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Heart Failure as a Consequence of Ischemic Heart Disease
Despite significant progress in the prevention and treatment of cardiovascular disease over the past 30 years, national statistics indicate that the incidence and prevalence of heart failure (HF) continue to rise. This has occurred during a time period in which death rates from coronary artery disease (CAD) and stroke have declined. HF and CAD are both age-related conditions (the prevalence of HF is 1% between the ages of 50 and 59 years, but 10% above the age of 75 years). The increased survival after myocardial infarction (MI) and advances in medical and device therapies (e.g., β-blockers and implantable cardioverter-defibrillators [ICDs]) for the prevention of sudden cardiac death (SCD) have increased the pool of patients with both CAD and HF.
Prevalence of Coronary Artery Disease in Heart Failure
CAD has emerged as a dominant causal factor in HF ( see also Chapter 18 ). Survivors of acute MI, even when not complicated by HF, have a relatively high incidence of subsequent HF hospitalization. This is due not only to the initial ventricular insult caused by the MI but also the progressive nature of CAD ( Fig. 19.1 ). The Framingham Heart Study suggests that the factors contributing to HF are changing, as evidenced by a decrease in valvular heart disease and left ventricular (LV) hypertrophy but an increase in MI as a risk factor from 1950 to 1998. In this analysis, the odds of a prior MI as a cause of HF increased by 26% per decade in men and 48% per decade in women. In contrast, hypertension as a cause of HF decreased by 13% per decade in men and 25% in women, and valvular heart disease as a cause of HF decreased by 24% per decade in men and 17% in women.
In the Studies of Left Ventricular Dysfunction (SOLVD) registry, which enrolled 6273 patients, CAD was determined as the underlying cause of chronic HF in approximately 70% of patients, whereas hypertension was invoked as the primary cause in only 7% of cases. Of note, there was a history of hypertension in 43% of patients. There were striking racial differences observed in this registry. HF was considered due to CAD in 73% of white patients but only 36% of African-American patients ( see also Chapter 40 ).
Pooling data from 26 multicenter trials of chronic HF since 1986, with greater than 43,000 patients, revealed that 62% carried a diagnosis of CAD ( Table 19.1 ). This number may actually underestimate the true prevalence of CAD in this population because in clinical practice and in most studies there is no systemic assessment of coronary artery anatomy. In addition, most of these trials excluded patients with a recent MI, angina, or objective evidence of active ischemia. In a study of 136 patients (<75 years old) hospitalized with de novo HF, a review of the clinical, angiographic, and myocardial perfusion imaging data was used to determine that CAD was the primary cause in greater than 50% of cases. In this study alone, two-thirds of all patients who underwent angiography had obstructive CAD (defined as >50% luminal stenosis), although CAD was not considered the primary causal factor in all cases. In a recent analysis of a large US acute HF registry, myocardial ischemia was found to be a leading precipitating factor for hospitalization.
TABLE 19.1
Prevalence of Coronary Artery Disease in 26 Multicenter Chronic Heart Failure Trials Reported by the New England Journal of Medicine Since 1986
CAD , Coronary artery disease.
| Trial | Year | N | CAD |
|---|---|---|---|
| VHEFT-1 | 1986 | 642 | 282 |
| CONSENSUS | 1987 | 253 | 146 |
| Milrinone | 1989 | 230 | 115 |
| PROMISE | 1991 | 1088 | 590 |
| SOLVD-T | 1991 | 2569 | 1828 |
| VHEFT-2 | 1991 | 804 | 427 |
| SOVLD-P | 1992 | 4228 | 3518 |
| RADIANCE | 1993 | 178 | 107 |
| Vesnarinone | 1993 | 477 | 249 |
| STAT-CHF | 1995 | 674 | 481 |
| Carvedilol | 1996 | 1094 | 521 |
| PRAISE | 1996 | 1153 | 732 |
| DIG | 1997 | 6800 | 4793 |
| VEST | 1998 | 3833 | 2236 |
| RALES | 1999 | 1663 | 907 |
| DIAMOND | 1999 | 1518 | 1017 |
| Nesiritide | 2000 | 127 | 58 |
| COPERNICUS | 2001 | 2289 | 1534 |
| BEST | 2001 | 2708 | 1587 |
| Val-HeFT | 2001 | 5010 | 2880 |
| MIRACLE | 2002 | 453 | 108 |
| COMPANION | 2004 | 1520 | 842 |
| SCD-HeFT | 2005 | 2521 | 1310 |
| CARE-HF | 2005 | 813 | 309 |
| RethinQ | 2007 | 172 | 90 |
| Dronedarone | 2008 | 627 | 407 |
| Total | 43,444 | 27,074 |
CAD was documented to be present in nearly 65% of patients.
Prognostic Significance of Coronary Artery Disease in Heart Failure
The presence of CAD in patients with HF has been shown to be independently associated with a worsened long-term outcome in numerous studies. Atherosclerosis is an important contributing cause of death in HF patients through a variety of mechanisms, including SCD, progressive ventricular failure, MI, renal failure, and stroke. In patients with HF, the long-term prognosis is directly related to the angiographic extent and severity of CAD. This has been demonstrated both in HF patients with LV systolic dysfunction and in those with preserved systolic function.
Recent data suggest that the mechanism of SCD may differ between ischemic and nonischemic HF, with acute coronary events representing the major cause of SCD in patients with CAD. In the Assessment of Treatment with Lisinopril and Survival (ATLAS) study, 54% of patients with chronic HF and CAD who died suddenly had autopsy evidence of acute MI. In another autopsy study of 180 patients with known ischemic cardiomyopathy, acute MI was responsible for 57% of the deaths. This study revealed that before autopsy data were available, many deaths as a result of acute MI in patients with HF were misclassified as caused by progressive HF or arrhythmias. In another study of patients with HF and left ventricular systolic dysfunction (LVSD) 25% of repeat hospitalizations were attributed to acute coronary syndrome (ACS). However, approximately 10% of patients with a history of HF who were subsequently hospitalized for ACS were originally classified as having a nonischemic cause. These findings further emphasize the importance of accurately assessing for the presence of CAD in patients with HF.
Pathophysiology of Acute Heart Failure in Patients With Coronary Artery Disease
Underlying Coronary Artery Disease
Patients hospitalized with acute HF differ from patients with chronic ambulatory HF with respect to prognosis and early management ( see also Chapter 36 ). Patients with CAD who develop acute HF do so with either an ACS or a non-ACS presentation. Although the majority of such patients do not have ACS, there is considerable overlap in these two presentations with respect to clinical characteristics ( Table 19.2 ) and potential therapies ( Table 19.3 ). However, the approach to the patient with ACS has become more standardized in clinical practice guidelines compared with the acute HF patient with a non-ACS presentation. Myocardial injury is common in both, but in ACS patients it is usually the principal cause of HF, whereas in non-ACS patients myocardial injury may be the result of worsening HF. In these latter patients, cardiac troponin levels are frequently elevated in patients with acute HF, representing myocardial injury ( see also Chapter 33 ). In the era of high-sensitivity troponin assays, the values of troponin in AHF patients often surpass the acute MI threshold (i.e., the 99th upper reference limit [URL]) and may demonstrate a typical rise and fall. Such events have been classified as “acute myocardial injury” rather than type II myocardial infraction in the new fourth universal definition of MI, although this is primarily a semantic distinction. Regardless, these acute elevations of troponin in HF are a marker of worse outcomes.
TABLE 19.2
Characteristics of Patients With Acute Heart Failure Syndrome and Coronary Artery Disease Versus Patients With Acute Coronary Syndrome Complicated by Heart Failure
| AHFS and CAD | ACS Complicated by HF | |
|---|---|---|
| Dyspnea | Common | Common |
| Chest discomfort | Uncommon | Common |
| Prior HF | Common | Uncommon |
| BNP/N-terminal pro-BNP | Elevated | Elevated |
| Troponin | Normal or elevated a | Usually elevated |
| Left ventricular systolic function | Normal or depressed | Normal or depressed |
| Diagnostic testing for CAD b (ischemia/viability/angiography) | Uncommon | Standard (per guidelines) |
| Myocardial revascularization | Uncommon b | Standard (per guidelines) |
| Secondary prevention for CAD | Underused | Standard (per guidelines) |
| In-hospital mortality | Relatively low | Relatively high |
| Early after-discharge death or rehospitalization | High | High |
ACS, Acute coronary syndrome; AHFS, acute heart failure syndrome; BNP, B-type natriuretic peptide; CAD, coronary artery disease; HF, heart failure.
TABLE 19.3
Therapies for Acute Heart Failure Syndrome and Coronary Artery Disease Versus Acute Coronary Syndrome Complicated by Heart Failure
From Flaherty JD, Bax JJ, De Luca L, et al. Acute heart failure syndromes in patients with coronary artery disease early assessment and treatment. J Am Coll Cardiol . 53:254−263, 2009.
| AHFS and CAD | ACS Complicated by HF | |
|---|---|---|
| Immediate Therapies | ||
| Nitrates | Yes | Yes |
| Antiplatelet agents | Yes | Yes |
| Anticoagulation | No | Yes |
| Inotropes | Avoid if possible | Avoid if possible |
| Statins | Yes | Yes |
| Renin-Angiotensin System Modulation | ||
| ACE-I or ARB | Yes | Yes |
| Aldosterone blockade (if LVSD) | Yes | Yes |
| β-blockers | Yes | Yes |
| Early angiography/revascularization | Yes a | Yes a |
ACE-I, Angiotensin-converting enzyme inhibitor; ACS, Acute coronary syndrome; AHFS, acute heart failure syndrome; ARB, angiotensin receptor blocker; CAD, coronary artery disease; HF, heart failure; LVSD, left ventricular systolic dysfunction.
a If jeopardized myocardium present (ischemia or viability).
In acute HF, a high LV diastolic pressure can result in subendocardial ischemia (even in the absence of epicardial coronary disease). Experimental evidence suggests that troponin release is correlated with both LV loading conditions and microvascular dysfunction. Excessive neurohormonal activation can exacerbate ischemia via increased cardiac contractility and reduced coronary perfusion because of endothelial dysfunction. In addition, patients with acute HF and CAD often have hibernating or stunned myocardium. Together, all of these factors may result in myocardial injury.
Low systemic blood pressure combined with elevated LV diastolic pressure reduces coronary perfusion, and in this setting, the autoregulation between coronary artery perfusion pressure and coronary vasoactive tone may be lost or impaired in patients with obstructive epicardial CAD. This may contribute to myocardial injury (as reflected by cardiac enzyme elevation) and worse outcomes. This may help to explain why patients with acute HF and underlying CAD have a worse outcome than those without CAD and have improved outcomes if they have a history of myocardial revascularization.
Acute Coronary Syndromes
Approximately 10% to 20% of patients with ACS have concomitant acute HF, and approximately 10% of ACS patients develop HF in-hospital. In the EuroHeart Survey II on HF, 42% of all de novo HF cases were due to ACS. Patients with ACS and ST-segment elevation typically have a high degree of myocardial injury. ACS patients with HF but without ST-segment elevation also have significant cardiac enzyme elevation but a smaller degree of injury. The short-term risk of adverse outcomes in ACS patients with HF is directly proportional to the level of troponin elevation. Most of these patients do not have a history of HF or LVSD.
Patients with ACS complicated by HF have markedly increased short- and long-term mortality rates compared with ACS patients without HF. ACS patients who develop HF after the initial presentation have even higher mortality rates. The prognosis of ACS complicated by HF is directly related to the Killip class. Compared with Killip class I patients, patients with an ACS in Killip class II or III HF are four times more likely to die in-hospital. The risk goes up to 10-fold for patients with cardiogenic shock (Killip class IV). Among ACS patients who recover from transient HF, the majority develop recurrent HF.
Pathophysiology of Chronic Heart Failure in Patients With Coronary Artery Disease and Reduced Ejection Fraction
HF in the setting of CAD is a heterogeneous condition with several possible factors contributing to clinical manifestations of HF and LVSD and/or diastolic dysfunction. First and foremost, the sequelae of MI, with loss of functioning myocytes, development of myocardial fibrosis, and subsequent LV remodeling, result in chamber dilation and neurohormonal activation that lead to progressive deterioration of the remaining viable myocardium. This is a well-recognized clinical process that can be ameliorated after acute MI by the use of angiotensin-converting enzyme (ACE) inhibitor therapy, beat-blocking agents, mineralocorticoid receptors, and myocardial revascularization. Second, the majority of patients surviving MI have significant atherosclerotic disease in coronary arteries other than the infarct-related artery. Thus superimposed on the LV with irreversibly damaged myocardium, there is often a considerable degree of jeopardized myocardium served by a stenotic coronary artery either within the infarct zone or remote from the infarcted tissue. This may result in myocardial ischemia/hibernation, contributing to LV dysfunction and the risk of recurrent MI producing further deterioration in LV function or SCD. Finally, endothelial dysfunction, a characteristic feature of atherosclerotic CAD, may also contribute importantly and independently to the progression of LV dysfunction ( Fig. 19.2 ).
Left Ventricular Remodeling (see also Chapter 12 )
LV remodeling is the process by which the LV’s size, shape, and function are altered in response to acute injury and/or hemodynamic overload. As reviewed in detail in Chapter 12 , LV remodeling occurs secondary to mechanical, neurohormonal, and genetic factors ( Fig. 19.3 ). The severe loss of myocardial cells after acute MI results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarct zone, the infarct border zone, and the remote noninfarcted myocardium. Myocyte necrosis initiates a process of reparative changes, which consist of dilation, hypertrophy, and the formation of a collagen scar. Other factors may influence this process, including the location and transmurality of the infarct, the extent of myocardial stunning beyond the initial infarction, infarct-related artery patency, and local trophic factors. Postinfarction remodeling has been arbitrarily divided into an early phase (within 72 hours) and a late phase (beyond 72 hours). In patients with transmural MI, the early phase involves expansion of the infarct, with thinning and bulging that may result in ventricular rupture, aneurysm, mitral insufficiency, and ventricular tachyarrhythmias. Late remodeling involves the LV globally and is associated morphologically with dilation, hypertrophy, and myocyte hypertrophy (see Fig. 19.3 ). Importantly, LV remodeling creates a de novo mechanical burden for the heart and can integrated processes contribute independently to the progression of HF.
Myocardial Ischemia
Under basal conditions, episodes of reversible myocardial ischemia caused by a severe coronary artery stenosis superimposed on the LV with depressed systolic function may produce transient worsening of LV function. This exacerbates dyspnea on exertion and fatigue. In many patients, these HF symptoms, stimulated by exercise, represent an anginal equivalent that may occur in the absence of chest pain.
Transient LV dysfunction can aggravate symptoms during stress or spontaneous ischemia in patients with CAD and HF. Ischemia can also produce a rapid and massive increase in the concentration of all three endogenous catecholamines (norepinephrine, epinephrine, dopamine) in the myocardial interstitium, which is mediated by inhibition of neuronal reuptake mechanisms. High myocardial catecholamine concentration may have a deleterious effect on cardiac myocytes.
Ischemia may also lead to myocyte apoptosis, which may result in progression of LV dysfunction without a clear ischemic event. This situation also indicates that ischemia from a chronic stenosis can produce substantial myocyte loss in the absence of significant necrosis or fibrosis. Ischemia may also cause an increase in endothelin production that may have a negative effect on LV function. Aggressive medical and surgical interventions designed to ameliorate ischemia appear to have a substantial impact on limiting apoptosis.
Hibernation/Stunning
Episodes of transient myocardial ischemia may cause prolonged LVSD that persists after the ischemic insult itself has resolved. This process is termed stunning, which is similar to more severe and protracted myocardial stunning that results from coronary occlusion and reperfusion ( Fig. 19.4A ). Recurrent episodes of myocardial ischemia that produce repetitive myocardial stunning may contribute to overall LV dysfunction and HF symptoms.
Another important mechanism for systolic dysfunction with additive effects on LV performance is myocardial hibernation. Once considered a process in which myocardial contraction is downregulated in response to chronic reduction in myocardial blood supply, the current evidence supports the hypothesis that persistent contractile dysfunction in patients with chronic CAD represents a process of programmed disassembly of contractile elements following repeated episodes of reversible ischemia (see Fig. 19.4B ). Thus rather than a “protective” mechanism, hibernation represents a disadvantageous process that, left uncorrected, may lead to apoptosis and myocyte loss, replacement fibrosis, graded and reciprocal changes in alpha- and beat-adrenergic receptor density, progressive LVSD, and the risk of ventricular arrhythmias ( Fig. 19.5 ). This process may affect a substantial number of HF patients. Among patients with HF, CAD, and LVSD, approximately 50% have evidence of viable but dysfunctional myocardium.
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