Henry Krum

Double-Blind, Placebo-Controlled Study of the Long-term Efficacy of Carvedilol in Patients With Severe Chronic Heart Failure

BACKGROUNDnClinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated.nnnMETHODS AND RESULTSnWe enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16 +/- 0.01 and a mean maximal oxygen consumption of 13.6 +/- 0.6 mL.kg-1.min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n = 33) or matching placebo (n = 16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P = .005) and stroke volume index (P = .010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P = .003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P = .002), functional class (P = .013), and submaximal exercise tolerance (P = .006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P = .028), but carvedilol-treated patients had more dizziness and advanced heart block.nnnCONCLUSIONSnCarvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure

OBJECTIVESnThis study was conducted to determine the effect of long-term digoxin therapy on autonomic function in patients with mild to moderate chronic heart failure.nnnBACKGROUNDnChronic heart failure is characterized by increased sympathetic activity and decreased parasympathetic activity. Intravenous digitalis has been found to reduce sympathetic activity immediately in these patients, but whether short-term neurohormonal effects are sustained during long-term oral therapy has not been assessed.nnnMETHODSnWe determined sympathetic activity in 26 patients with heart failure by measuring plasma norepinephrine levels and parasympathetic activity from variables of heart period variability derived from 24-h ambulatory electrocardiographic Holter recordings obtained before and after 4 to 8 weeks of digoxin therapy.nnnRESULTSnAfter digoxin therapy, plasma norepinephrine decreased significantly from a mean +/- SEM of 552 +/- 80 to 390 +/- 37 ng/ml. In addition, the RR interval increased significantly from 719 +/- 19 to 771 +/- 20 ms. High frequency power increased from 84 +/- 24 to 212 +/- 72 ms2, and the root mean square of successive differences in RR interval increased from 20.3 +/- 1.8 to 27.0 +/- 3.4 ms, indicating a substantial increase in parasympathetic activity. Low frequency power, an index of baroreflex activity, was also significantly increased (239 +/- 80 to 483 +/- 144 ms2) by digoxin therapy.nnnCONCLUSIONSnThese results indicate 1) that long-term therapy with digoxin acts to ameliorate the autonomic dysfunction of patients with heart failure, and 2) that the short-term neurohormonal effects of digoxin are sustained during prolonged treatment with the drug.

Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure : Role of endothelium-derived nitric oxide

OBJECTIVESnThis study was undertaken to investigate the role of endothelium-derived nitric oxide in the regulation of forearm blood flow during exercise in normal subjects and patients with congestive heart failure.nnnBACKGROUNDnNitric oxide-mediated vasodilation in response to muscarinic stimulation is impaired in the peripheral circulation of patients with congestive heart failure. Whether nitric oxide-mediated vasodilation during exercise is also impaired in patients with congestive heart failure is unknown.nnnMETHODSnForearm blood flows (ml/min per 100 ml) were determined during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction by venous occlusion plethysmography before and after regional inhibition of nitric oxide synthesis with administration of L-NG-monomethylarginine (L-NMMA) in the brachial artery of 17 patients with congestive heart failure (mean age 49 years, mean left ventricular ejection fraction 0.22) and 10 age-matched normal subjects.nnnRESULTSnBefore administration of L-NMMA in the brachial artery, forearm blood flows in patients with congestive heart failure during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction were slightly but not significantly lower than that of normal subjects ([mean +/- SE] 6.8 +/- 1.0, 8.5 +/- 1.0 and 12.9 +/- 1.7 ml/min per 100 ml, respectively, in patients with congestive heart failure vs. 6.6 +/- 1.2, 11.6 +/- 1.9 and 16.2 +/- 1.9 ml/min per 100 ml, respectively, in normal subjects, p = NS). After administration of L-NMMA in the brachial artery, forearm blood flows in normal subjects significantly decreased by 10% to 21% during hand grip exercise but did not change during exercise in patients with congestive heart failure.nnnCONCLUSIONSnRegional inhibition of nitric oxide synthase with administration of L-NMMA in the brachial artery significantly decreased forearm blood flows during rhythmic hand grip exercise in normal subjects but not in patients with congestive heart failure. These findings suggest that nitric oxide-mediated vasodilation during submaximal exercise is impaired in the forearm circulation of patients with congestive heart failure.

Role of Endothelin in the Exercise Intolerance of Chronic Heart Failure

In conclusion, plasma levels of the endothelial-derived vasoconstrictor endothelin-1 (but not those of other neurohormonal vasoconstrictor factors), measured during exercise correlated closely with objective variables of exercise capacity in patients with heart failure. These findings suggest that endothelin-1 may contribute to exercise intolerance in patients with heart failure, perhaps by limiting the ability of the peripheral vasculature to dilate during exercise.

Potential of left ventricular assist devices as outpatient therapy while awaiting transplantation

Left ventricular assist devices (LVADs) increasingly are being used as a bridge to transplantation. We studied changes in New York Heart Association class, mean arterial pressure, resting cardiac output, end-organ function, exercise oxygen consumption, and exercise cardiac output in 12 LVAD recipients. In addition, resting levels of neurohormonal factors were evaluated 4 to 16 weeks after implantation. Two of the 12 patients died of right heart failure and 1 of aspiration; all deaths occurred in the first 2 weeks after LVAD implantation. Of the other 9 patients, 8 improved to New York Heart Association class I and 1 to class II, all of whom were in class IV preoperatively. The 4 patients who underwent exercise testing achieved an exercise oxygen consumption of 15.0 +/- 2.7 mL.kg-1.min-1, which was paralleled by an increase in resting cardiac output from 3.07 +/- 0.9 L.min-1 preoperatively to 5.66 +/- 1.1 L.min-1 at 2 months, and mean arterial pressure from 60 +/- 8 to 91 +/- 10 mm Hg at 2 months, a benefit that was maintained for up to 10 months. End-organ function revealed comparable improvement at 2 months for both creatinine (1.68 +/- 0.7 to 1.0 +/- 0.19 mg.dL-1) and total bilirubin (1.37 +/- 1.17 to 0.54 +/- 0.26 mg.dL-1) levels. Levels of neurohormones were within normal limits. Adverse clinical events after the perioperative period were minimal, and no thromboembolic complications occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure

To determine the effect of beta blockade on parasympathetic nervous system activity, we assessed RR variability during 24-hour Holter monitoring in 10 patients with congestive heart failure before and after 3 to 4 months of treatment with the beta blocker carvedilol. High-frequency power increased from 26 to 64 ms2, root-mean-square of successive differences in RR interval increased from 14.3 to 23.7 ms2, and percentage of absolute differences >50 ms between successive normal RR intervals increased from 0.8% to 4.7%, all p <0.01, indicating a substantial increase in parasympathetic modulation of RR intervals.

Catalytic Degradation of Vitamin D Up-regulated Protein 1 mRNA Enhances Cardiomyocyte Survival and Prevents Left Ventricular Remodeling after Myocardial Ischemia *

Vitamin D3 up-regulated protein 1 (VDUP1) is a key mediator of oxidative stress on various cellular processes via downstream effects on apoptosis signaling kinase 1 (ASK1) and p38 mitogen-activated protein kinase (MAPK). Here, we report that VDUP1 expression is significantly increased in rat hearts following acute myocardial ischemia, suggesting it may have important regulatory effects on cardiac physiological processes during periods of oxidative stress. Transfection of H9C2 cardiomyoblasts with a sequence-specific VDUP1 DNA enzyme to down-regulate VDUP1 mRNA expression significantly reduced apoptosis and enhanced cell survival under conditions of H2O2 stress, and these effects involved inhibition of ASK1 activity. Direct intracardiac injection of the DNA enzyme at the time of acute myocardial infarction reduced myocardial VDUP1 mRNA expression and resulted in prolonged reduction in cardiomyocyte apoptosis and ASK1 activity. Moreover, down-regulation of VDUP1 was accompanied by significant reduction in cardiac expression of pro-collagen type I α2 mRNA level, as well as marked reduction in myocardial scar formation. These features were accompanied by significant improvement in cardiac function. Together, these results suggest a direct role for VDUP1 in the adverse effects of ischemia and oxidative stress on cardiomyocyte survival, left ventricular collagen deposition, and cardiac function. Strategies to inhibit VDUP1 expression and/or function during acute ischemic events may be beneficial to cardiac functional recovery and prevention of left ventricular remodeling.

Acetylcholine-Mediated Vasodilation in the Forearm Circulation of Patients With Heart Failure: Indirect Evidence for the Role of Endothelium-Derived Hyperpolarizing Factor

Vasomotor responses to intraarterial administration of acetylcholine are mediated by release of nitric oxide, prostaglandins, and an unidentified hyperpolarizing factor from vascular endothelial cells. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to the vasodilatory response to acetylcholine in the skeletal muscle circulation of patients with congestive heart failure (CHF) has not been previously characterized. Accordingly, to specifically assess the role of EDHF, the regional vascular effects of sequential administration of acetylcholine and nitroglycerin in the brachial artery were determined in the forearm circulation with strain-gauge venous occlusion plethysmography in patients with CHF and in normal subjects during combined systemic inhibition of cyclooxygenase activity with indomethacin and regional inhibition of nitric oxide synthase activity with l-N(G)-monomethylarginine (l-NMMA). After administration of indomethacin, infusion of l-NMMA significantly decreased the forearm blood flow response to acetylcholine in normal subjects (5.4 +/- 1.2 to 3.5 +/- 0.6 ml/min/100 ml, p < 0.05) but not in patients with CHF (5.7 +/- 1.3 to 5.7 +/- 1.4 ml/min/100 ml). Infusion of l-NMMA did not change forearm blood flow responses to nitroglycerin in either group. The presence of a noncyclooxygenase, non-nitric-oxide relaxing factor indicates that EDHF, rather than nitric oxide, may be the predominant endothelium-derived substance mediating vasodilation in response to acetylcholine in patients with CHF.

Effect of Endothelin-1 on Exercise-Induced Vasodilation in Normal Subjects and in Patients With Heart Failure

Forearm blood flow (ml/min/100 ml) was determined with strain-gauge venous occlusion plethysmography at rest and in response to handgrip exercise in 7 patients with congestive heart failure and in 9 normal subjects before and after regional administration of endothelin-1 in the brachial artery. Administration of endothelin-1 significantly decreased forearm blood flow at rest and during exercise in normal subjects but did not change it at rest or during exercise in patients with congestive heart failure.

SPONTANEOUS ENDOTHELIN PRODUCTION BY CIRCULATING MONONUCLEAR CELLS FROM PATIENTS WITH CHRONIC HEART FAILURE BUT NOT FROM NORMAL SUBJECTS

1. Plasma endothelin‐1 (ET‐1) levels are increased in chronic heart failure (CHF). Because chronic immunologic activation occurs in CHF and mononuclear cells (MNC) are capable of ET‐1 production, the possible contribution of circulating MNC to the increased plasma ET‐1 levels in CHF patients was investigated.