Histologic compaison of allograft myocardium between short- and long-term survivors of human cardiac transplantation.

Myocardial histology of cardiac allografts differed between short-term (<5 years) and long-term (>5 years) survivors after transplantation. These differences may partially be attributable to a higher prevalence of systemic hypertension and allograft rejection in the short-term survivors, affecting hemodynamics and allograft function.

Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators.

BACKGROUND: We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. METHODS AND RESULTS: One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) who had a pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Plasma atherogenic markers in congestive heart failure and posttransplant (heart) patients.

OBJECTIVES: We hypothesized that plasma factors important for the development of atherosclerosis play a major role in the occurrence of cardiac allograft vasculopathy (CAV). BACKGROUND: Cardiac allograft vasculopathy is a major cause of death among heart transplant recipients, has a poorly understood pathogenesis and has similarities to atherosclerotic coronary disease. METHODS: The study population consisted of 93 postcardiac transplant recipients. Thirty-one patients with congestive heart failure (CHF) and 18 healthy individuals served as control subjects. Posttransplant coronary anatomy was evaluated by angiography and intravascular ultrasound. Laboratory analyses of lipids, homocysteine, vitamin B12 and folate, fibrinogen, von Willebrand factor antigen (vWFAg) and renin were obtained on all participants. RESULTS: Posttransplant patients were found to have elevated serum triglycerides, total cholesterol/ high-density lipoprotein cholesterol ratio, lipoprotein (a), homocysteine, vWFAg, fibrinogen and renin and lower high-density lipoprotein cholesterol. Most of these laboratory atherogenic factors were also elevated to a similar degree in the CHF control population. Although most atherogenic markers were elevated, there was little correlation with CAV severity. Cardiac allograft vasculopathy severity varied with time after transplantation, 3-hydroxy-methyl-glutaryl-coenzyme A reductase inhibitor use and prior cytomegalovirus infection. Even within the normal range, lower RBC folate levels were associated with increased severity of CAV. CONCLUSIONS: The posttransplant course is associated with increased clinical and laboratory atherogenic factors, some of which likely contribute to the severity of coronary vasculopathy. Compared with normal control subjects, many of these markers are already increased in pretransplant CHF patients with or without occlusive coronary artery disease.

The problem of ventricular dysrhythmias and sudden death mortality in heart failure: the impact of current therapy.

Congestive heart failure (CHF), one of the few cardiovascular conditions increasing in incidence and prevalence, is characterized by high morbidity and mortality. Up to 50% of the mortality is attributable to dysrhythmic sudden death. Risk stratification to identify those most susceptible to sudden death remains imperfect. The advances in CHF therapeutics and management over the past 16 years have had a favorable impact on CHF mortality including sudden death. The role of amiodarone and implantable cardioverter-defibrillator intervention is evolving and discussed in the context of current CHF management and available trials.

Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure.

BACKGROUND: Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone. METHODS: Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group. RESULTS: Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group. CONCLUSIONS: Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation.

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.

BACKGROUND: Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS: This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation.

OBJECTIVES: This study was performed to determine the degree and time course over 6 years of cardiomyocyte hypertrophy and myocardial fibrosis of the cardiac allograft in transplanted patients. BACKGROUND: Diastolic dysfunction and to a certain extent systolic dysfunction are common cardiac findings after heart transplantation. The development of posttransplant cardiomyocyte hypertrophy and myocardial fibrosis likely contributes to these derangements. METHODS: Cardiomyocyte diameter and percent fibrosis were determined in serial endomyocardial biopsy specimens obtained from 1 month up to 6 years following heart transplantation in 50 patients. Endomyocardial biopsy specimens from 40 patients with primary dilated cardiomyopathy and 11 normal subjects were similarly analyzed for control data. Analyses were performed in a blinded format using a validated computerized image analysis system (Optimas 5.2). RESULTS: Early (1 month) cardiomyocyte enlargement decreased to the smallest diameter 6 months posttransplant, but thereafter progressively increased by 10% to 20% over the subsequent 5- to 6-year period. Although not statistically established, principal stimuli may include a discrepancy in body size (recipient > donor), coronary allograft vasculopathy and posttransplant systemic hypertension. Percent myocardial fibrosis rose early (1 to 2 months) posttransplant and thereafter remained at the same modest level of severity. CONCLUSIONS: Cardiomyocyte diameter of the transplanted heart gradually increases over time, while percent myocardial fibrosis rises early and remains in a modestly elevated plateau after 2 months posttransplant. These histostructural changes likely contribute to the hemodynamic and cardiac functional alterations commonly observed posttransplant.

Parenteral inotropic support for advanced congestive heart failure.

Parenterally administered positive inotropic agents remain an important component of the therapeutics of cardiac dysfunction and failure. Dobutamine, a catechol, remains the prototype of this drug group, but recently has been joined by the phosphodiesterase III inhibitor, milrinone. Compared with dobutamine, milrinone has greater vasodilating-unloading properties. The catecholamine, dopamine, is often used as a parenteral positive inotrope; but at moderate to high dose, it evokes considerable systemic vasoconstriction. At lower doses, dopamine appears to augment renal function. Levosimendan and toborinone, new compounds with several mechanisms of action, are under active clinical investigation and review for approval. Parenteral positive inotropic therapy is indicated for short-term (hours to days) treatment of cardiovascular decompensation secondary to ventricular systolic dysfunction, low-output heart failure. More prolonged or continuous infusion of one of these agents may be necessary as a "pharmacologic bridge" to cardiac transplantation, another definitive intervention, or more advanced, intense medical therapy. An occasional patient will require a continuous infusion via indwelling venous catheter and portable pump, simply to be able to be discharged from the hospital setting and function in the home environment. Intermittent parenteral inotropic therapy for chronic heart failure has provoked considerable controversy and passion among cardiologists and heart failure specialists; an attempt is made to present this topic in an objective manner.

Removal from the "waiting list" for heart transplantation: a risk factor for sudden death?

METHODS AND RESULTS: Over an 18-month period, the patients on the heart transplantation waiting list at our institution were evaluated to determine if continued listing was appropriate. Ten patients were removed because of significant improvement in clinical status and exercise capacity (n = 9) or because of criteria violation (n = 1). Four of these patients died suddenly and unexpectedly within 4 months of delisting, resulting in a 6-month survival of 60% for the patients removed. During the same period, the 6-month survival for newly listed patients (n = 10) was 80% and that for newly transplanted patients (n = 13) was 92%. An elevated pulmonary capillary wedge pressure (> or = 18 mmHg) was the only clinical or laboratory feature that appeared to distinguish the four patients who died suddenly following delisting. CONCLUSION: The results of this preliminary study suggest that removal of a patient from a heart transplant waiting list may represent a risk for sudden death, particularly in patients with elevated ventricular filling pressures, irrespective of otherwise favorable clinical status and exercise performance.

Anomalous origin of the left main coronary artery from the pulmonary trunk masquerading as peripartum cardiomyopathy.

We present a 16-year-old girl who developed congestive heart failure during and after delivery of her first child, and who was diagnosed as having peripartum cardiomyopathy. Cardiac catheterization with coronary arteriography confirmed the correct diagnosis of anomalous origin of the left main coronary artery from the pulmonary trunk.

Aorto-left atrial fistula. A reversible cause of acute refractory heart failure.

Fistulas between the aorta and left atrium, invariably a complication of aortic valvular endocarditis, are rare and infrequently diagnosed premortem. We describe a patient who presented with this entity and review the reports of five other patients for whom a diagnosis was made premortem. A number of causative organisms have been identified. The clinical course is characteristically one of rapidly progressive heart failure. Notably, only half of these fistulas were detected by transthoracic echocardiography, whereas all were identified by transesophageal echocardiography when utilized. Once the diagnosis is made, prompt surgical repair is required to avert the high mortality from rapidly developing refractory congestive heart failure.

Increased ventricular contractility is not sufficient for effective positive inotropic intervention.

Positive inotropic intervention with dobutamine in patients with congestive heart failure is accompanied by complementary vascular changes, as measured by the aortic input impedance spectrum, that promote the efficient transfer of augmented myocardial contractile power. It is unknown whether this is a nonspecific response to increased ventricular contractility or is a function of the properties of the positive inotropic agent employed. Therefore, the influence of two different positive inotropic interventions, dobutamine and dopamine, on ventricular-vascular coupling was examined in 15 patients with congestive heart failure. Significant reductions in characteristic aortic impedance, wave reflection, and low-frequency impedance moduli were noted with dobutamine and were not seen with dopamine. Consequently, a significantly (P = 0.0008) greater increase in pulsatile, rather than steady-state, power output was noted with dopamine that was reflective of a significantly diminished efficiency of power transfer. Therefore, optimal transfer of increased ventricular contractile power in patients with congestive heart failure requires increases in large vessel compliance and complementary changes in ventriculoarterial coupling.

Electrolyte disturbances in chronic heart failure: metabolic and clinical aspects.

The pathophysiology of congestive heart failure (CHF) includes conditions (e.g., activation of the renin-angiotensin-aldosterone system) which, when combined with CHF therapies, make patients afflicted with this syndrome quite susceptible to electrolyte disturbances. The most commonly encountered are hyponatremia, hypokalemia, and hypomagnesemia. These derangements are of vast clinical importance; their development not only represents an immediate threat to the CHF patient (e.g., dysrhythmias secondary to hypokalemia), but are also indicative of underlying pathophysiologic events, an unfavorable clinical course, and occasionally an adverse therapeutic response. The optimal care of CHF patient includes the recognition and management of these electrolyte disturbances.

Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia.

Electrolyte disturbances are a common complication of CHF. CHF provides a perfect milieu for the development of these disturbances; renal dysfunction, elevation of neurohormonal substances, activation of the renin-angiotensin-aldosterone axis, and diuretic therapy represent the major contributory factors. Hyponatremia is closely aligned with an unfavorable clinical course. Hypokalemia is associated with increased ventricular dysrhythmias. Hypomagnesemia noted in advanced CHF can be accompanied by arrhythmias and refractory hypokalemia. CHF also offers the ideal milieu (diseased, ischemic, and arrhythmogenic myocardium; elevated catecholamines; and arrhythmogenic drugs) for the threatening clinical consequences (clinical deterioration, dysrhythmias, or death) of these disturbances. These consequences underscore the importance of the recognition, appreciation, and management of these electrolyte abnormalities.