Biomedical subjects
Publications and source records attributed to Henry Krum.
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BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors and beta-blockers are standard therapy for chronic heart failure (CHF). beta-blockers are recommended to be initiated after ACE-inhibitors, but this order is not evidence based. The initiation order may be important since many, especially elderly CHF patients cannot tolerate target doses of both. Data suggest that beta-blockers may be more important to CHF patients than ACE-inhibitors, especially in early stages of CHF. AIMS: To compare the effect on combined death or hospitalisation of initial monotherapy with either bisoprolol or enalapril, followed by combination therapy. METHODS: One-thousand CHF patients without ACE-inhibitor, beta-blocker or angiotensin-receptor-blocker therapy will be randomised 1:1 to monotherapy with either enalapril or bisoprolol for 6 months, followed by combined therapy for 6-18 months. The primary objective is to show non-inferiority for bisoprolol-first vs. enalapril-first regarding combined death or hospitalisation. If that is shown, superiority for bisoprolol-first will be tested. CONCLUSIONS: If the trial shows non-inferiority for bisoprolol-first vs. enalapril-first, the first CHF therapy may be chosen based on individual judgement in each patient. If bisoprolol-first is superior to enalapril-first, a beta-blocker should be given prior to an ACE-inhibitor in CHF, and the paradigm of testing CHF compounds against a background of ACE-inhibitor therapy will be challenged.
AIMS: To investigate the effect of valsartan in the Valsartan-Heart Failure Trial (Val-HeFT) when added to angiotensin-converting enzyme inhibitor (ACEi) alone in patients with heart failure (HF). METHODS: Subjects in Val-HeFT receiving ACEi but not beta-blocker at baseline were analysed; 1532 were assigned to valsartan and 1502 assigned to placebo. Primary outcome events (all-cause mortality, hospitalisation for adjudicated heart failure, sudden death with resuscitation and need for >4 h of parenteral therapy for worsening heart failure) were monitored. RESULTS: Mortality was not affected by valsartan but morbidity endpoints were significantly reduced (36.3% in placebo, 31.0% in valsartan, p=0.002) in patients receiving an ACEi but no beta-blocker. Quality of life (QOL) was significantly improved, ejection fraction (EF) significantly increased, left ventricular (LV) diameter significantly reduced and plasma B-type natriuretic peptide, norepinephrine and aldosterone levels significantly reduced with valsartan compared to placebo. The morbidity benefit was significant in patients on ACEi doses below the median (22% reduction, p=0.003) and not statistically significant in those receiving ACEi doses above the median (14% reduction, p=0.143). CONCLUSION: Valsartan reduces heart failure hospitalisations and slows LV remodelling in patients treated with an ACEi in the absence of beta-blockade, particularly in those on lower doses of ACEi.
Urotensin II (UII) is a potent vaso-active peptide thought to have multiple roles in the regulation of cardiovascular physiology and pathophysiology. The actions of UII are complex and difficult to interpret given its systemic hemodynamic effects and variable action on different vascular beds and isolated vessels. Direct effects of UII on the myocardium, include myocyte hypertrophy, extracellular matrix deposition and contractility. These observations, together with elevated plasma levels found in disease, are common traits reported in other pathophysiologically implicated neurohormonal systems. In this review, we include original data obtained from chronic infusion of UII in rats. We report a reduction in first derivative of left ventricular pressure (+dP/dt), as well as an increase in the ratio of left ventricular collagen I:III, that may contribute to the reduced myocardial contractility observed in these animals.
BACKGROUND: Resistance exercise training was applied to patients with chronic heart failure (CHF) on the basis that it may partly reverse deficiencies in skeletal muscle strength and endurance, aerobic power (VO(2peak)), heart rate variability (HRV), and forearm blood flow (FBF) that are all putative factors in the syndrome. METHODS AND RESULTS: Thirty-nine CHF patients (New York Heart Association Functional Class=2.3+/-0.5; left ventricular ejection fraction 28%+/-7%; age 65+/-11 years; 33:6 male:female) underwent 2 identical series of tests, 1 week apart, for strength and endurance of the knee and elbow extensors and flexors, VO(2peak), HRV, FBF at rest, and FBF activated by forearm exercise or limb ischemia. Patients were then randomized to 3 months of resistance training (EX, n=19), consisting of mainly isokinetic (hydraulic) ergometry, interspersed with rest intervals, or continuance with usual care (CON, n=20), after which they underwent repeat endpoint testing. Combining all 4 movement patterns, strength increased for EX by 21+/-30% (mean+/-SD, P<.01) after training, whereas endurance improved 21+/-21% (P<.01). Corresponding data for CON remained almost unchanged (strength P<.005, endurance P<.003 EX versus CON). VO(2peak) improved in EX by 11+/-15% (P<.01), whereas it decreased by 10+/-18% (P<.05) in CON (P<.001 EX versus CON). The ratio of low-frequency to high-frequency spectral power fell after resistance training in EX by 44+/-53% (P<.01), but was unchanged in CON (P<.05 EX versus CON). FBF increased at rest by 20+/-32% (P<.01), and when stimulated by submaximal exercise (24+/-32%, P<.01) or limb ischemia (26+/-45%, P<.01) in EX, but not in CON (P<.01 EX versus CON). CONCLUSIONS: Moderate-intensity resistance exercise training in CHF patients produced favorable changes to skeletal muscle strength and endurance, VO(2peak), FBF, and HRV.
Plasma levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP (N-BNP) are highly sensitive markers of ventricular dysfunction and/or hypertrophy and, in established disease, offer prognostic value and may be useful for guidance of therapy. Ng and co-workers report in this issue of Clinical Science that urinary levels of N-BNP may be as useful as plasma levels for the discrimination of patients with and without heart failure. This raises the potential for a relatively simple urine test that could be used for the diagnosis of heart failure. Roles in prognostication and the guidance of therapy may also be possible but, perhaps of most significance, measurement of urinary N-BNP may be applied to screening of patients at high risk of heart failure. The main limitations of the study were that the sample of heart failure patients comprised only 34 individuals with New York Heart Association functional Class IV and that the observed correlation between levels of urinary N-BNP and plasma creatinine seemed counter-intuitive. The latter issue needs clarification, as renal impairment is a frequent co-morbidity among patients with heart failure and will potentially confound any observed association between ventricular dysfunction and urinary N-BNP levels. Another caveat is that it is unclear if testing for urinary N-BNP can be cheaply and conveniently administered on a large scale. Nevertheless, this first demonstration of elevated N-BNP in the urine of patients with heart failure raises a number of exciting possibilities with regard to the management of patients with established or possible heart failure. Further investigation is required and eagerly awaited.
Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective 'conventional' nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I2 over thromboxane A2 within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E2 and I2 within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is the urgent need for randomized clinical trials designed specifically to examine the impact of selective cyclooxygenase-2 inhibitors on cardiovascular risk.
There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone), Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.
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The pronounced pharmacodynamic effects of human urotensin-II (U-II), a 'somatostatin-like' cyclic undecapeptide, are mediated via the G protein-coupled receptor UT (formerly known as GPR14). Emerging clinical studies implicate U-II in the etiology of several cardiorenal and metabolic disease states in humans. Although the specific pathogenic role(s) of U-II remain to be clearly defined, existing data warrant further clinical investigation. The therapeutic development of specific U-II/UT inhibitors will assist in establishing a causative role for U-II in the progression and/or maintenance of hypertension, heart failure, renal tubular disease and diabetes.
Chronic heart failure is an increasingly common cause of premature death and poor quality of life. Community-based epidemiological studies have provided much-needed information on the demography of chronic heart failure, providing insight into its influence on public health. In most patients, chronic heart failure is accompanied by a range of concomitant disorders that both contribute to the cause of the disease and have a key role in its progression and response to treatment. Information on the most common comorbidities in chronic heart failure--ischaemic heart disease, hypertension, and diabetes mellitus--is presented for prespecified subgroups in the reports of many large-scale, multicentre trials; despite their limitations, these subanalyses provide guidance in therapeutic decision-making. Similarly, because chronic heart failure is commonly an endpoint in intervention trials of both hypertension and diabetes, such studies afford important information on the prevention of chronic heart failure in these common diseases.
Urotensin II (UII) is a somatostatin-like peptide recently identified as a potent vasoconstrictor. In this study, we examined whether UII promotes cardiac remodeling through nonhemodynamic effects on the myocardium. In a rat model of heart failure after myocardial infarction (MI), increased UII peptide and UII receptor protein expression was observed in both infarct and noninfarct regions of the left ventricle compared with sham. Moreover, post-MI remodeling was associated with a significant 75% increase in UII receptor gene expression in the heart (P<0.05 versus sham controls), with this increase noted in both regions of the left ventricle. In vitro, UII (10-7 mol/L) stimulation of neonatal cardiac fibroblasts increased the level of mRNA transcripts for procollagens alpha1(I), alpha1(III), and fibronectin by 139+/-15% (P<0.01), 59+/-5% (P<0.05), and 141+/-14% (P<0.01), respectively, with a concomitant 23+/-2% increase in collagen peptide synthesis as determined by 3H-proline incorporation (P<0.01). UII had no effect on cellular hypertrophy, as determined by changes in total protein content in isolated neonatal cardiomyocytes. However, expression of recombinant rat UII receptor in neonatal cardiomyocytes resulted in significant UII-dependent activation of hypertrophic signaling as demonstrated by increased total protein content (unstimulated, 122.4+/-4.0 microg/well; rat UII, 147.6+/-7.0 microg/well; P<0.01) and activation of the hypertrophic phenotype through Galpha(q)- and Ras-dependent pathways. These results indicate that, in addition to potent hemodynamic effects, UII may be implicated in myocardial fibrogenesis through increased collagen synthesis by cardiac fibroblasts and may also be an important determinant of pathological cardiac hypertrophy in conditions characterized by UII receptor upregulation.
CONTEXT: Beta-blockers remain underused despite their established utility for improving outcome in heart failure. Concerns that initiation of treatment produces few immediate benefits and may have important risks may be deterring widespread use. OBJECTIVE: To evaluate the early effects of the beta-blocker carvedilol in patients with severe heart failure. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled trial conducted from October 28, 1997, to March 20, 2000, at 334 hospital centers in 21 countries among 2289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had a left ventricular ejection fraction of less than 25%. INTERVENTION: Patients were randomly assigned to receive carvedilol, with start dosage of at 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily (n = 1156), or placebo (n = 1133), in addition to their usual medications for heart failure. MAIN OUTCOME MEASURES: Death, hospitalization, or permanent withdrawal from study drug, as well as adverse events during the first 8 weeks of treatment. RESULTS: The carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 vs 25; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.41-1.35); who died or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs 188; HR, 0.83; 95% CI, 0.68-1.03). These effects were similar in direction and magnitude to those observed during the entire study, and were apparent particularly in the 624 patients with recent or recurrent decompensation or a very depressed left ventricular ejection fraction. Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs 5.1%). CONCLUSIONS: These data suggest that, in clinically euvolemic patients, the relation of benefit to risk during initiation of treatment with carvedilol is similar to that seen during long-term therapy with the drug. Our findings should provide the reassurance needed to encourage the high levels of use that are warranted by the results of long-term clinical trials.
COENZYME Q10 IN PHYSICAL EXERCISE. We identified eleven studies in which CoQ10 was tested for an effect on exercise capacity, six showed a modest improvement in exercise capacity with CoQ10 supplementation but five showed no effect. CoQ10 IN HYPERTENSION. We identified eight published trials of CoQ10 in hypertension. Altogether in the eight studies the mean decrease in systolic blood pressure was 16 mm Hg and in diastolic blood pressure, 10 mm Hg. Being devoid of significant side effects CoQ10 may have a role as an adjunct or alternative to conventional agents in the treatment of hypertension. CoQ10 IN HEART FAILURE. We performed a randomised double blind placebo-controlled pilot trial of CoQ10 therapy in 35 patients with heart failure. Over 3 months, in the CoQ10 patients but not in the placebo patients there were significant improvements in symptom class and a trend towards improvements in exercise time. META-ANALYSIS OF RANDOMISED TRIALS OF COENZYME Q10 IN HEART FAILURE. In nine randomised trials of CoQ10 in heart failure published up to 2003 there were non-significant trends towards increased ejection fraction and reduced mortality. There were insufficient numbers of patients for meaningful results. To make more definitive conclusions regarding the effect of CoQ10 in cardiac failure we recommend a prospective, randomised trial with 200-300 patients per study group. Further trials of CoQ10 in physical exercise and in hypertension are recommended.
BACKGROUND: Diabetes mellitus is a frequent comorbid condition in patients with chronic heart failure (CHF) and confers a worse prognosis. Furthermore, although patients with CHF derive considerable benefit from beta-blockers, these agents are thought by many physicians to be contraindicated in patients with diabetes mellitus. Most published studies on beta-blockers in CHF have been unable to reach definitive conclusions about the mortality benefits of these agents in patients with diabetes mellitus. We therefore performed a meta-analysis of beta-blocker trials that reported mortality outcomes in patients with diabetes mellitus who had CHF to pool all available trial evidence on the benefits (or otherwise) of these agents in this setting. METHODS: All-cause mortality data on patients with diabetes mellitus were obtained from all completed beta-blocker CHF randomized placebo-controlled trials involving >100 patients exposed to beta-blockers, in which outcomes in patients with diabetes mellitus were described. When events were not directly reported, risk ratios (RRs) were derived from analysis of figures and other manuscript data. Results were pooled with the Mantel-Haenszel method. RESULTS: A total of 24.6% of patients were reported to have diabetes mellitus in the 6 studies analyzed (Australia and New Zealand [ANZ]-Carvedilol, Beta-blocker Evaluation of Survival Trial [BEST], Carvedilol US Trials, Cardiac Insufficiency Bisoprolol Study [CIBIS-II], Carvedilol Prospective Randomized Cumulative Survival Trial [COPERNICUS], and Metoprolol Controlled-release Randomized Intervention Trial in Heart Failure [MERIT-HF]). Patients with diabetes mellitus had increased mortality rates overall compared with subjects without diabetes mellitus (RR, 1.25; 95% CI, 1.15-1.36; P <.001). Compared with placebo, beta-blocker therapy for CHF was beneficial in patients with diabetes mellitus (RR, 0.84; 95% CI, 0.73-0.96; P =.011) and in subjects without diabetes mellitus (RR, 0.72; 95% CI, 0.65-0.79; P <.001). The absolute risk reduction in mortality with beta-blocker therapy was greater in patients with heart failure but without diabetes mellitus than in patients with diabetes mellitus (P =.023). CONCLUSIONS: Patients with diabetes mellitus and CHF appear to derive prognostic benefit from beta-blocker therapy, although the magnitude of that benefit is somewhat less than that observed in subjects without diabetes mellitus.
BACKGROUND: Antihypertensive drug therapy is considered lifelong but in the family practice environment drug cessation may provide an opportunity to attempt nonpharmacologic strategies for blood pressure (BP) control with a clear outcome, maintaining drug-free status. The identification of simple predictors would assist the family physician to select who may or may not have their medication ceased. METHODS: To monitor a drug cessation program in currently treated hypertensive patients in Australian family practice, 25,826 patients aged 65 to 84 years currently receiving antihypertensive medication, were offered drug withdrawal as part of the run-in phase of a large clinical trial. Outcomes investigated were the proportion of patients completing drug withdrawal and maintaining short-term BP control and factors that predicted these patients. RESULTS: A total of 18,993 patients did not enter the withdrawal program; 6291 (92% of those who entered) completed drug withdrawal. In comparison to patients who did not complete drug withdrawal, they were younger and more likely male. A total of 1,228 (18% of those who entered) ceased medication and maintained adequate BP control for 0 to 76 weeks (median, 4 weeks). Cox regression analysis identified lower on therapy systolic and diastolic BP, younger age, type of agent, and monotherapy as predictors of successful drug withdrawal and maintenance of BP control. CONCLUSIONS: Cessation of antihypertensive drug therapy is possible in a substantial proportion (18%) of patients attending family practice who are willing to do so and is most successful in those who are younger with BP controlled on monotherapy. Where this strategy is initiated, use of such predictors, effective behavioral change, and systematic follow-up is recommended.
Current heart failure guidelines mandate the use of beta-blockers in patients with symptomatic systolic heart failure. In the past 12-18 months, there have been several reported advances in our understanding of beta-blocker therapy for heart failure. Despite these advances, there remain several unanswered questions with regard to beta-blockers. These involve, firstly, clarifying the underlying mechanisms of action of beta-blockers; secondly, further analysing patients with systolic heart failure who are not well-studied in major clinical trials (e.g. the elderly); thirdly, investigating unexplored indications for beta-blockers in heart failure; and finally, directly examining the clinical relevance of pharmacological differences among agents. The impact of genetic polymorphisms on the response to beta-blocker therapy, as well as interaction of these agents with future heart failure therapies, requires extensive investigation.
There has been considerable recent disappointment with the failure of a number of major new pharmacological strategies for the treatment of chronic heart failure. In turn, there has been much speculation as to why trials of these therapies have not shown benefit. Among a number of plausible and scientifically valid reasons, consideration should be afforded to the potential contribution of "regression to the truth." Regression to the truth derives from the biological concept of regression to the mean, whereby random fluctuations in a biological variable occur over time, such that the true value of the variable is approached with repeated measurements. This same concept can be applied to clinical trial programs for new drugs for heart failure. Because only strongly positive trials generally go on to phase III testing, and some of these early phase studies are positive by chance alone, on retesting in phase III the results are very likely not be as strongly positive. Numerous examples of regression to the truth apply for trials of heart failure therapies, as well as in other areas. A major concern is how to minimize negative outcomes in phase III trials. One approach is to perform major rigorous phase II testing. Alternatively, avoidance of phase II testing will minimize "regression to the truth" because there are no data in phase II from which regression might occur. However, this approach does not obviate the need for an evaluation process in the selection of candidate agents (and their appropriate dose) in order to proceed to definitive testing.