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Metabolic syndrome (MS) is commonly associated with left ventricular (LV) diastolic dysfunction and LV hypertrophy. We sought to examine whether preclinical LV diastolic dysfunction can occur independent of LV hypertrophy in MS. We recruited 90 consecutive participants with MS and without cardiovascular disease (mean age 46 years, 78% women) and 26 controls (no risk factors for MS; mean age 43 years, 65% women). Participants underwent echocardiography with tissue Doppler imaging. In age- and gender-adjusted analyses, MS was associated with higher left atrial (LA) diameter, higher LV mass, lower E/A ratio, and lower mean e' (p <0.001 for all). These associations remained significant after further adjusting for blood pressure, antihypertensive medication use, and body mass index. After adjusting for LV mass, MS remained independently associated with higher LA diameter, lower E/A ratio, and lower mean e' (p ≤0.01 for all). Specifically, subjects with MS had a 1.8 cm/s lower mean e' compared with controls (p = 0.01). Notably, differences in mean e' between those with and without MS were more pronounced at younger ages (p for interaction = 0.003). In conclusion, MS was associated with preclinical LV diastolic dysfunction independent of LV mass, as reflected by higher LA diameter, lower E/A ratio, and lower mean e'. This suggests that MS can lead to the development of diastolic dysfunction through mechanisms independent of hypertrophy. Differences in diastolic function were more pronounced at younger ages, highlighting the potential importance of early risk factor modification and preventive strategies in MS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The management of acute heart failure syndromes (AHFS) focuses primarily on improving hemodynamic function and alleviating symptoms. Emerging evidence has raised the possibility that patients with AHFS may be susceptible to progressive myocardial failure because of the accelerated loss of cardiac myocytes. Although there are circumstantial data to suggest that the choice of therapeutic agent may affect long-term outcomes in such patients, the responsible mechanism is not known. Activation of mitochondrial adenosine triphosphate-dependent potassium (K(ATP)) channels in cardiac myocytes is a potent cardioprotective mechanism. We studied cardiac myocytes in culture to determine whether levosimendan can protect against apoptotic cell death in response to oxidative stress, a stimulus that appears to mediate myocyte loss in response to hemodynamic overload and beta-adrenergic stimulation, conditions commonly encountered in acute HF. Levosimendan, at concentrations below the therapeutic range in humans, protected myocytes from hydrogen peroxide-induced apoptosis. This effect was prevented by K(ATP) channel inhibitors. The demonstration that levosimendan can oppose myocyte apoptosis via the activation of mitochondrial K(ATP) channels provides a potential mechanism by which this agent might protect cardiac myocytes during episodes of acute HF. Although the alleviation of symptoms should remain an important goal of therapy in acute HF, a therapeutic approach that includes a cardioprotective strategy may be able to exert a clinically meaningful benefit on disease progression. This speculation, if proved true, would mandate a fundamental paradigm shift in the acute management of acute HF.

The benefit of beta-blockers for secondary prevention of death and reinfarction after myocardial infarction (MI) has been conclusively demonstrated in randomized clinical trials. Before the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study (CAPRICORN)-a multicenter, multinational, double-blind, randomized, placebo-controlled trial that enrolled 1,959 patients who had an acute MI and a left ventricular ejection fraction of <==0.40-it was not known whether beta-blockers confer additional benefit when used in the context of modern post-MI management (eg, fibrinolytic therapy and primary percutaneous transluminal coronary angioplasty, aspirin, and angiotensin-converting enzyme inhibitors). Patients in CAPRICORN were treated with a maximum dose of 25 mg bid and observed until 633 validated primary end points had occurred. Because the overall mortality was lower than had been predicted, a co-primary end point was adopted that included the original primary end point (all-cause mortality) plus the first of the prespecified secondary end points (all-cause mortality or cardiovascular hospitalizations). A significant 23% reduction in the original primary end point of all-cause mortality was observed. A total of 340 (35%) patients died or had a cardiovascular hospitalization in the carvedilol group versus 367 (37%) in the placebo group. Therefore, the revised primary end point of all-cause mortality or cardiovascular hospitalization was reduced by 8%, which was not statistically significant. Significant reductions in cardiovascular mortality, nonfatal MI, and the combination of all-cause mortality or nonfatal MI were observed. Although statistical significance for the revised primary end point was not reached, CAPRICORN has an important role in guiding future use of beta-blockers in the early post-MI period.

Myocardial remodeling is a central feature in the progression of myocardial failure. This process, which can be stimulated by factors that are increased as a result of myocardial dysfunction such as mechanical stress, angiotensin, and norepinephrine, consists of a variety of molecular and cellular events that can lead to important changes in myocardial structure and function (or phenotype). These alterations include hypertrophy and cellular apoptosis of myocytes, changes in the molecular phenotype of the myocardium with reinduction of a fetal gene program, and alterations in the quantity and composition of the extracellular matrix. Agents that counteract these factors, such as vasodilators, angiotensin-converting enzyme inhibitors, and beta-adrenergic antagonists, slow the progression of myocardial failure and are of clinical value in the treatment of heart failure. Several additional mechanisms have recently been identified that could also be important in mediating myocardial remodeling. These include oxidative stress, inflammatory cytokines, nitric oxide, endothelin, and peptide growth factors. It is likely that additional strategies to inhibit these mechanisms will exert beneficial effects on the process of myocardial remodeling and the development of clinical heart failure.

Speculations about development of tolerance to the inotropic effect of digitalis have been engendered since studies in various in vitro systems and tissues not representative of the heart have shown up-regulation of sodium potassium adenosine triphosphatase (Na,K-ATPase) when exposed to digitalis. Moreover the digitalis receptor (i.e., Na,K-ATPase) concentration in the normal, vital human left ventricle has not been previously determined. On this basis, digitalis receptor concentration was quantified in the left ventricle of explanted hearts from subjects without heart disease and from patients with end-stage heart failure who had received digitalis therapy. This was performed using vanadate-facilitated 3H-ouabain binding to intact tissue samples giving values of 728 +/- 58 (n = 5) and 467 +/- 55 pmol/g wet weight (n = 6) (mean +/- SEM) (p < 0.005), respectively. However, some of the digitalis receptors may have retained digoxin before 3H-ouabain binding and thus may have escaped detection. To eliminate this effect of retained digoxin, samples were exposed to prolonged washing in buffer containing excess digoxin antibody, a method recently shown to clear digoxin from receptors and allow subsequent complete digitalis receptor quantification by 3H-ouabain binding. After washing in digoxin specific antibody, specific digitalis receptor concentration was 760 +/- 58 pmol/g (n = 5) and 614 +/- 47 pmol/g (n = 6) wet weight in samples of the normal and failing hearts, respectively (p < 0.08). Thus, digitalization was associated with occupancy of digitalis receptors in the failing human heart of 24% (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the effect of prostacyclin on the diseased coronary circulation basally and, in particular, on the coronary responses to the cold pressor test, a small dose of 4 ng/kg/min and a large dose of 8 to 10 ng/kg/min was infused in 11 patients with stable angina pectoris. Coronary blood flow was measured by coronary sinus thermodilution technique. The mean blood pressure decreased from 97 +/- 5 to 89 +/- 5 mm Hg during the low-dose infusion (p less than 0.005) and to 81 +/- 5 mm Hg during the high-dose infusion (p less than 0.001); the heart rate increased from 65 +/- 4 to 69 +/- 4 beats/min during the low-dose infusion (p less than 0.05) and to 78 +/- 5 beats/min during the high-dose infusion (p less than 0.001). Systemic vascular resistance decreased by 11 +/- 4% with small doses (p less than 0.05) and by 38 +/- 4% with large doses (p less than 0.001) of prostacyclin, and coronary vascular resistance decreased by 16 +/- 7% (p less than 0.05) with the small dose and by 29 +/- 6% (p less than 0.001) with the large dose of prostacyclin. Seven of 11 patients showed a baseline vasoconstrictor response to the cold pressor test (increase in coronary vascular resistance of 11 +/- 2%). This increase in coronary vascular resistance was not altered by either the small or the large dose of prostacyclin. Thus, prostacyclin causes marked coronary and systemic vasodilation, with no evidence of selective enhancement of the sensitivity of the diseased coronary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

In patients with congestive heart failure (CHF) due to dilated cardiomyopathy, nifedipine, diltiazem and several of the newer calcium antagonists including nicardipine, nitrendipine, felodipine and PN 200-110 (isradipine) improve left ventricular function. Because of its relatively more pronounced negative inotropic and chronotropic actions, verapamil is generally not tolerated by patients with left ventricular failure. In addition, even relatively vascular-selective agents such as nifedipine can occasionally cause significant left ventricular depression, particularly if combined with beta-adrenergic blocking agents. Comparative studies using nitroprusside to cause an equivalent decrease in arterial pressure indicate that nifedipine acts predominantly on the arterial vasculature, and that a small but significant decrease in contractility occurs, apparently due to a direct myocardial action. Although diltiazem causes a depression in myocardial contractility in dogs with volume overload heart failure, limited data show no significant negative inotropic action in patients with heart failure. The negative inotropic effects, if any, of newer and possibly more vascular-selective agents are not yet known. Calcium antagonists appear to act predominantly on the limb and coronary vasculature, with relatively less effect on renal and hepatic vessels. In patients with CHF, nifedipine causes an increase in coronary blood flow and a decrease in the aorto-coronary sinus oxygen difference indicating an improvement in myocardial energetics. Although nifedipine causes an increase in cardiac index and decreases in systemic vascular resistance and pulmonary capillary wedge pressure during exercise, the limited data available fail to show a short- or long-term increase in exercise capacity. Nifedipine causes an increase in plasma renin activity, possibly due to a direct action on the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind, placebo-controlled protocol was used to determine whether milrinone exerts an immediate effect on exercise performance in patients with severe congestive heart failure. In each of 14 patients with New York Heart Association class III or IV congestive heart failure, intravenous milrinone (mean 57 +/- 5 micrograms/kg) and placebo were randomly administered just before maximal progressive upright cycle ergometry. The duration of exercise was significantly longer with milrinone than with placebo treatment (placebo 11.0 +/- 0.6 minutes, milrinone 12.5 +/- 0.9 minutes, p = 0.01). Compared with placebo, milrinone caused a higher peak oxygen uptake (placebo 10.8 +/- 0.6 ml/kg/min, milrinone 12.4 +/- 0.7 ml/kg/min, p = 0.001) and oxygen uptake at the anaerobic threshold (placebo 7.8 +/- 0.4 ml/kg/min, milrinone 9.2 +/- 0.4 ml/kg/min, p = 0.001). At peak exercise intensity, systolic blood pressure (placebo 119 +/- 5 mm Hg, milrinone 131 +/- 5 mm Hg, p = 0.001) and heart rate (placebo 114 +/- 5 beats/min, milrinone 126 +/- 6 beats/min, p = 0.001) were both increased with milrinone. Likewise, at matched submaximal exercise intensities, heart rate (placebo 111 +/- 19 beats/min, milrinone 117 +/- 20 beats/min, p less than 0.05) and systolic blood pressure (placebo 116 +/- 19 mm Hg, milrinone 121 +/- 19 mm Hg, p = 0.04) were higher with milrinone; plasma norepinephrine (placebo 1,692 +/- 208 ng/liter, milrinone 1,320 +/- 216 ng/liter, p = 0.05) and blood lactate concentrations (placebo 2.2 +/- 0.2 mM, milrinone 1.9 +/- 0.2 mM, p less than 0.05) were lower.(ABSTRACT TRUNCATED AT 250 WORDS)

The vascular postsynaptic alpha 1 receptor is the major locus through which adrenergically determined vascular tone is mediated. Therefore, blockade of this receptor is a particularly specific approach to the major pathophysiologic defect in hypertension--an elevation of peripheral vascular resistance. Although the mechanism responsible for this increase in peripheral vascular resistance in hypertension is not known, it is apparent that the sympathetic nervous system plays a key role. In addition, considerable evidence suggests that a common abnormality in hypertension is an increase in the sensitivity of vessels to alpha-adrenergic stimulation, a defect potentially located at the alpha-receptor level. Basic radioligand binding studies of vascular alpha 1 receptors, in fact, demonstrate that the affinity, or avidity, of binding of these sites is under the regulation of both neural and humoral factors. Although diuretics, and more recently, beta-adrenergic blocking agents, have been utilized for the initial treatment of hypertension, recent information about the adverse effects of these agents has led to a reappraisal of the role of alpha-receptor blockade as a rational approach to the initial treatment of hypertension.

Vasodilators play an important role in the treatment of the patient with severe heart failure and increased systemic vascular resistance. However, there are both clinical data and theoretic reasons to anticipate that some degree of tolerance may develop during the long-term use of most agents. The cause of the increased vascular resistance of heart failure is not completely understood, but it appears to be related to a number of neuroendocrine, molecular and physical mechanisms including increased activity of the sympathetic nervous and renin-angiotensin systems, and increased vascular stiffness due to intra- and extracellular sodium and fluid accumulation. Not surprisingly, a lowering of systemic vascular resistance either by direct smooth muscle relaxers or by blockade of specific neuroendocrine systems may result in a number of compensatory responses at the neuroendocrine and/or molecular level. The over-all effectiveness of a particular vasodilator is the net sum of its direct pharmacologic action, and the neuroendocrine and molecular responses to the drug. The specific compensatory mechanisms activated depend on several factors including the type of vasodilator used, the dose employed, the baseline neuroendocrine status of the patient, the severity of heart failure and the functional integrity of various reflex systems. Although not directly applicable to patients with heart failure, much information derived from the use of these agents to treat patients with hypertension and angina pectoris suggests several potential mechanisms by which tolerance may develop to virtually all classes of vasodilators. The major types of vasodilators are discussed with regard to their potential mechanisms of tolerance. Finally, the evidence currently available from long-term studies is reviewed in order to assess the potential relevance of vasodilator tolerance to the clinical management of the patient with heart failure.

Administration of the positive inotropic vasodilator milrinone results in immediate improvement in the maximal and submaximal metabolic responses to exercise. To determine whether these effects persist during long-term therapy, nine patients with severe congestive heart failure were evaluated by upright maximal exercise testing before therapy (baseline), after 10 +/- 1 weeks of oral therapy, and during double-blind, placebo-controlled readministration of intravenous milrinone after withdrawal of oral drug for 24 hours. During long-term oral therapy, maximal oxygen uptake was unchanged (baseline 792 +/- 72 ml per minute, oral therapy 820 +/- 83 ml per minute), whereas the anaerobic threshold was increased significantly from 570 +/- 53 ml per minute to 681 +/- 61 ml per minute. After withdrawal of milrinone, maximal oxygen uptake and anaerobic threshold decreased significantly; subsequent intravenous administration caused significant increases in maximal oxygen uptake and anaerobic threshold, back to the values measured during oral therapy. After oral milrinone withdrawal, maximal oxygen uptake decreased below baseline values, suggesting progression of the underlying disease. The anaerobic threshold expressed as a percent of maximal oxygen uptake was significantly increased during oral therapy (baseline 73 +/- 2 percent, oral therapy 84 +/- 2 percent) and remained significantly increased after drug withdrawal, suggesting a peripheral circulatory effect. These results indicate that in selected patients with severe congestive heart failure, milrinone exerts persistent effects on the metabolic responses to both maximal and submaximal exercise. Because of progressive deterioration in exercise capacity during long-term oral therapy, the effects of milrinone may not be apparent unless it is withdrawn. The relation of milrinone therapy to disease progression is not known.

To determine whether oral milrinone therapy has an effect on complex ventricular arrhythmias in patients with severe congestive heart failure and, if so, whether a change in the severity of complex ventricular arrhythmias after 1 week of milrinone therapy is associated with a change in the mode or frequency of cardiac mortality, a retrospective analysis was performed to determine the frequency of ventricular tachycardia and the density of ventricular couplets on 24-hour ambulatory electrocardiographic recordings performed before and 1 week after initiation of oral milrinone therapy in 74 consecutive patients with New York Heart Association functional class III or IV congestive heart failure. The endpoints of mortality and mode of death were assessed during a mean follow-up of 6 months. In 91% of the patients, 1 week of oral milrinone therapy was associated with no significant change (85%) or a significant decrease (6%) in the density of ventricular couplets and frequency of ventricular tachycardia. However, in 9% of patients the frequency of complex ventricular arrhythmias increased significantly at the end of 1 week of oral milrinone therapy. In this subgroup, neither total cardiac mortality nor the incidence of sudden cardiac death was significantly higher than that in patients with no change or a decrease in complex ventricular ectopic activity.

Although it has been suggested that calcium channel blocking agents may be utilized as vasodilators in patients with congestive heart failure, these agents also have the potential to cause a deterioration in cardiac function because of their negative inotropic actions. There is considerable variation among the available agents with regard to their relative effects on the vasculature, myocardial inotropy, and myocardial chronotropy. Thus, at clinically relevant dosages, nifedipine is a potent systemic and coronary vasodilator, but it has little or no direct effect on inotropy and chronotropy. In contrast, verapamil exerts significant negative inotropic and chronotropic effects at vasodilatory dosages, whereas diltiazem is a potent vasodilator with a negative chronotropic action at dosages that do not affect inotropy. In patients with heart failure, the largest experience so far has been with nifedipine. Data derived from over 100 patients with moderate to severe congestive heart failure indicate a generally beneficial net hemodynamic response to nifedipine, with substantial improvements in cardiac index (+24 percent) and left ventricular filling pressure (-15 percent). The major effect seems to be on arteriolar resistance vessels, resulting in a reduction in afterload, with relatively little effect on venous pressures. Limited data suggest that the initial effect is sustained during long-term therapy. The clinical experience with verapamil and diltiazem in patients with heart failure is at present limited. In patients with normal or mildly impaired left ventricular function, verapamil's vasodilator and negative inotropic effects are counterbalanced. With severe left ventricular dysfunction, however, treatment with verapamil can result in abrupt decompensation and development of overt pulmonary edema and hypotension. Diltiazem's relative lack of negative inotropic effects may allow it to be used safely in patients with congestive heart failure, particularly when control of supraventricular tachyarrhythmia is required.

A direct intracoronary infusion technique was used to characterize the mechanisms of action of milrinone, a new phosphodiesterase inhibitor. Because of the small quantity of drug infused, it is possible to achieve a therapeutic concentration of drug in the heart with little or no systemic accumulation. Because loading conditions are largely unaffected during intracoronary drug infusion, it is possible to use left ventricular +dP/dt as a convenient measure of changes in contractility. Intracoronary milrinone infusion caused a dose-related increase in +dP/dt associated with a substantial improvement in left ventricular pump function. In addition, there is a small decrease in heart rate, which appeared to be secondary to reflex withdrawal of sympathetic tone, since it was associated with a decrease in plasma norepinephrine. Measurement of forearm vascular resistance and forearm venous capacitance by plethysmography indicated that although there was no significant decrease in forearm vascular resistance during intracoronary drug infusion, there was a small increase in venous capacitance. Subsequent intravenous administration of milrinone caused a substantial further improvement in left ventricular pump function, associated with a substantial decrease in left- and right-sided cardiac filling pressures and forearm vascular resistance, and an increase in forearm venous capacitance. These findings suggest that reflex sympathetic withdrawal may contribute to the venous dilation that occurs with milrinone, but that the major effects of milrinone on vascular tone are due to a direct vascular action of the drug. Intracoronary infusion of dobutamine has also demonstrated a substantial decrease in the inotropic response to beta-adrenergic stimulation in patients with congestive heart failure, presumably because of down-regulation of beta-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurohumoral modulation of cardiovascular function is an important component of the hemodynamic alterations in patients with chronic congestive heart failure (CHF). Analysis of heart rate (HR) variability is a noninvasive means of investigating the autonomic control of the heart. The variability of HR and respiratory signals, both derived from ambulatory electrocardiographic recordings, were analyzed with power spectral analysis to evaluate autonomic control in 25 patients with chronic stable CHF (class III or IV) and 21 normal control subjects. In the patients with CHF, HR spectral power was markedly reduced (p less than 0.0001) at all frequencies examined (0.01 to 1.0 Hz, period 1 to 100 seconds) and virtually absent at frequencies greater than 0.04 Hz. Heart rate fluctuations at very low frequencies (0.01 to 0.04 Hz) less effectively differentiated CHF patients from control subjects, due to discrete (about 65 seconds, 0.015 Hz) oscillation in HR, which was associated with a similar pattern in respiratory activity in many of the patients with CHF. These findings demonstrate a marked derangement of HR modulation in patients with severe CHF. The frequency characteristics of HR fluctuations in these patients are consistent with abnormal baroreflex responsiveness to physiologic stimuli, and suggest that there is diminished vagal, but relatively preserved sympathetic, modulation of HR.

Although the effect of systemic vasodilator therapy on left ventricular function in congestive heart failure has been extensively evaluated, little is known about its effect on pulmonary vascular resistance and right ventricular function. Since pulmonary vascular resistance is mediated in part by alpha-adrenergic receptors, we studied the effects of the alpha-adrenergic antagonist prazosin on right ventricular function as determined by a radionuclide ventriculographic technique which assessed right and left ventricular ejection fractions simultaneously. In 11 patients treated for two months with prazosin, right ventricular ejection fraction increased from 0.28 +/- 0.04 to 0.44 +/- 0.07 (p less than 0.01). In 10 patients who received a single dose of prazosin 48 hours after withdrawal of prior prazosin therapy, right ventricular ejection fraction increased from 0.29 to 0.05 to 0.38 +/- 0.06 (p less than 0.02). In nine patients who received a single dose of prazosin during right sided heart catheterization, pulmonary vascular resistance decreased from 358 +/- 70 to 236 +/- 60 dyne-sec-cm -5 (p less than 0.01). These studies suggest that prazosin has beneficial effects on right ventricular function both immediately and long-term in patients with severe congestive heart failure. Although the mechanism of this effect is not known, possibilities include a direct effect of prazosin on the pulmonary vasculature, a secondary reduction in right ventricular afterload due to improved left ventricular performance and a withdrawal of reflex-mediated pulmonary vasoconstriction due to improved left ventricular performance.