Months

CRT: MIRACLE Trial Results

Quality of Life:
Total Score

30 40 50 60 70 Baseline

P=0.020

P=0.051

P=0.013

Improvement

1 Month Control N=114

3 Months

6 Months

CRT N=121

CRT: MIRACLE Trial Results

NYHA Class
100% 80% 60%

P < 0.001
13%

27% 52%

93%
40% 20% 0%

90% 64%

Class I II III IV

32%

Baseline 6-Months

Baseline 6-Months

Chi-square test

Control (N = 117)

CRT(N = 124)

Proportion

CRT: MIRACLE Trial Results Composite Response: patient survival hospitalizations for heart failure patients own assessment of 70% P < 0.001 status 60% 63% changes in heart failure class 50%
40% 30% 20% 10% Improved No Change Worsened

38%

Echocardiographic measures:

0% Reduced systolic and diastolic volumes Increase in LV EF Reduction in severity of mitral regurgitation

Control N=132

CRT N=134

Chi-square test

Resynchronization
pharmacological therapy in patients with moderate and severe heart failure due to LV systolic dysfunction complicated by cardiac dyssynchrony.

CArdiac REsynchronization in Heart Failure Study (CARE-HF) Purpose:To assess the effect on morbidity and mortality of adding CRT to optimized Primary endpoint:

All-cause mortality or unplanned cardiovascular hospitalization. (Hospitalizations were adjudicated by a blinded end-point committee.) Enrollment period: January 2001 to March 2003 Follow-up: 18 months minimum Sample size: 813 patients

Results:
The study found that cardiac resynchronization therapy administered in combination with optimal medical therapy saves lives and reduces hospitalizations:

37% reduction in combined all-cause mortality or unplanned cardiovascular hospitalizations 36% reduction in all-cause mortality
52% reduction in unplanned cardiovascular hospitalizations CRT was found to improve cardiac function and structure, specifically CRT: Provides sustained improvement in cardiac function and structure. Improves systolic function Reduces pro-BNP levels

Other Electrical Abnormalities

Bradycardia: If patient has underlying bradycardic rhythm, overall hemodynamics affected
Pathologic Medications

Permanent pacing to allow adequate increase in heart rate for metabolic needs

Atrio-Ventricular Synchrony
Just as ventricular synchrony is important to maximize cardiac functioning, so is AV synchrony Atrial kick accounts for about 10% of cardiac output in a normal heart Can be up to 50% in a CHF heart Loss of that much output can be devastating to a CHF patient Examples of loss of AV synchrony: Complete Heart Block Also 1st and 2nd degree heart blocks Atrial arrhythmias Atrial fibrillation Atrial flutter Atrial tachycardias other supraventricular arrhythmias

Heart Failure Management: Success Demands a Team Effort

Copyright CWRU-CME 2003 All Rights Reserved

CHF CARE A Team Approach (inpatient and outpatient setting)

Generalists Specialists Palliative Care/Hospice Social Work Nursing Patient Education/Support Group

CHF CLINIC 2008

NON CHF CLINIC Pts VS HF CLINIC Pts LOS 4.56 Days vs 3.82 Days 30 day readmission rate for CHF 6% vs 2% All cause 30 day readmission rate 20% vs 11%

Advance Therapies When you need a little extra help.

Stem Cell

Stem Cell

Stem Cell

Stem Cell
Transcoronary Transplantation of Progenitor Cells After Myocardial Infarction
Citation: N Engl J Med. 2006;355:1222-1232. Clinical Trial: yes Does intracoronary infusion of progenitor cells into the infarct-related artery at least 3 months after myocardial infarction (MI) improve global and regional left ventricular (LV) function? The TOPCARE-CHD (Transplantation of Progenitor Cells and Recovery of LV Function in Patients With Chronic Ischemic Heart Disease) randomized controlled crossover study 75 patients with stable ischemic heart disease who had an MI at least 3 months previously received either no cell infusion (23 patients) or infusion of circulating blood (CPC) (24 patients) or bone marrow cell (BMC) (28 patients) into the patent coronary artery supplying the most dyskinetic LV area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3-month follow-up. The primary endpoint of the study was the absolute change in global LV ejection fraction (LVEF), as measured by quantitative LV angiography 3 months after cell infusion.

Stem Cell
The TOPCARE-CHD Results: The absolute change in LVEF was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (-0.4 percentage point, p = 0.003) or no infusion (-1.2 percentage point, p < 0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of BMC. The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional LV function, regardless of whether patients crossed over from control to BMC or from CPC to BMC. Conclusions: The authors concluded that transplantation of BMC is associated with moderate but significant improvement in the LVEF after 3 months.

Stem Cell
The TOPCARE-CHD Perspective: This study demonstrates that infusion of BMC into the infarct-related artery is associated with moderate but significant improvements in both global and regional LV contractile function in patients with chronic ischemic heart disease who had an MI at least 3 months previously. It is unclear why BMC had a better effect than progenitor cells, and moreover, the benefit observed with the BMC was modest, with an increase in EF of 2.9%. The study performed by the REPAIR-AMI group showed similar positive results, in contrast to the lack of benefit in the ASTAMI trial. This small pilot study needs to be replicated in larger cohorts in other centers. In the future, the inclusion of heart failure patients with LV assist devices as a bridge to transplantation may provide a unique opportunity to examine cellular and molecular mechanisms through analyses of cardiac tissue acquired before and after BMC infusion.

Patients With Refractory End-Stage Heart Failure (Stage D)

Severe Symptoms in Patients With Refractory End-Stage HF
I IIa IIb III

I IIa IIb III

Options for end-of-life care should be discussed with the patient and family when severe symptoms in patients with refractory end-stage HF persist despite application of all recommended therapies. NO CHANGE Patients with refractory end-stage HF and implantable defibrillators should receive information about the option to inactivate defibrillation. NO CHANGE Consideration of an left ventricular assist device as permanent or destination therapy is reasonable in highly selected patients with refractory end-stage HF and an estimated 1-year mortality over 50% with medical therapy. NO CHANGE

I IIa IIb III

LV Assist Devices
The use of mechanical support of the circulation with ventricular assist devices for refractory heart failure is increasing. This is due to expanding indications, including for acute heart failure and shock, and the development of a number of new types and designs, both for temporary and more long-term support

LV Assist Devices
The major application of VADs has been for longterm support (typically for months and even years) as a so-called Bridge to Transplant (BTT) until a donor heart becomes available. Until recently, the most commonly used devices were those that used a pulsatile, volume displacement design. They were very effective for short duration of support, but they had suboptimal durability due to failure of the multiple moving parts, including prosthetic valves or bearings. Their use for longer periods in patients who were not transplant candidates demonstrated the durability problem, with over 50% of pumps requiring replacement by 18 months of support.

LV Assist Devices

Pulsatile volume displacement pumps have evolved to continuous flow pumps, a whole new type of design for the long-term pumps.

LV Assist Devices
Available for acute cardiogenic shock Placed percutaneously in the cath lab by interventional cardiologists or surgically implanted via a sternotomy. Temporary devices are designed to provide only a few days of support, but can allow 1) an adequate assessment of recovery of native cardiac function followed by discontinuation, or 2) stabilization and recovery from shock to allow the placement of devices suited for long-term support, typically for support to a heart transplant. The advantages of the percutaneous devices include speed of implant and no requirement for surgery, while the surgical devices provide more blood flow and likely more rapid recovery of organ function from shock. The comparative maximum flow ranges from 2.5 to 3.5 liters with the percutaneous devices and 5 to 6 liters with the surgically implanted temporary devices.

LV Assist Devices
The newest rotary pump is the Heartware HVAD This device is unique in that it is smaller than other continuous flow pumps, but more importantly, the pump is placed totally within the pericardium and therefore does not require a surgically created pocket. This feature should reduce the long-term complication of late pump pocket infection. The pericardium also serves to keep the canula within the LV cavity in a stable and fixed location. This pump is now in clinical trials in the US

LV Assist Devices
Other advantages of the new second generation of continuous flow design LVADs is that they operate silently, unlike the bellows sound of the pulsatile pumps. The also have only one moving part, the rotor, which provides a tremendous improvement in projected durability, now estimated at 5 to 10 years without replacement. Poor durability is a major cause of morbidity and mortality with VADs, and this improvement is one of the important contributions to the longer-term outcomes now being reported. The results of the Heartmate II DT trial will be available at the AHA meeting in November, and will confirm the durability at the study end point of two years of support.

LV Assist Devices
There are several new devices, such as the Circulite pump that employ unique design, including one that is very small in size and placed by local surgical incision much like a pacemaker pocket. It is designed to only provide 2 to 2.5 liters of flow and is for use in patients before their disease advances and they require higher levels of flow and support.

THE END THANK YOU!