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Advances in the Treatment of Heart Failure

By W. David Hager, M.D., Marybeth Barry, A.P.R.N., and Laura Kearney, R.N.

Clinical trials involving patients with severe heart failure defined by marked reductions in the left ventricular ejection fraction have been underway for a number of years in the Pat and Jim Calhoun Cardiology Center at UConn Health. Here and at other hospitals, these trials have led to the development of Heart Failure Centers which have become widely recognized for their value in helping patients with significant congestion stay out of the hospital.

We have worked with clinical protocols in heart failure since the 1980’s, and during this time many of the currently recognized therapies for chronic heart failure have been defined. Appreciation has grown for the importance of the rennin-angiotensin-aldosterone system and the sympathetic nervous system in promoting a remodeling of the left ventricle. The pharmacologic blockade of these systems has lowered mortality and improved lifestyle for many patients. More recently, the value of biventricular pacing and protection against sudden death with internal cardiodefibrillators (ICDs) has been defined, increasing their benefit to the growing population of patients with heart failure.

Today there are over 4.5 million Americans with heart failure and 550,000 new cases each year. As a result of factors like success in aging, progress in managing ischemic heart disease, cholesterol, and hypertension, and the noted variety of pharmacologic and surgical therapies and devices available for the management of patients with heart failure, there is a continually growing population of patients who need therapy.

Careful surveys of heart failure populations have revealed that 30 to 40% of patients do not have depressed left ventricular function. Rather, these patients have normal systolic function but symptomatic profiles very similar to those patients with low ejection fractions. The terms diastolic heart failure or heart failure with preserved systolic function have been used to define this population. Much less is known about this group of patients. The population is heterogeneous and, as a result, progress in defining specific therapy has been slower. The symptom of shortness of breath is central to patients with both systolic and diastolic heart failure. There are characteristics which can differentiate the two populations, but the central factor characterizing diastolic failure is a preserved ejection fraction.

Because the acute presentation of heart failure with abnormal or preserved systolic function can be identical, it is important to determine whether a patient who is short of breath is suffering from primarily systolic dysfunction or has preserved systolic function with diastolic abnormalities. The table below defines some of these characteristics and the initial approach to these two heart failure populations.

Presentation, Characteristics, and Initial Treatment of Systolic and Diastolic Heart Failure

 
Dyspnea

Marked shortness of breath

Pulmonary edema

Elevated BNP

Biventricular congestion

Peripheral edema

Congested on chest X-ray

 
Systolic Failure

Often <65 years

Frequently a prior MI

More likely ETOH use

Unlikely hypertensive when congested

More likely LBBB or IVCD

Often an S3

Often cardiomegaly

 
Diastolic Failure

Usually >70 and often >80

More often women

Frequent history of hypertension

Frequently hypertensive when congested

More often LVH on electrocardiogram

More likely an S4

Heart size not enlarged

 
Initial Treatment

Diuretics and relief of anxiety

Define left ventricular systolic function (echocardiogram, nuclear angiogram, or left ventricular angiogram)

 

When studied hemodynamically, most patients with diastolic dysfunction have normal sized left ventricles and elevated left ventricular diastolic pressures (LVEDP) at rest when congestion is not present. This is a marker of increased stiffness. More refined hemodynamics indicate that left ventricular relaxation is slowed. Because of these changes, these patients have an inability to increase left ventricular end diastolic volume (LVEDV) without a great increase in end diastolic pressures. This inability to use the Frank-Starling mechanism of increasing LVEDV limits exercise since any increased volume markedly increases LVEDP and clinical dyspnea.

Hence a vicious cycle develops since the increased left ventricular pressure results in shortness of breath. This generates anxiety, increased sympathetic tone, an increased heart rate and possibly an arrhythmia such as atrial fibrillation. Ischemia secondary to coronary stenosis impairs relaxation further and increases LVEDP. Hypertension intensifies the impaired diastole further by enhancing concentric hypertrophy, a myocardium which is strong, but stiff. The inability to increase LVEDV compromises the ability to increase cardiac output, which, in turn, also stimulates the sympathetic and rennin angiotensin-aldosterone systems leading to volume retention and a further increase in LVEDP.

illustration showing high LVEDP = Clinical Dyspnea

While less is known about the best treatment of heart failure with preserved systolic function, several approaches are suggested by the above figure. Relieving ischemia, treating atherosclerosis, and correcting renal artery stenosis are most helpful. In addition, efforts to keep patients dry, maintain a slow sinus rhythm, and control blood pressure provide a basic approach to diastolic dysfunction.

The role of the sympathetic and renin-angiotensin-aldosterone systems in treating impaired diastole is under evaluation in several large clinical trials. Unlike the multiple studies which have shown the benefit of pharmacologic therapies for systolic failure, few data exist on the best therapy for diastolic dysfunction. Nevertheless, the role of norepinephrine, angiotensin and aldosterone in promoting myocardial fibrosis, interstitial collagen and matrix changes, and endothelial dysfunction must be important to the development of the stiffened, noncompliant left ventricle and blood vessels.

In the CHARM trial (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity), candesartan was found to be useful in reducing hospitalizations in heart failure patients with preserved systolic function. We are participating in the I-RESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) study. This is a multicenter randomized placebo controlled trial evaluating the impact of another angiotensin receptor blocker on mortality and hospitalizations in patients with diastolic dysfunction.

The recognition of diastolic dysfunction is increasing, but a great deal of work remains in defining the best approach to therapy. The frequency with which the symptom of breathlessness occurs in the aging population is considerable. Since multiple disease processes can lead to the end result of a noncompliant left ventricle, it is likely that multiple approaches to treatment will need definition so that therapy can be tailored to individual patients.