Generalized nonlinear models for pharmacokinetic data

Phase I trials to study the pharmacokinetic properties of a new drug generally involve a restricted number of healthy volunteers. Because of the nature of the group involved in such studies, the appropriate distributional assumptions are not always obvious. These model assumptions include the actual distribution but also the ways in which the dispersion of responses is allowed to vary over time and the fact that small concentrations of a substance are not easily detectable and hence are left censored. We propose that a reasonably wide class of generalized nonlinear models allowing for left censoring be considered now that this is feasible with current computer power and sophisticated statistical packages. These modelling strategies are applied to a Phase I study of the drug flosequinan and its metabolite. This drug was developed for the treatment of heart failure. Because the metabolite also exhibits an active pharmacologic effect, study of both the parent drug and the metabolite is of interest.     

Clinical Evaluation of Practolol,a New Cardioselective Beta-blocking Agent in Angina Pectoris

In a controlled double-blind study practolol, a new cardioselective beta-blocking drug, was given to 15 patients with angina pectoris, and compared with propranolol 80 mg. q.d.s. The dose of practolol ranged from 200 to 600 mg.b.d. and was decided by initial open titration in individual patients. Though practolol did not influence the incidence of angina or glyceryl trinitrate consumption, it increased the duration of exercise possible in exercise tests and reduced the amount of ischaemic S—T depression in the radiocardiogram during exercise. Propranolol reduced the incidence of angina and, in the exercise tests, increased the amount and duration of exercise but did not affect the degree of S—T depression. Unlike propranolol, practolol did not produce any adverse effects on bronchial smooth muscle. Hence it is concluded that practolol is an effective drug in treating angina, and in the dosage used is of potential value in patients with asthmatic bronchitis and angina. It should, however, be used cautiously in anginal patients with heart failure.     

有氧康复运动对慢性心力衰竭患者心室重构及血管内皮功能的影响

目的:探讨有氧康复运动对慢性心力衰竭(chronic cardiac failure,CHF)患者心室重构及血管内皮功能的影响。方法:78例CHF患者随机分为运动组(n=39)、对照组(n=39)。对照组给予常规内科药物治疗、日常活动能力训练,运动组在此基础上根据美国心脏病学会(American Heart Association,AHA)的《三阶段康复运动方案》进行有氧康复运动,共持续12周。比较两组治疗前后心脏结构和功能、血管内皮功能及生活质量的改善情况。结果:干预后,两组左室收缩末期内径(left ventricular end systolic diameter,LVESD)、左室舒张末期内径(left ventricular end-diastolic diameter,LVEDD)、明尼苏达心衰生活质量(Minnesota Living With Heart Failure,MLHF)评分、血清内皮素-1(Endothelin-1,ET-1)、血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)水平均明显减小,左室射血分数(left ventricular ejection fraction,LVEF)、6分钟步行试验(6 minute walking test,6MWT)、血清一氧化氮(nitric oxide,NO)、降钙素基因相关肽(calcitonin gene-related peptide,CGRP)水平均明显升高,且运动组LVESD、LVEDD、MLHF评分、血清ET-1、Ang Ⅱ水平明显低于对照组,LVEF、6MWT、血清NO、CGRP水平明显高于对照组,差异均有统计学意义(P0.05)。运动组干预期间心衰再入院率显著低于对照组,差异均有统计学意义(P0.05)。结论:有氧运动康复训练有助于改善CHF患者的血管内皮功能,延缓或逆转心室重构,提高生活质量,改善预后。     

Exhaled nitric oxide and exercise performance in heart failure

BACKGROUND: In heart failure abnormalities of pulmonary function are frequently observed particularly during exercise, which is characterized by hyperpnea, low tidal volume, early expiratory flow limitation and reduced lung compliance. Exhaled nitric oxide (NO) is increased in asthma. We evaluated whether a correlation between exhaled NO and lung mechanics exists during exercise in heart failure. METHODS: We studied 33 chronic heart failure patients and 11 healthy subjects with: a) standard pulmonary function, b) lung diffusion for carbon monoxide (DLCO) including its subcomponents, capillary volume and membrane resistance and eNO both at rest and during light exercise, c) maximal cycloergometer cardiopulmonary exercise test. RESULTS: Forced expiratory volume in 1 second (FEV1) was reduced in heart failure patients (83 +/- 17% of predicted) as was DLCO (75 +/- 18% of predicted) due to reduced membrane resistance (32.6 +/- 10.3 ml/mmHg/min vs. 39.9 +/- 6.9 in patients vs. controls, p < 0.02). eNO was lower in patients vs. controls (9.7 +/- 5.4 ppm vs. 14.4 +/- 6.4, p < 0.05) and was, during exercise, constant in patients and reduced in controls. No significant correlation was found between eNO and lung function. Vice-versa eNO changes during exercise were correlated with peak exercise oxygen consumption (r = 0.560, p < 0.001). CONCLUSIONS: The hypothesis of a link between eNO and lung function in heart failure was not proved. The correlation between eNO changes during exercise and peak VO2 might be due to hemoglobin oxygenation which binds NO to hemoglobin.     

Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure

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.     

Clinical importance of the renin-angiotensin system in chronic heart failure: double blind comparison of captopril and prazosin.

Nineteen patients with chronic heart failure participated in a double blind crossover trial of captopril and prazosin--two drugs with differing neuroendocrine effects--to determine whether neuroendocrine changes could explain clinical and haemodynamic responses to treatment. Patients were assessed before and after acute and long term (four weeks'') treatment with each drug given in random order. Sixteen patients completed the study. During captopril haemodynamic improvement was maintained by inhibition of the renin-angiotensin system. Breathlessness was relieved in 15 patients and exercise capacity increased. During prazosin a reduction in systemic vascular resistance was maintained, but plasma renin activity and aldosterone and noradrenaline concentrations increased, fluid retention developed, and clinical benefit did not occur. These results suggest that clinical and haemodynamic responses to long term vasodilator treatment for chronic heart failure are related to neuroendocrine changes. In patients with chronic heart failure inhibition of the renin-angiotensin system results in clinical benefit, whereas inhibition of the alpha adrenergic system does not.     

Exercise training in chronic heart failure: mechanisms and therapies

Decreased exercise capacity negatively affects the individuals’ ability to adequately perform activities required for normal daily life and, therefore, the independence and quality of life. Regular exercise training is associated with improved quality of life and survival in healthy individuals and in cardiovascular disease patients. Also in patients with stable heart failure, exercise training can relieve symptoms, improve exercise capacity and reduce disability, hospitalisation and probably mortality. Physical inactivity can thus be considered a major cardiovascular risk factor, and current treatment guidelines recommend exercise training in patients with heart failure in NYHA functional classes II and III. Exercise training is associated with numerous pulmonary, cardiovascular, and skeletal muscle metabolic adaptations that are beneficial to patients with heart failure. This review discusses current knowledge of mechanisms by which exercise training is beneficial in these patients.     

Effect of Voluntary Ethanol Consumption Combined with Testosterone Treatment on Cardiovascular Function in Rats: Influence of Exercise Training

This study evaluated the effects of voluntary ethanol consumption combined with testosterone treatment on cardiovascular function in rats. Moreover, we investigated the influence of exercise training on these effects. To this end, male rats were submitted to low-intensity training on a treadmill or kept sedentary while concurrently being treated with ethanol for 6 weeks. For voluntary ethanol intake, rats were given access to two bottles, one containing ethanol and other containing water, three 24-hour sessions per week. In the last two weeks (weeks 5 and 6), animals underwent testosterone treatment concurrently with exercise training and exposure to ethanol. Ethanol consumption was not affected by either testosterone treatment or exercise training. Also, drug treatments did not influence the treadmill performance improvement evoked by training. However, testosterone alone, but not in combination with ethanol, reduced resting heart rate. Moreover, combined treatment with testosterone and ethanol reduced the pressor response to the selective α₁-adrenoceptor agonist phenylephrine. Treatment with either testosterone or ethanol alone also affected baroreflex activity and enhanced depressor response to acetylcholine, but these effects were inhibited when drugs were coadministrated. Exercise training restored most cardiovascular effects evoked by drug treatments. Furthermore, both drugs administrated alone increased pressor response to phenylephrine in trained animals. Also, drug treatments inhibited the beneficial effects of training on baroreflex function. In conclusion, the present results suggest a potential interaction between toxic effects of testosterone and ethanol on cardiovascular function. Data also indicate that exercise training is an important factor influencing the effects of these substances.     

诺欣妥联合心脏运动康复对射血分数降低的心力衰竭疗效的研究

目的:探讨诺欣妥联合心脏运动康复对射血分数降低(HFr EF)的心力衰竭(HF)的临床疗效。方法:将我院心内科于2018年1月～2019年4月收治的70例HFr EF患者随机分为两组,各35例。对照组均给予诺欣妥规范治疗,实验组在此基础上根据心肺运动测试(CPET)测得代谢当量制定个性化心脏运动康复,包括院内、院外心脏康复干预及定期随访,为期6个月。采用彩色心脏超声诊断仪、心肺运动测试(CPET)分析两组治疗前后心肺功能变化,同时观察住院及随访期间的预后情况。结果:治疗6个月后,两组左心室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、左心室射血分数(LVEF)均明显改善,且实验组显著优于对照组(P0.05)。治疗6个月后,实验组AT明显升高,峰值VO2/kg、峰值VO2水平均有一定程度上升,且明显优于对照组(P0.05)。与对照组比较,实验组90d内HF再住院率(8.6%vs.28.6%)、随访期间MACEs发生率(17.1%vs.40.0%)均显著降低(P0.05)。结论:诺欣妥联合心脏运动康复治疗可使HFr EF患者显著获益,在改善心肺功能、运动能力及近期预后方面疗效显著,可作为HFr EF患者的一线治疗方案。     

Troponin I phosphorylation in human myocardium in health and disease

Cardiac troponin I (cTnI) is well known as a biomarker for the diagnosis of myocardial damage. However, because of its central role in the regulation of contraction and relaxation in heart muscle, cTnI may also be a potential target for the treatment of heart failure. Studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on cTnI (i.e. site-specific phosphorylation). This is caused by altered expression and/or activity of kinases and phosphatases during heart failure development. It is not known whether these (transient) alterations in cTnI phosphorylation are beneficial or detrimental. Knowledge of the effects of site-specific cTnI phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies in patients with heart failure. In this review we focus on the role of cTnI phosphorylation in the healthy heart upon activation of the beta-adrenergic receptor pathway (as occurs during increased stress and exercise) and as a modulator of the Frank-Starling mechanism. Moreover, we provide an overview of recent studies which aimed to reveal the functional consequences of changes in cTnI phosphorylation in cardiac disease.     

Effects of chronic beta-adrenergic blockade on exercise training in dogs

To assess the role of beta-adrenergic stimulation in cardiovascular conditioning we examined the effects of a beta-adrenergic blocker, propranolol, in mongrel dogs during an 8-wk treadmill-training program. Seven dogs were trained without a drug (NP), six were trained on propranolol 10 mg.kg-1.day-1 (P), and five served as caged controls (C). Effective beta-adrenergic blockade was documented by a decrease in peak exercise heart rate of 54 +/- 11 (SE) beats/min (P less than 0.05) and a one-log magnitude of increase in the isoproterenol-heart rate dose-response curve. Testing was performed before drug treatment or training and again after training without the drug for 5 days. Submaximal exercise heart rate decreased similarly in both NP and P (-26 +/- 4 NP vs. -25 +/- 9 beats/min P, P less than 0.05 for both) but peak heart rate decreased only with NP (-33 +/- 9 beats/min, P less than 0.05). Treadmill exercise time increased similarly in both groups: 3.4 +/- 0.6 min in NP and 3.0 +/- 0.2 min in P (both P less than 0.05). Blood volume also increased after training in both groups: 605 +/- 250 ml (26%) in NP and 377 +/- 140 ml (17%) in P (both P less than 0.05). Submaximal exercise arterial lactates were reduced similarly in both groups but peak exercise lactate was reduced more in NP (-1.4 +/- 0.3 NP vs -0.3 +/- 0.12 mmol/l P, P less than 0.05). Lactate threshold increased in both groups but the increase was greater in NP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

伊伐布雷定治疗高龄老年射血分数中间值心衰患者的疗效观察

目的 评价伊伐布雷定治疗高龄老年射血分数中间值心衰(HFmrEF)患者的临床疗效.方法 选择我院治疗的120例高龄老年HFmrEF患者,按随机数字表法分为观察组和对照组各60例,对照组给予规范化抗心衰治疗,观察组在此基础上加用伊伐布雷定治疗.随访6个月后,比较两组治疗前后静息心率(RHR)、氨基末端脑钠肽前体(NT-p...     

Skeletal muscle myofibrillar protein metabolism in heart failure: relationship to immune activation and functional capacity

Chronic heart failure is characterized by changes in skeletal muscle that contribute to physical disability. Most studies to date have investigated defects in skeletal muscle oxidative capacity. In contrast, less is known about how heart failure affects myofibrillar protein metabolism. Thus we examined the effect of heart failure on skeletal muscle myofibrillar protein metabolism, with a specific emphasis on changes in myosin heavy chain (MHC) protein content, synthesis, and isoform distribution in 10 patients with heart failure (63 +/- 3 yr) and 11 controls (70 +/- 3 yr). In addition, we examined the relationship of MHC protein metabolism to inflammatory markers and physical function. Although MHC and actin protein content did not differ between groups, MHC protein content decreased with increasing disease severity in heart failure patients (r = -0.748, P < 0.02), whereas actin protein content was not related to disease severity. No difference in MHC protein synthesis was found between groups, and MHC protein synthesis rates were not related to disease severity. There were, however, relationships between C-reactive protein and both MHC protein synthesis (r = -0.442, P = 0.05) and the ratio of MHC to mixed muscle protein synthesis (r = -0.493, P < 0.03). Heart failure patients showed reduced relative amounts of MHC I (P < 0.05) and a trend toward increased MHC IIx (P = 0.06). In regression analyses, decreased MHC protein content was related to decreased exercise capacity and muscle strength in heart failure patients. Our results demonstrate that heart failure affects both the quantity and isoform distribution of skeletal muscle MHC protein. The fact that MHC protein content was related to both exercise capacity and muscle strength further suggests that quantitative alterations in MHC protein may have functional significance.     

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H₂O₂ release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H₂O₂ resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca²⁺-induced permeability transition and reduced H₂O₂ release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a non-pharmacological tool for heart failure therapy.     

Role of nitric oxide in heart failure

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.     

Haemodynamic Studies with Peruvoside in Human Congestive Heart Failure

The immediate haemodynamic effects of peruvoside, a cardiac glycoside obtained from the Indian plant Thevetia neriifolia Juss, were studied in six patients with congestive heart failure. The drug was found to have an immediate and powerful positive inotropic and negative chronotropic effect, like ouabain, on the failing human heart. Oral peruvoside was also effective in the treatment of congestive heart failure when used on a short-term as well as a long-term basis. It therefore seems that peruvoside is a useful cardiac glycoside in the management of congestive heart failure in man as a quick-acting intravenous preparation. It is equally effective when used orally.     

Changes of bone metabolism based on the different interventions with exercise type or additional intake material in ovariectomized rats

[Purpose]

This study is aimed at providing clear guidance on treatment and prevention of osteoporosis by comparing and analyzing some well-known methods out of drug and exercise therapies.

[Methods]

For this purpose, eight-week experiments (drug therapy and exercise therapy) were carried out by using rats whose menopause was induced by the removal of an ovary. In the treatment of the drug therapy, the effects of soy protein, one of the well-known alendronate and estrogen replacement therapy, were compared and analyzed. In the treatment of the exercise therapy, endurance exercise using a treadmill and resistance exercise through climbing a special cage were compared and analyzed. Based on these results, this study will be able to suggest the most appropriate way to deal with osteoporosis which requires long-term treatment. Sixty eight-week-old Sprague-Dawley female rats had a week to adapt to the new environment. After that, they were randomly divided into four groups (Sham-Sedentary; SS, ovariectomized-control; OC, ovariectomized-soy protein; OS: ovariectomized-alendronate; OA, ovariectomized-endurance exercise; OE, ovariectomized-resistance exercise; OR) before having an operation for the removal of an ovary. After surgery, the rats convalesced for a week. Alendronate (0.4mg / kg of body weight) and isoflavones (200g / 1 kg of feed) were given to two groups respectively for eight weeks. The rats in the other two groups performed resistance exercise (climbing) and endurance exercise (20 m/min; 60min/day) five days a week for eight weeks.

[Results]

Ovariectomy increased the body weight and body fat like menopause did. Soy protein and alendronate intake for eight weeks had no effect on body weight but reduced the body fat increased by ovariectomy to the level of the SS group. The menopause induced by ovariectomy did not affect total bone density and bone mass as well as bone density in specific areas of the body. Soy protein and alendronate intake for eight weeks did not significantly affect them either. However, the eight-week treatment with soy protein and alendronate significantly reduced the level of osteocalcin in blood. Resistance exercise more noticeably increased body weight and bone mass than running on the low-intensity treadmill but serum osteocalcin levels were notably increased in both cases.

[Conclusion]

These results show that soy protein which is natural produce and low-intensity, regular endurance exercise also have an effect on the treatment and prevention of osteoporosis caused by menopause.     

Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure

We sought to elucidate the relationship between diastolic intraventricular pressure gradients (IVPG) and exercise tolerance in patients with heart failure using color M-mode Doppler. Diastolic dysfunction has been implicated as a cause of low aerobic potential in patients with heart failure. We previously validated a novel method to evaluate diastolic function that involves noninvasive measurement of IVPG using color M-mode Doppler data. Thirty-one patients with heart failure and 15 normal subjects were recruited. Echocardiograms were performed before and after metabolic treadmill stress testing. Color M-mode Doppler was used to determine the diastolic propagation velocity (Vp) and IVPG off-line. Resting diastolic function indexes including myocardial relaxation velocity, Vp, and E/Vp correlated well with VO2max (r = 0.8, 0.5, and -0.5, respectively, P < 0.001 for all). There was a statistically significant increase in Vp and IVPG in both groups after exercise, but the change in IVPG was higher in normal subjects compared with patients with heart failure (2.6 +/- 0.8 vs. 1.1 +/- 0.8 mmHg, P < 0.05). Increase in IVPG correlated with peak VO2max (r = 0.8, P < 0.001) and was the strongest predictor of exercise capacity. Myocardial relaxation is an important determinant of exercise aerobic capacity. In heart failure patients, impaired myocardial relaxation is associated with reduced diastolic suction force during exercise.     

运动康复训练对冠心病多支病变患者运动耐量及血脂的影响

目的:探讨运动康复训练对冠心病多支病变患者活动耐量及血脂的影响。方法:选取冠心病多支病变患者,所有患者均进行不完全血运重建术,分为运动康复训练组及对照组,运动康复训练组自术后第三日起治疗组进行运动康复训练,对照组对运动量无要求。3月后,测量两组患者血脂水平及6分钟步行试验,比较两组患者步行距离、心绞痛发作次数、运动至心绞痛出现时间、6分钟内累积运动时间及血脂水平。结果:经运动康复训练治疗3月后,治疗组6分钟步行距离、运动至心绞痛出现时间及运动累积时间较对照组均明显增加,发生心绞痛次数较对照组明显减少。运动康复训练组治疗后甘油三酯、总胆固醇及低密度脂蛋白水平较治疗前明显降低,对照组仅总胆固醇有所降低,甘油三酯及低密度脂蛋白水平较治疗前无统计学差异。结论:运动康复训练可减少冠心病多支病变患者心绞痛发作次数,增加患者运动耐量并调节血脂代谢。     

Cardiac autonomic function in Blacks with congestive heart failure: vagomimetic action, alteration in sympathovagal balance, and the effect of ACE inhibition on central and peripheral vagal tone.

Cardiac autonomic dysfunction is common in heart disease with or without congestive heart failure, and can cause sudden cardiac death. However, cardiac autonomic abnormalities in non-ischemic (hypertensive) heart failure, which is prevalent in Black Africans is poorly documented. We conducted a cross-sectional study of 32 patients with congestive heart failure, mostly secondary to hypertension (aged 52 +/- 15 years, with ejection fraction of 0.38 +/- 11) and 30 age- and sex-matched healthy volunteers (aged 51 +/- 11 years, 14 males/16 females). Cardiac autonomic function was assessed by the Valsalva's maneuver, respiratory sinus arrhythmia (for cardiac vagal tone) and the pressor and chronotropic changes following forearm isometric handgrip exercise and the assumption of upright posture (tests of sympathetic function). The exercise tolerance of the cardiac patients was assessed by the distance covered during 6 min of walking. The Valsalva ratio was significantly lower in chronic heart failure, 1.10 +/- 0.08 compared to the healthy controls 1.47 +/- 0.20 (p<0.001). Specifically, the phase IV bradycardia in heart failure, was significantly attenuated to 650 +/- 121 msec compared to the value of 935 +/- 101 msec in healthy controls (p<0.001). The phase 11 Valsalva tachycardia did not differ between the patients and controls. The respiratory sinus arrhythmia was also significantly reduced in chronic heart failure (p<0.05) compared to controls. Treatment of the heart failure patients with enalapril-digoxin and diuretics by 4 weeks, resulted in a reversal of the autonomic abnormalities. The phase IV bradycardia increased significantly to 798 +/- 164 msec (p<0.01) and the Valsalva ratio to 1.35 +/- 0.25 (p<0.01) and the respiratory sinus arrhythmia increased toward normal. There was close positive correlation between the Valsalva's ratio and the 6 min self paced distance covered (r = 0.44, p = 0.03 ANOVA), and a weak inverse correlation to cardiac size and cardiothoracic ratio (r = -0.31, p = 0.09). This study demonstrates cardiac autonomic dysfunction (especially reduced vagal tone) in Black Nigerians with mainly non-ischemic congestive heart failure. The parasympathetic dysfunction significantly correlates with severity of heart failure. Current treatment reverses autonomic dysfunction to values seen in healthy age matched controls, mainly through augmentation of cardiac parasympathetic activity.