Coronary artery disease is now recognized as the major etiologic factor in the development of heart failure in the United States and other developed nations. As the techniques used for percutaneous and surgical revascularization continue to be refined, the ability to protect myocardium from ischemia and/or infarction can only be expected to improve. The realization of very short “door to open vessel” times for acute myocardial infarction (MI) in most metropolitan areas has resulted in substantial myocardial salvage that will, by inference, reduce progressive left ventricular (LV) dysfunction and the development of heart failure. For those with chronic ischemic disease that is not amenable to coronary revascularization, an intriguing possibility is the potential for delivery of growth factors such as vascular endothelium growth factor (VEGF) or basic fibroblast growth factor (bFGF) to jeopardized areas of myocardium. Preliminary studies have indicated that growth factors can promote capillary growth to these areas from other, not critically stenosed, vessels (1,2). A randomized clinical trial directly injecting plasmid DNA for VEGF2 (pVGI.1) into ischemic myocardium (catheter technique) in patients with refractory angina is currently under way. Whether this or similar techniques ultimately produce adequate neovascularization and whether neovascularization ultimately prevents myocardial dysfunction are both critical issues that need to be resolved.

In view of the ongoing heart failure pandemic, treatment of risk factors for coronary artery disease should be a high priority for the health care system over the next decade. The power of preventive measures was made very apparent by the results of the Scandinavian Simvastatin Survival Study (4S) trial in which the use of the HMG-CoA reductase inhibitor simviastatin not only improved survival but also significantly reduced the future risk of developing heart failure (3). Another potentially fertile area is in the treatment of hypertension. Not only is this condition widespread in the United States, but it is estimated that only approximately one in four hypertensive patients is receiving adequate therapy. When hypertension is treated, the impact on preventing heart failure is substantial. In the Systolic Hypertension in the Elderly Program (SHEP), treatment of elderly patients with systolic hypertension resulted in a 49% reduction in the likelihood of developing heart failure (4).

Additional targets that demand increased attention include diabetes and obesity. Both of these conditions are
increasing in prevalence at alarming rates and both are important risk factors for heart failure. Parenthetically, the lack of success in treating risk factors and preventing heart failure is somewhat surprising, even given the “crazy quilt” of health care systems that have evolved in the United States. It will take a concerted and sustained effort by numerous concerned parties, including the government, pharmaceutical companies, consumer and physician groups, and enlightened health maintenance organizations, to bring about change in this area. If risk factor management can be improved, however, it will have a substantial effect on the incidence of heart failure and its clinical sequelae.

The syndrome of heart failure is a continuum in which some injurious process activates a coordinated series of structural and functional changes that result in cardiac remodeling. Neurohormones such as angiotensin II, norepinephrine, aldosterone, proinflammatory cytokines, and other mediators are believed to play important roles in this process. There is evidence that early initiation of neurohormonal blockers can be used to successfully inhibit remodeling and help avert progression to heart failure. The successful use of angiotensin-converting enzyme inhibitors (ACEIs) in the post-MI population and in asymptomatic patients with LV dysfunction in the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial provided the initial proof of principle for this approach (5,6,7). Further evidence has become available with the use of beta-blocking drugs in the Carvedilol Post-Infarct Survival Control In LV Dysfunction (CAPRICORN) study (8).

What is needed, however, is a means of reliably and inexpensively screening a population at risk for early indicators of cardiac dysfunction. Some evidence suggests that the family of natriuretic peptides (i.e., atrial and B-type natriuretic peptides [ANP and BMP, respectively]) that are released from the heart in response to stretch may be useful to detect evidence of incipient heart failure (9). If this proves to be the case, one could envision screening populations at risk (e.g., elderly patients with one or more cardiac risk factors) with a blood test to help select patients for early initiation of neurohormonal blockade.

Using modern techniques of linkage analysis, investigators have uncovered genetic mutations that result in a number of inherited cardiovascular diseases, including hypertrophic cardiomyopathy. A genetic basis for dilated cardiomyopathy was felt to be rare, with perhaps 1% to 2% of cases being familial. More recently, two reports suggest that a familial component is present in 35% to 48% of cases if LV enlargement is included as a clinical indicator for association (10,11). To date, 16 autosomal genes, two major x-linked gene families (dystrophin and tafazzin), and one family with a troponin I defect have been described (12). Progress in understanding these point mutations and specifically how they lead to dilated cardiomyopathy should help reveal intracellular pathways and mechanisms that give rise to the heart failure phenotype.

Alternatively, in many and probably most cases, the development of heart failure is not caused by a monogenic disorder. Rather, progressive changes in response to injury lead to structural and functional changes that are the cause of heart failure First, what is the injury, and second, what are the modifiers to that injury? Recent studies have again raised the possibility that viruses are a likely cause of initial injury. In one study, viral genomes were present in biopsy samples of more than 60% of patients with dilated cardiomyopathy (13). In another study, parvovirus B19 was a commonly detected viral pathogen (14).

The likelihood and rapidity of the development of heart failure, as previously suggested, appear to vary greatly among patients, suggesting that there may be genetic modifiers of the rate of progression (15). Polymorphisms in genes encoding receptors, enzymes, as well as structural and contractile proteins could be responsible for these differences among patients. One of the first of these polymorphisms to be recognized as a gene that could affect the progression of heart failure in susceptible populations was the polymorphism in the ACE gene (16). Whether or not individuals homozygous for the deletion mutation and who express higher levels of ACE activity are at increased risk of developing the heart failure phenotype or developing more severe disease, however, is uncertain. Although polymorphisms in a great many other genes could potentially alter the likelihood of development and rate of progression of cardiac dysfunction, reports in the literature have been inconsistent, with some surveys concluding that there is increased risk with a particular polymorphism while others report the absence of any increased risk. Clearly, this is a area that will require increased attention in the future.

Over the past 5 years we have laid to rest the controversy of mortality associated with invasive hemodynamic monitoring and can be assured that we are not committing medical homicide by placement of a Swan-Ganz catheter (17). On the other hand, based on the results of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial (17), we are not so sure that we are helping patients when we employ this strategy for directing management of heart failure. Although we have been clearly seduced by a blood test that diagnoses heart failure (BNP) and are ready to embrace its use to follow heart failure therapy (18), the effectiveness of this test in altering long-term outcomes remains uncertain. The use of this diagnostic test would appear to have the greatest value in the emergency room setting, particularly when there is uncertainty about the interpretation of the signs and symptoms that motivated the patient to seek urgent medical attention.