Profiles in Cardiomyopathy and Heart Failure
James C. Fang
Barry A. Borlaug
Heart failure (HF) is a chronic progressive condition that arises when the heart cannot provide adequate cardiac output to meet the systemic metabolic demands or cannot accommo-date the venous return without elevation of filling pressure. Thus, HF is a clinical syndrome that can be produced by a number of processes. Examples include any primary insult to the myocardium: infarction, chronic volume or pressure over-load, or a frank disorder of the heart muscle itself—a cardiomyopathy. Cardiomyopathies are generally divided into three categories, two of which are morphologic (dilated and hypertrophic); the third one is functional (restrictive). Alternatively, some authorities have divided patients based on whether the clinical syndrome of HF occurs in a patient with reduced ejection fraction (HFrEF or “systolic” HF) or with preserved EF (HFpEF or “diastolic” HF). Other nonmyocardial processes may cause the clinical syndrome of HF, such as valvular stenosis or pericardial disease, and these are reviewed elsewhere.
Heart failure occurs in part owing to the adverse effects of ongoing neurohormonal activation. There is a fairly good correlation between clinical manifestations and the hemodynamic profile. The most recent classification system emphasizes the progression of hemodynamic and neurohormonal stages rather than symptomatic status (which may wax and wane over time) as traditionally embodied by the New York Heart Association (NYHA) classification. Patients thus evolve from being at risk for developing heart failure (stage A), to structural heart disease (stage B), to symptomatic heart failure (stage C), and finally to medically refractory heart failure (stage D).1 Therapy is driven by both symptoms and the stage of disease and may include diuretic, vasodilator, and inotropic therapies that target the hemodynamic derangements of heart failure (low output, high resistance, elevated filling pressures) and thereby improve symptoms. Antagonism of the adrenergic and renin-angiotensin systems also helps to prevent further injury to the myocardium and thereby slow down the progression of heart failure, at least in the case of HFrEF.
Cardiac catheterization is performed in patients with heart failure for several reasons: (1) to assess etiology, (2) to define both resting and exercise hemodynamic status, and (3) to evaluate therapeutic interventions. In most patients with HF, all three goals can usually be addressed in a single procedure. The hemodynamic profile is generally characterized in the supine state, where resting and exercise conditions can be studied (see Chapter 20), although some centers prefer measurements in the upright state, especially if exercise is being used for diagnostic or prognostic purposes. After the hemodynamic assessment has been completed, angiography should be performed to define the coronary anatomy. Clinical criteria such as the presence or absence of angina are poor predictors of the presence or absence of clinically relevant coronary artery disease.2 Ventriculography should also be considered to assess systolic function, mitral regurgitation, and ventricular size and shape, although most patients will have had echocardiographic assessment prior to catheterization. If sufficient evidence of coronary artery disease is not present to explain the degree of ventricular dysfunction, an endomyocardial biopsy should be considered to help to define the etiology, especially when a specific diagnosis is suspected on clinical grounds3 (see Chapter 26).
HEART FAILURE WITH REDUCED EJECTION FRACTION
There are many potential causes of HFrEF, with the most common one in the United States being coronary artery disease (roughly two-thirds of cases), and in most circumstances
this is clinically obvious based upon medical history, electrocardiography, and echocardiogram.1 Because coronary disease is so common, and because it represents a potentially reversible cause of HF (if viable myocardium is present), cardiac catheterization including coronary angiography is recommended for most patients with new-onset HFrEF. Noninvasive assessment of ischemic heart disease is advocated by some but can be misleading with both false positives and false negatives.2 Once coronary disease has been excluded, the differential diagnosis includes the various causes of dilated cardiomyopathy (DCM; Table 43.1). The noninvasive clinical assessment may suggest a specific diagnosis such as sarcoidosis or Chagas disease, but in most instances the cause will remain undefined (i.e., idiopathic). Most cases of idiopathic cardiomyopathy likely represent the sequelae of prior myocarditis4 or genetic mutations.5 Indeed, a recent study reported that ∽25% of patients with “apparent” DCM had mutations within the titin gene.6 Only a few etiologies of DCM have pathognomonic histologic findings, but endomyocardial biopsy may be helpful in confirming or excluding those diseases. In 1230 patients who underwent endomyocardial biopsy at the Johns Hopkins Hospital (Baltimore, MD) for unexplained HFrEF, a specific cause was eventually determined in 50% of the patients using the results of the endomyocardial biopsy in combination with clinical information, although only 15% had a specific histologic diagnosis3, but using the results of the endomyocardial biopsy in combination with clinical information, a specific cause was eventually determined in 50% of the patients. In addition to coronary angiography and biopsy, ventriculography allows assessment of mitral regurgitation and dyskinesis, both of which can be targeted surgically. Ventriculography is used predominantly when other imaging techniques such as echocardiography or MRI are inadequate or inconsistent with the clinical examination.
this is clinically obvious based upon medical history, electrocardiography, and echocardiogram.1 Because coronary disease is so common, and because it represents a potentially reversible cause of HF (if viable myocardium is present), cardiac catheterization including coronary angiography is recommended for most patients with new-onset HFrEF. Noninvasive assessment of ischemic heart disease is advocated by some but can be misleading with both false positives and false negatives.2 Once coronary disease has been excluded, the differential diagnosis includes the various causes of dilated cardiomyopathy (DCM; Table 43.1). The noninvasive clinical assessment may suggest a specific diagnosis such as sarcoidosis or Chagas disease, but in most instances the cause will remain undefined (i.e., idiopathic). Most cases of idiopathic cardiomyopathy likely represent the sequelae of prior myocarditis4 or genetic mutations.5 Indeed, a recent study reported that ∽25% of patients with “apparent” DCM had mutations within the titin gene.6 Only a few etiologies of DCM have pathognomonic histologic findings, but endomyocardial biopsy may be helpful in confirming or excluding those diseases. In 1230 patients who underwent endomyocardial biopsy at the Johns Hopkins Hospital (Baltimore, MD) for unexplained HFrEF, a specific cause was eventually determined in 50% of the patients using the results of the endomyocardial biopsy in combination with clinical information, although only 15% had a specific histologic diagnosis3, but using the results of the endomyocardial biopsy in combination with clinical information, a specific cause was eventually determined in 50% of the patients. In addition to coronary angiography and biopsy, ventriculography allows assessment of mitral regurgitation and dyskinesis, both of which can be targeted surgically. Ventriculography is used predominantly when other imaging techniques such as echocardiography or MRI are inadequate or inconsistent with the clinical examination.
Table 43.1 Causes of Dilated Cardiomyopathies (in the Order of Decreasing Frequency) | ||||||||||||||||||||||||||||||
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Invasive hemodynamic assessment is also important, as physical examination may underestimate the degree of congestion7 and noninvasive methods are limited in accuracy.8, 9, 10 Many hemodynamic profiles are common to all forms of HF (e.g., elevated right and left heart filling pressure, pulmonary hypertension, low output) and not necessarily unique to particular cardiomyopathies.11 However, defining the hemodynamic profile in an individual patient can be used to optimally titrate vasodilators and diuretics.12 In some instances, this tailored management adjusted with an indwelling Swan-Ganz catheter over 48 hours can prolong or even obviate the need for cardiac transplantation.13 Furthermore, a detailed hemodynamic profile provides prognostic information.14,15 In a consecutive series of 152 advanced heart failure patients referred to the University of California, Los Angeles (UCLA) health system for cardiac transplantation, the presenting capillary wedge pressure (mean of 28 mmHg) was not predictive of survival, but the ability to reduce the pulmonary capillary wedge pressure to <16 mmHg by the end of the hospitalization was predictive of outcome with a 1-year survival of 83% (as compared with 38% if the filling pressures could not be so lowered by the end of hospitalization). The effect was independent of the final cardiac index achieved.14 Finally, while one of the key goals of inpatient management for decompensated HF remains volume removal, registry data have revealed that only ∽50% of patients achieve adequate diuresis.16 Part of this problem may relate to the inability to clinically estimate hemodynamic status.10 In select patients, catheterization to identify the presence or absence of an optimal volume status after aggressive treatment for decompensated HF may be useful and reduce subsequent risk for rehospitalization owing to inadequate treatment. However, the routine use of an invasive hemodynamic approach for decompensated heart failure does not appear to decrease mortality or rehospitalization.17
Responses to exercise, vasodilators, and inotropes are also optimally assessed with invasive hemodynamic measurements, although it should be noted that hemodynamics may improve significantly in the absence of drug therapy over time presumably owing to favorable changes in neurohormonal tone. In 21 patients who had their hemodynamics serially assessed over a 24-hour period, the cardiac index (CI) rose by an average of 0.23 L/minute per m2 and the left ventricular filling pressure decreased by 5.9 mmHg.18 Some patients even had spontaneous improvements that rivaled the effects of oral and intravenous vasodilator therapies. Postprandial improvements were also seen, confirming the importance of studying patients in the fasting state.
CASE STUDIES
CASE 43.1 Progressive Dyspnea in a Patient with HFrEF.
A 50-year-old man presented with worsening exertional dyspnea, 4 years after presenting with newonset heart failure. Evaluation at that time had revealed compensated hemodynamics, normal coronary angiography, and an ejection fraction of 10% with an end-diastolic dimension of 7.2 cm plus moderately severe mitral regurgitation. An endomyocardial biopsy had demonstrated myocyte hypertrophy and interstitial fibrosis. With an ACE inhibitor, a beta-blocker, digoxin, and diuretics, his condition had improved to NYHA II, and cardiac transplantation was deferred because of his preserved functional capacity and a maximal oxygen consumption of 17 mL/kg per minute. One year before the current presentation, repeat right heart catheterization demonstrated compensated hemodynamics at baseline but significant increases in wedge and pulmonary pressures with exercise. Biventricular pacing with an implantable cardiac defibrillator improved his symptoms and increased his oxygen consumption to 19 mL/kg per minute.
Over the few weeks prior to the current presentation, however, he developed increasing dyspnea and orthopnea despite an augmented diuretic regimen. Repeat cardiopulmonary exercise testing demonstrated a fall in his oxygen consumption to 15 mL/kg per minute, and he was readmitted for transplant evaluation. Repeat right heart catheterization demonstrated borderline systemic arterial hypotension, pulmonary hypertension, and elevated biventricular filling pressures, which were responsive to acute vasodilator therapy with nitroprusside but were reproduced with oral vasodilators and diuretics (see Table 43.2). His condition returned to NYHA II, and cardiac transplantation was again deferred.
Table 43.2 Serial Hemodynamics in Chronic Heart Failure Owing to an Idiopathic Dilated Cardiomyopathy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Illustrative Points. Ambulatory patients with HFrEF are usually characterized by a relatively normal or mildly depressed resting cardiac output and a modest elevation in both right- and left-sided filling pressures. In advanced heart failure, the systemic vascular resistance rises significantly in response to the reduced cardiac output and neurohormonal response, and may be quite elevated despite a reduced systolic blood pressure of 80 to 100 mmHg. In 1,000 consecutive patients with chronic heart failure electively referred for transplantation (mean ejection fraction [EF] 22%, end-diastolic dimension 7.3 cm, NYHA class 3.4), the initial right atrial pressure was 11 ± 7 mmHg, the pulmonary capillary wedge pressure was 25 ± 9 mmHg, the pulmonary arterial (PA) systolic pressure was 50 ± 16, the cardiac index was 2.1 ± 0.7 L/minute per m2, and the systemic vascular resistance was 1,610 ± 610 dynes·second·cm-5.19 The right atrial (RA) pressure is typically 50% to 60% of the pulmonary capillary wedge pressure (PCWP) and often correlates with left-side filling pressures regardless of heart failure etiology or tricuspid regurgitation. In the series of patients reported by Drazner,10,19,20 the positive predictive value of an RA pressure of >10 mmHg for a PCW pressure of >22 mmHg was 88% (Figure 43.1), and more recent studies have confirmed the high correlation between right and left heart filling pressures in HF patients with any EF.10,20 The PCW pressure usually correlates with the PA systolic
pressure (usually 50% of the PA systolic) as well as with the PA diastolic pressure (PAD; usually within 1 to 2 mmHg of PCWP) as long as pulmonary vascular resistance is <2 Wood units.17 Right ventricular pressure can also be used to estimate the PAD, since right ventricular pressure closely approximates pulmonary end-diastolic pressure at the time of pulmonary valve opening21 (maximal right ventricular dP/dt; Figure 43.2).
pressure (usually 50% of the PA systolic) as well as with the PA diastolic pressure (PAD; usually within 1 to 2 mmHg of PCWP) as long as pulmonary vascular resistance is <2 Wood units.17 Right ventricular pressure can also be used to estimate the PAD, since right ventricular pressure closely approximates pulmonary end-diastolic pressure at the time of pulmonary valve opening21 (maximal right ventricular dP/dt; Figure 43.2).
 Figure 43.1 The relationship between (A) right atrial (RA) and pulmonary capillary wedge (PCW) pressure and (B) pulmonary capillary wedge pressure and pulmonary artery (PA) systolic pressure in 1,000 consecutive patients with chronic heart failure. (Reproduced with permission from Drazner MH, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999;18:1126.) |
 Figure 43.2 The pulmonary artery diastolic (PAD) pressure can be estimated from the right ventricular pressure (RVP) tracing since PAD is equal to right ventricular pressure at the maximal dP/dt (see asterisk). (Reproduced with permission from Reynolds DW, et al. Measurement of pulmonary artery diastolic pressure from the right ventricle. J Am Coll Cardiol 1995;25:1176.) |
Pulmonary hypertension (PH) is also common in HFrEF and is predictive of prognosis. In patients with dilated cardio-myopathy and myocarditis, every 5-mmHg rise in the mean pulmonary artery pressure increased mortality, with a relative hazard ratio of 1.85 (range 1.50 to 2.29).11 Mean PA pressure is equal to the product of cardiac output and pulmonary vascular resistance summed with PCWP. PH in HFrEF may be
entirely passive (i.e., owing simply to elevated PCWP, often termed “precapillary”) or owing to a combination of passive effects (e.g., elevated PCWP) and high pulmonary vascular resistance (i.e., >2.5 to 3 WU; often termed “reactive” or “postcapillary” PH). Recent data have shown that the presence of any type of PH is associated with increased risk of death or HF hospitalization in HFrEF, but “reactive” PH in particular is associated with a grim prognosis.22 Currently PH in HFrEF is not a specific therapeutic target, but recent studies using phosphodiesterase inhibitors have shown improvement in hemodynamics and quality of life, and multicenter clinical trials of pulmonary-specific vasodilators are underway.23
entirely passive (i.e., owing simply to elevated PCWP, often termed “precapillary”) or owing to a combination of passive effects (e.g., elevated PCWP) and high pulmonary vascular resistance (i.e., >2.5 to 3 WU; often termed “reactive” or “postcapillary” PH). Recent data have shown that the presence of any type of PH is associated with increased risk of death or HF hospitalization in HFrEF, but “reactive” PH in particular is associated with a grim prognosis.22 Currently PH in HFrEF is not a specific therapeutic target, but recent studies using phosphodiesterase inhibitors have shown improvement in hemodynamics and quality of life, and multicenter clinical trials of pulmonary-specific vasodilators are underway.23
Advanced HFrEF is characterized by biventricular failure. The right atrial pressure waveform will often demonstrate steep x and y descents indicative of severe volume overload and right ventricular systolic and diastolic dysfunction (Figure 43.3A). Lack of the normal inspiratory fall (or an actual increase) in the right atrial pressure (i.e., the Kussmaul sign) is also common as a result of pericardial constraint in the massively dilated heart, significant tricuspid regurgitation, and right ventricular diastolic dysfunction. The y descent is typically very steep as a result of concomitant tricuspid regurgitation and excessive volume overload leading to rapid, early diastolic inflow. The right ventricular diastolic waveform may also demonstrate a rapid early diastolic filling wave creating a “dip and plateau” configuration, which becomes more prominent during inspiration (Figure 43.3B). This finding reflects abrupt cessation of diastolic inflow as the point of pericardial restraint is reached in the left and right ventricles. The pulmonary capillary wedge pressure may demonstrate a prominent V wave that may exceed twice the magnitude of the post A-wave pressure owing to reduced left atrial compliance, even in the absence of severe mitral regurgitation (Figure 43.3C). The V wave may even be discernible in the pulmonary arterial waveform (Figure 43.3E). The left ventricular pressure tracing is characterized by an elevation in pressure through-out early diastole. The systolic left ventricular waveform may be triangular owing to the reduced + and − dP/dt, and there may be loss of the normal improvement in dP/dt with increasing heart rate (Bowditch treppe effect). In low-output states, the arterial waveform demonstrates a narrow pulse pressure (pulsus parvus), which may be <25% of the systolic pressure when the cardiac index falls below 2.2 L/minute per m2.7 In severe heart failure, there may also be pulsus alternans (Figure 43.3D), owing to oscillations in myocardial contractility with cyclic changes in cytosolic calcium.24,25
 Figure 43.3 Hemodynamic findings in decompensated heart failure from dilated cardiomyopathy. (See text for discussion.) |
A common misconception about HFrEF is that elevated filling pressures are required to maximize preload-sensitive
contractility (Starling’s law). Severe left ventricular dysfunction can be well tolerated with normal or near-normal cardiac filling pressures, concomitant satisfactory functional capacity comparable to that of transplantation,26 and reasonable long-term survival. In fact, a low ejection fraction alone is not an indication for cardiac transplantation for morbidity or mortality reasons, and many patients with low EF are asymptomatic.27 In patients with HFrEF, stroke volume, stroke work index, and cardiac output can be maximized at pulmonary capillary wedge pressures as low as 10 mmHg (Figure 43.4).28 There is no justification for insufficient diuresis and dyspnea resulting from inadequate lowering of filling pressures, although recent data suggest that half of the patients with decompensated HF lose no weight or even gain weight during hospitalization for diuresis.16 In 754 consecutive patients with chronic heart failure referred electively for cardiac transplantation, tailored doses of vasodilators and diuretics increased the cardiac index from 2.1 ± 0.7 to 2.6 ± 0.6 L/minute per m2 despite a fall in the pulmonary capillary wedge pressure from 25 ± 9 to 16 ± 6 mmHg. In part, this improvement in forward cardiac output despite significant reduction of filling pressures is due to a decrease in mitral regurgitation caused by favorable changes in ventricular, atrial, and mitral annular geometry. This change can cause an increased forward stroke volume rather than an increase in total stroke volume.29,30 Left ventricular myocardial systolic performance can also improve owing to elimination of right ventricular volume overload with diuretics or nitrates,31,32 whereas myocardial diastolic performance can improve owing to reduced myocardial turgor that follows decreased venous congestion.33
contractility (Starling’s law). Severe left ventricular dysfunction can be well tolerated with normal or near-normal cardiac filling pressures, concomitant satisfactory functional capacity comparable to that of transplantation,26 and reasonable long-term survival. In fact, a low ejection fraction alone is not an indication for cardiac transplantation for morbidity or mortality reasons, and many patients with low EF are asymptomatic.27 In patients with HFrEF, stroke volume, stroke work index, and cardiac output can be maximized at pulmonary capillary wedge pressures as low as 10 mmHg (Figure 43.4).28 There is no justification for insufficient diuresis and dyspnea resulting from inadequate lowering of filling pressures, although recent data suggest that half of the patients with decompensated HF lose no weight or even gain weight during hospitalization for diuresis.16 In 754 consecutive patients with chronic heart failure referred electively for cardiac transplantation, tailored doses of vasodilators and diuretics increased the cardiac index from 2.1 ± 0.7 to 2.6 ± 0.6 L/minute per m2 despite a fall in the pulmonary capillary wedge pressure from 25 ± 9 to 16 ± 6 mmHg. In part, this improvement in forward cardiac output despite significant reduction of filling pressures is due to a decrease in mitral regurgitation caused by favorable changes in ventricular, atrial, and mitral annular geometry. This change can cause an increased forward stroke volume rather than an increase in total stroke volume.29,30 Left ventricular myocardial systolic performance can also improve owing to elimination of right ventricular volume overload with diuretics or nitrates,31,32 whereas myocardial diastolic performance can improve owing to reduced myocardial turgor that follows decreased venous congestion.33
In general, optimization of hemodynamics is best achieved with intravenous vasodilators and diuretics rather than with inotropic support. Vasodilator therapy takes advantage of the inverse relationship between resistance and output (Figure 43.5) and is especially effective when systemic vascular resistance is >2,000 dynes·second·cm-5. Indeed, the failing left ventricle is exquisitely afterload-sensitive. This is reflected in the pressure-volume plane by the shallow end-systolic pressure-volume relationship (ESPVR) in HFrEF. This shallow ESPVR graphically shows how vasodilators produce marked improvements in stroke volume with minimal drop in blood pressure, in contrast to the normal heart or HFpEF, where there tends to be larger arterial pressure drop with less enhancement in stroke volume (Figure 43.6).34,35 Once an optimal hemodynamic profile is achieved, the effects of intravenous vasodilators, such as nitroprusside, can be replicated by oral vasodilators like ACE inhibitors, hydralazine, and nitrates.36 As in the case above, intravenous nitroprusside34,37,38 can be used even in the presence of relative hypotension (systolic blood pressure <100 mmHg) if the hypotension is the result of low cardiac output and high vascular resistance. If clinically significant ischemia is present, intravenous nitroglycerin is preferred over nitroprusside owing to considerations of coronary steal. Intravenous nitroglycerin and nesiritide31,39 can also be used to acutely improve the hemodynamics, especially when pulmonary hypertension and high central venous pressures are present.
 Figure 43.4 Maximal stroke volumes can be achieved at low filling pressures in advanced heart failure from dilated cardiomyopathy. (Reproduced with permission from Stevenson LW, et al. Maintenance of cardiac output with normal filling pressures in patients with dilated heart failure. Circulation 1986;74:1303.) |
 Figure 43.5 The effects of acute administration of nitroprusside on left ventricular filling pressures (LVFP) and stroke volume in patients with advanced heart failure. Maximal stroke volume is preserved at pulmonary capillary wedge pressures as low as 10 mmHg. (Reproduced with permission from Guiha NH, et al. Treatment of refractory heart failure with infusion of nitroprusside. N Engl J Med 1974;291:587.) |
The use of inotropic agents to optimize hemodynamics is limited by the inability to replicate the direct inotropic effects with oral vasodilators. Clinical trials have suggested a worsening of mortality with intermittent use of inotropes for the longitudinal management of heart failure,40,41 but some patients may still require inotropic support despite attempts
to tailor their hemodynamics with vasodilators and diuretics. Such patients in general will be bridged to more definitive treatments such as mechanical support or cardiac transplantation. Inotropic agents, such as phosphodiesterase 3 inhibitors (e.g., milrinone) or beta agonists (e.g., dobutamine), will increase contractility (+dP/dt) and also decrease early and late diastolic pressures through their lusitropic (−dP/dt) effects42 (Figure 43.7; see also Chapter 28). Milrinone is also a vasodilator, which can augment the cardiac output over and above its direct inotropic action.43 Unfortunately these agents also increase myocardial oxygen demand, decrease LV efficiency, and have well-documented proarrhythmic effects.
to tailor their hemodynamics with vasodilators and diuretics. Such patients in general will be bridged to more definitive treatments such as mechanical support or cardiac transplantation. Inotropic agents, such as phosphodiesterase 3 inhibitors (e.g., milrinone) or beta agonists (e.g., dobutamine), will increase contractility (+dP/dt) and also decrease early and late diastolic pressures through their lusitropic (−dP/dt) effects42 (Figure 43.7; see also Chapter 28). Milrinone is also a vasodilator, which can augment the cardiac output over and above its direct inotropic action.43 Unfortunately these agents also increase myocardial oxygen demand, decrease LV efficiency, and have well-documented proarrhythmic effects.
 Figure 43.6 Effects of nitroprusside (SNP) on ventricular hemodynamics in HFpEF and HFrEF. In HFrEF, contractile function is severely depressed, resulting in a shallow end-systolic pressure-volume relation-ship (ESPVR, red straight line). The slope of the ESPVR is end systolic elastance (Ees). The shallow ESPVR in HFrEF explains how acute vasodilation with SNP (reduction in arterial elastance, Ea) results in small drop in blood pressure (−18 mmHg) and large enhancement in stroke volume (+23 mL). Conversely, HFpEF is characterized by a steep ESPVR (black solid line), and similar dosage and extent of vasodilation with SNP result in much more dramatic drop in blood pressure with less enhancement in stroke volume and cardiac output. (Reproduced with permission from Schwartzenberg, et al. Effects of vasodilation in heart failure with preserved or reduced ejection fraction: Implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol 2012;59:442-451.) |
In chronic heart failure, hemodynamic goals include a right atrial pressure of <10 mmHg, pulmonary capillary wedge pressure of <15 mmHg, and a systemic vascular resistance of <1,200 dynes·second·cm-5, maintaining a systolic blood pressure of >80 mmHg to avoid light-headedness.13 Cardiac output can be measured reliably with the thermodilution technique in advanced heart failure, even in the presence of moderate to severe tricuspid regurgitation.44,45 It may even be preferred over the Fick method when oxygen consumption cannot be directly measured, because of the substantial variability in body size-based estimation of resting oxygen consumption. It is rare that hemodynamic monitoring is required for >72 hours to tailor hemodynamics in chronic heart failure, but some chronic monitoring is better than relying solely on measurements in the catheterization laboratory.18 Because hemodynamic goals are tailored and achieved in the supine position, the tolerability of an oral vasodilator regimen should be assessed after 24 hours of ambulation. With careful attention to volume status and vasodilators in follow-up, these hemodynamic profiles can also be maintained for months and years.
Exercise hemodynamic responses can be used to delineate the cause of persistent dyspnea, especially when resting hemodynamics are unremarkable (Figure 43.8), or to assess cardiovascular reserve and prognosis46,47 (see Chapter 20). Invasive hemodynamic exercise testing is more frequently utilized in the evaluation of HFpEF and is discussed further in the corresponding section later in this chapter.
HEART TRANSPLANTATION
Despite the radical nature of replacing a human heart with another, cardiac allograft has emerged as an effective way of restoring essentially normal cardiovascular function in endstage heart failure. However, the transplanted heart is subject to a number of post-transplant factors that can influence cardiac function including denervation, organ preservation/ ischemic injury, myocardial rejection, donor/recipient size mismatch, allograft coronary artery disease, and hypertension/ ventricular hypertrophy. Initially the transplanted heart also demonstrates a restrictive hemodynamic profile; this resolves over days to weeks,48,49 although the less dramatic abnormalities in diastolic function may persist50, 51, 52 (Table 43.3). Resting contractility and ejection fraction are relatively normal,53 but total blood volume, cardiac volume, and end-systolic wall
stress increase even if myocardial mass is unchanged.48 In general, mild impairment of ventricular functional reserve is present, but it is demonstrable only with maximal exercise stress and may be in part a result of decreases in coronary flow reserve.54 The primary limitation in maximal cardiac output is owing to the denervated heart having a blunted heart rate response, and the Frank-Starling mechanism is exhausted early in the response to supine55,56 and upright exercise.57 This is partially offset by an increased sympathetic sensitivity, with dependence on circulating catecholamines for an adequate but delayed chronotropic exercise response.58
stress increase even if myocardial mass is unchanged.48 In general, mild impairment of ventricular functional reserve is present, but it is demonstrable only with maximal exercise stress and may be in part a result of decreases in coronary flow reserve.54 The primary limitation in maximal cardiac output is owing to the denervated heart having a blunted heart rate response, and the Frank-Starling mechanism is exhausted early in the response to supine55,56 and upright exercise.57 This is partially offset by an increased sympathetic sensitivity, with dependence on circulating catecholamines for an adequate but delayed chronotropic exercise response.58
 Figure 43.7 The hemodynamic effects of an inotropic agent, milrinone, in dilated cardiomyopathy. Milrinone increases contractility (positive dP/dt), improves lusitropy (negative dP/dt), and lowers preload (decreased left ventricular end-diastolic pressure [LVEDP]). The improvement in systolic and diastolic function occurs without an increase in systolic blood pressure. (Reproduced with permission from Baim DS, et al. Evaluation of a new bipyridine inotropic agent—milrinone—in patients with severe congestive heart failure. N Engl J Med 1983; 309:748.) |
 Figure 43.8 Effects of exercise on hemodynamics in dilated cardiomyopathy. Note the development of prominent V waves and dramatic increase of pulmonary capillary wedge pressure with exercise. This effect was achieved with supine arm exercise (moving bags of saline up and down in supine position) resulting in an almost twofold increase in heart rate (HR). The patient had an ejection fraction of 20%, an end-diastolic dimension of 7 cm, and moderately severe mitral regurgitation at rest. The lack of V waves and normal wedge pressure at rest are indicative of the chronic nature of the regurgitation. BP, blood pressure. |
Although left ventricular responses to hypertension and acute increases in afterload are normal after cardiac transplantation, the denervated heart does not tolerate hypotension well, presumably because of lack of ventricular compliance and reflex sympathetic tone. Denervation also leads to several other clinically relevant hemodynamic abnormalities in addition to the obvious loss of cardiac pain sensation. Efferent parasympathetic denervation of the heart leads to a resting tachycardia of 90 to 110 beats per minute (bpm), lack of heart rate variability, and the ineffectiveness of atropine and digoxin; efferent sympathetic denervation leads to blunted
and delayed increases in heart rate in response to physiologic stress. Afferent denervation results in dysregulation of sodium and water homeostasis as well as in abnormalities in peripheral vascular responses.59
and delayed increases in heart rate in response to physiologic stress. Afferent denervation results in dysregulation of sodium and water homeostasis as well as in abnormalities in peripheral vascular responses.59
Table 43.3 Resting and Exercise Hemodynamics After Cardiac Transplantation | ||||||||||||||||||||||||||||||
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Right ventricular function is critical in the early post-transplant period. The normal right ventricle cannot accommodate significant acute pressure overload,60 and nowhere is this more apparent than in the post—cardiac transplant setting. Acute right heart failure accounts for 50% of all peri—and post—cardiac transplant complications and is a leading cause of early allograft failure and death. Not surprisingly, an elevated preoperative pulmonary vascular resistance predicts early postoperative death from acute right heart failure,61, 62, 63 and severe fixed pulmonary hypertension is a contraindication to cardiac transplantation.
CASE 43.2 Assessing Pulmonary Vascular Resistance Prior to Transplantation.
A 45-year-old woman with a 30-pack-year smoking history is transferred with advanced heart failure for consideration of heart transplantation following an anterior myocardial infarction 2 years earlier. She had three hospitalizations in the past year for heart failure and was readmitted 3 days prior to transfer after stabilization on lisinopril, carvedilol, digoxin, and furosemide. Pulmonary evaluation was remarkable for mild obstructive pulmonary disease. Acute vasodilator testing in the catheterization lab with various agents demonstrated reversible pulmonary hypertension, and she was considered acceptable for transplantation (see Table 43.4).
Table 43.4 Changes in Pulmonary Vascular Resistance to Various Maneuvers | ||||||||||||||||||||||||||||||||||||||||
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However, repeat catheterization 3 months later demonstrated recurrent severe pulmonary hypertension. Because of relative hypotension, milrinone was used to assess pulmonary vasoreactivity. Bolus milrinone did lower the pulmonary vascular resistance to an acceptable extent, and she was maintained on continuous intravenous milrinone while awaiting transplantation.
Illustrative Points. Pulmonary hypertension, defined as a pulmonary artery systolic pressure of ≥35 mmHg or mean pulmonary artery pressure of ≥25 mmHg, is a common complication of heart failure as discussed above. Resting pulmonary vascular resistance predicts exercise tolerance in heart
failure and is inversely correlated with oxygen consumption in these patients.64,65 The right ventricular (RV) response to chronic afterload increase is even more important than the load itself. Indeed, exercise capacity is better predicted by RV ejection fraction than by the left ventricular ejection fraction or pulmonary vascular resistance, reflecting the importance of the interaction between the pulmonary vasculature and right heart in limiting exercise capacity in heart failure.66
failure and is inversely correlated with oxygen consumption in these patients.64,65 The right ventricular (RV) response to chronic afterload increase is even more important than the load itself. Indeed, exercise capacity is better predicted by RV ejection fraction than by the left ventricular ejection fraction or pulmonary vascular resistance, reflecting the importance of the interaction between the pulmonary vasculature and right heart in limiting exercise capacity in heart failure.66
In heart failure, the elevated left ventricular end-diastolic pressure and thus elevated left atrial pressure result in a passive or reactive increase in the pulmonary venous pressure and a consequent increase in the upstream pulmonary arterial pressure. These passive changes may also be accompanied by an increase in the transpulmonary gradient (mean PA minus mean PCWP) reflected by increases in pulmonary vascular resistance (PVR) and right ventricular afterload. These changes in PVR in heart failure are mediated by alterations in pulmonary smooth muscle vascular tone as well as by structural changes in the pulmonary vessels. Changes in smooth muscle tone are generally reactive and reversible over the course of hours to days, whereas structural remodeling of the pulmonary vascular tree has less plasticity but may be reversible over the course of months to years, especially with chronic LV unloading as with ventricular assist devices (see below).
Pulmonary hypertension becomes a concern in the pretransplant setting when the pulmonary artery systolic pressure is >60 mmHg, the transpulmonary gradient is >15 mmHg, and/or the pulmonary vascular resistance is >4 Wood units (320 dynes·second·cm-5). Although in the Bethesda consensus conference on heart transplantation PVR of >6 to 8 Wood units was considered high-risk,27 most centers do not use a fixed cutoff value for an acceptable PVR.67 In fact, in some patients with severe pulmonary hypertension who have successfully undergone heart transplantation or long-term ventricular assist device support, pulmonary pressures have returned to normal.49,68 Therefore, it is essential to ensure that pretransplant elevations in PVR are reversible. If so, specific chronic interventions such as continuous inotropic support or a ventricular assist device (VAD) may be required to keep their PVR low while patients await transplantation. This reduces the risk of allograft right ventricular failure in the early transplant course.
Costard-Jäckle and Fowler at Stanford reported the predictive value of acute testing of pulmonary vasoreactivity with nitroprusside in 301 consecutive cardiac transplant candidates.69 The 3-month post-transplant mortality in this cohort was high in those candidates with a baseline PVR of >2.5 Wood units (or 200 dynes·second·cm-5; 17.9% versus 6.9% for PVR <2.5 Wood units). Using graded incremental doses of nitroprusside in patients with either a PVR of >2.5 Wood units or a PA systolic pressure of >40 mmHg, the hemodynamic response was predictive of outcome. If the PVR could be reduced to <2.5 Wood units without hypotension (>85 mmHg), the 3-month mortality was only 3.8%. In contrast, if the PVR could not be reduced to <2.5 Wood units or only at the expense of hypotension, the mortality was high (40.6% and 27.5%, respectively). In addition, in their series, all patients who died of right heart failure were from these latter two groups.69
At the Mayo Clinic (Rochester, MN) and University Hospitals Case Medical Center (Cleveland, OH), nitroprusside is started at 0.5 to 1.0 µg/kg/minute and increased in 0.5 to 1.0 µg/kg increments every 3 minutes with reassessment of the pulmonary vascular resistance (PCWP, mean PA, and cardiac output) after each change in dose.34 Cardiac output is best assessed with thermodilution in this setting unless it is possible to directly measure oxygen consumption during each phase of infusion. Smaller increments or slower titration schemes should be considered when left ventricular filling pressures are low (<10 mmHg).
Various other agents have been used to assess the reversibility of pulmonary hypertension (Table 43.5), although the mechanism by which PVR falls differs between agents. High-flow oxygen should be considered first, especially if the baseline arterial saturation is <95%. Nitroprusside, an endothelium-independent nitric oxide donor, decreases PVR by both decreasing the transpulmonary gradient and increasing the cardiac output.70,71 Dobutamine and other inotropes increase pulmonary blood flow with subsequent recruitment of parallel vessels in the pulmonary circulation and produce flow-mediated vasodilation.70 Bolus milrinone is simple and attractive since it avoids the need for titration.72 Using 50 µg/ kg over 1 minute via a systemic vein, the peak lowering of PVR occurs within 5 to 10 minutes and is typically not associated with changes in systemic blood pressure or heart rate. Milrinone lowers the PVR by approximately 30% with a concomitant significant increase in the cardiac output but with little change in the transpulmonary gradient.
Selective pulmonary vasodilators are also attractive alternatives since they lack the systemic hypotensive effects of traditional vasoactive agents. For example, inhaled nitric oxide lowers PVR by decreasing the transpulmonary gradient and increasing the left ventricular filling pressure without significant changes in cardiac output or mean PA pressure.73, 74, 75 Although not useful for chronic therapy owing to its short half-life and potential toxicity, nitric oxide has been used for assessing pulmonary vasoreactivity in cardiac transplant candidates,76 supporting high-risk surgical patients undergoing coronary bypass or valve replacement77 and treating right ventricular dysfunction after heart transplantation or implantation of a ventricular assist device.78,79 Phosphodiesterase inhibitors may also potentiate nitric oxide-dependent vasodilation by preventing the degradation of cGMP. Thus, in similar clinical contexts, the phosphodiesterase type 5 inhibitor sildenafil has been used successfully to decrease the PVR.80, 81, 82 When left ventricular function is normal, the increase in left ventricular filling from increased volumetric flow across the pulmonary circulation can be easily accommodated without significant symptomatic increases in the filling pressure. However, when left ventricular diastolic function is not normal and baseline
filling pressures are elevated, the increase in pulmonary blood flow can result in further increases in left ventricular filling pressure in a noncompliant ventricle and may produce alveolar pulmonary edema.83 However, in some patients there may be acute elevation in PCWP that remains asymptomatic.84 Adenosine85 and prostaglandin E186 produce similar effects. For these reasons, we generally avoid pulmonary-specific vasodilators for acute vasoreactivity testing when the PCWP or LVEDP is >20 to 25 mmHg and instead use nitroprusside, nitroglycerin, or milrinone. Table 43.5 summarizes the use of various acute vasodilators to assess reversibility of pulmonary hypertension in the catheterization lab. Endothelin antagonists also selectively vasodilate the pulmonary circulation87 and have been used in primary forms of pulmonary hypertension when left ventricular function is normal.88 However, oral endothelin antagonists in heart failure do not appear to be beneficial in clinical trials, and these agents have not been used for acute testing of pulmonary vasoreactivity.
filling pressures are elevated, the increase in pulmonary blood flow can result in further increases in left ventricular filling pressure in a noncompliant ventricle and may produce alveolar pulmonary edema.83 However, in some patients there may be acute elevation in PCWP that remains asymptomatic.84 Adenosine85 and prostaglandin E186 produce similar effects. For these reasons, we generally avoid pulmonary-specific vasodilators for acute vasoreactivity testing when the PCWP or LVEDP is >20 to 25 mmHg and instead use nitroprusside, nitroglycerin, or milrinone. Table 43.5 summarizes the use of various acute vasodilators to assess reversibility of pulmonary hypertension in the catheterization lab. Endothelin antagonists also selectively vasodilate the pulmonary circulation87 and have been used in primary forms of pulmonary hypertension when left ventricular function is normal.88 However, oral endothelin antagonists in heart failure do not appear to be beneficial in clinical trials, and these agents have not been used for acute testing of pulmonary vasoreactivity.
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