B-type natriuretic peptide in lymphedema.

Lymphedema often responds to compression therapy which can also cause undesirable cardiac overload if heart failure coexists. We hypothesized that the biomarker B-type natriuretic peptide (BNP) can be used to screen lymphedema patients for undetected cardiac dysfunction. We studied unselected consecutive patients with lymphedema to determine their BNP status and compared these data with those obtained from healthy subjects without known cardiovascular diseases. Out of a total of 305 subjects with lymphedema screened, 102 (33%) consented to take part in this study. The majority (87%) were female with a mean age of 60.5 +/- 13.2 (SD) years, and 47% had just lower limb swelling. The groups were equally divided between cancer and non-cancer related causes. There were 45 females and 4 males under 60 years old, and 44 female and 9 male patients over 60 years old. Median (IQR) BNP (ng/L) were as follows: <60 years females = 17.9 (15.2) (median [RR: 3 - 64] and males = 12.4 (14.7) [RR: 0.2 - 44], >60 years females = 35.8 (57.9) [RR: 2 -247)] and males = 47.2 (44.1) [RR: 2 - 238]. For this population, the BNP concentration 100 ng/L was adopted as the value to exclude heart failure. Using this definition, 7 lymphedema subjects had BNP concentrations of 120 (19.8) ng/L, and all were found to have cardiac abnormalities on echocardiography. This study demonstrated that 93% of unselected subjects with lymphedema had BNP concentrations that exclude a diagnosis of heart failure. Those subjects with elevated BNP were found on subsequent echocardiography to have cardiac abnormalities. The use of a BNP assay is of potential value in screening patients who are more likely to have cardiac failure. Indicative factors include bilateral leg swelling, over the age of 50 years, breathlessness, where there is no known cause for the swelling. A BNP assay using a BNP concentration threshold of 100 ng/L (29 pmol/L) will identify those patients who require more detailed investigations.

CRT improves the exercise capacity and functional reserve of the failing heart through enhancing the cardiac flow- and pressure-generating capacity.

BACKGROUND: While information on how cardiac resynchronisation therapy (CRT) affects cardiac performance at rest is readily available, the mechanisms whereby CRT alters cardiac function during maximal exercise are unclear. AIMS: We examined the medium-term effects of CRT on cardiac and physical functional reserve of patients with severe heart failure (CHF) and prolonged QRS duration. METHODS: Seventeen consecutive patients with severe CHF (NYHA III-IV) and widened QRS underwent maximal cardiopulmonary exercise testing with non-invasive central haemodynamic measurements before and 6-8 weeks after CRT pacemaker implantation. RESULTS: After CRT there were significant increases in exercise cardiac output by 19.3% (P=0.0048) from 9.5+/-3.4 l min(-1), peak mean arterial blood pressure by 14.1% (P=0.0001) from 91.3+/-13.6 mm Hg, and peak cardiac power output by 37.2% (P=0.0008) from 1.92+/-0.74 W. There were no significant changes in these variables at rest. Exercise duration (+42.3%, P=0.0002), NYHA functional class (P=0.0001) and SF-36 symptom score (P=0.0006) were also significantly improved. Powerful surrogate indicators of prognosis were also significantly improved with CRT: peak O(2) consumption (+20.9%, P=0.0007), VE/VCO(2) slope (-20.0%, P=0.005) and circulatory power (+42.0%, P=0.0012). CONCLUSION: In this cohort of patients, post-implant CRT significantly improved the flow-, pressure- and power-generating capacity of the failing hearts. This may be causally related to the improvements observed in exercise capacity, functional class and symptom scores.

Plasma concentrations of coffee polyphenols and plasma biomarkers of diabetes risk in healthy Japanese women.

Coffee consumption has been reported to reduce the risk of type 2 diabetes in experimental and epidemiological studies. This anti-diabetic effect of coffee may be attributed to its high content in polyphenols especially caffeic acid and chlorogenic acid. However, the association between plasma coffee polyphenols and diabetic risks has never been investigated in the literature. In this study, fasting plasma samples were collected from 57 generally healthy females aged 38-73 (mean 52, s.d. 8) years recruited in Himeji, Japan. The concentrations of plasma coffee polyphenols were determined by liquid chromatography coupled with mass tandem spectrometer. Diabetes biomarkers in the plasma/serum samples were analysed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman's correlation coefficients. The results showed that plasma chlorogenic acid exhibited negative associations with fasting blood glucose, glycated hemoglobin and C-reactive protein, whereas plasma total coffee polyphenol and plasma caffeic acid were weakly associated with these biomarkers. Our preliminary data support previous findings that coffee polyphenols have anti-diabetic effects but further replications with large samples of both genders are recommended.

Complementary roles of simple variables, NYHA and N-BNP, in indicating aerobic capacity and severity of heart failure.

AIMS: The extent of exercise intolerance in patients with chronic heart failure (CHF) is dependent on and representative of the severity of heart failure. However, few primary care physicians have direct access to facilities for formal exercise testing. We have therefore explored whether information readily obtainable in the community can reliably predict the functional capacity of patients. METHODS AND RESULTS: Ninety-six subjects with a wide range of cardiac function (10 healthy controls and 86 CHF patients with NYHA classes I-IV, LVEF 36.9+/-15.2%) were recruited into the study and had resting plasma N-BNP and cardiopulmonary exercise testing to measure peak oxygen consumption (VO2). Significantly higher N-BNP levels were found in the CHF group (299.3 [704.8] fmol/ml, median [IQR]) compared with the healthy control group (7.2 [51.2] fmol/ml), p<0.0001. There were significant correlations between peak VO2 and N-BNP levels (R=0.64, P<0.001), peak VO2 and NYHA class (R=0.76, P=0.001), but no significant correlation was seen between peak VO2 and LVEF (R=0.0788, P=0.33). Multivariate analysis identified plasma N-BNP (P<0.0001) and NYHA class (P<0.0001) as significant independent predictors of peak VO2. Logistic modelling with NYHA class and log N-BNP to predict peak VO2<20 ml/kg/min showed that the area under the curve of receiver-operating-characteristic (ROC) curve was 0.906 (95% CI 0.844-0.968). A nomogram based on the data has been constructed to allow clinicians to estimate the likelihood of peak VO2 to be <20 ml/kg/min for given values of plasma N-BNP and NYHA class. CONCLUSIONS: By combining information from a simple objective blood test (N-BNP) and a simple scoring of functional status (NYHA), a clinician can deduce the aerobic exercise capacity and indirectly the extent of cardiac dysfunction of patients with CHF.

Clinical and research implications of new concepts in the assessment of cardiac pumping performance in heart failure.

Every cardiac pump has its own maximum performance, which denotes its pumping capability. The difference between the performance in the resting state and that at maximum is called pumping reserve. Cardiac pumping performance is therefore best quantified by its hydraulic power output. Cardiac pumping capability is predictive of the ultimate prognosis of patients in severe heart failure whereas pumping reserve is a major determinant of exercise capacity. The therapeutic efficacy of cardiotonic drugs used in the treatment of ambulant heart failure patients should be evaluated with reference to the way they alter the relation between cardiac pumping reserve and exercise capacity.

Inhibition of ACE/kininase-II, acute myocardial infarction, and survival.

Three major trials, in patients with chronic heart failure, have shown that treatment with an ACE inhibitor reduces mortality. However, at the time of writing this review there continue to be strong grounds for uncertainty as to the role of these drugs after acute myocardial infarction in man. This uncertainty is exemplified by the findings of two recently published mortality trials, the CONSENSUS II and the SAVE investigations. Despite virtually identical premises, though widely differing therapeutic approaches, the observations reported in these two papers contrast markedly. In this review we have sought to analyse the possible reasons why the findings of the two trials differ. In our attempt to understand this important issue we have necessarily turned to smaller clinical studies, and also to investigations performed in animals. Furthermore, we review the investigational strategies which have been employed by other, currently unreported, large scale survival studies, as these will certainly hold many of the answers to the questions which the SAVE and CONSENSUS II trials have raised.

beta Adrenergic receptor desensitisation may serve a cardioprotective role.

OBJECTIVE: The aim was to test the hypothesis that beta adrenoceptor desensitisation is a form of cardioprotection whereby the myocardium is protected from the injurious effects of excessive adrenergic stimulation by isoprenaline. METHODS: A new sensitive and specific method of identifying cardiac myocyte necrosis with monoclonal antimyosin was employed. Antibody labelled necrotic cardiomyocytes from male Sprague-Dawley rats (190-300 g) were identified by immunofluorescence. Homologous beta adrenoceptor desensitisation was induced by 9 d pretreatment with isoprenaline infusion (20 mg.kg-1.d-1), and heterologous desensitisation by treatment with 0.15% propylthiouracil in the diet for six weeks. The effects of isoprenaline induced cardiomyocyte injury in these animals were compared with those in control rats. RESULTS: In euthyroid control rats, treatment with the beta adrenergic agonist, isoprenaline, produced prolonged tachycardia and hypotension, and a significant amount of cardiac myocyte necrosis subendocardially. When the same isoprenaline challenge was given to rats pretreated for 9 d with an isoprenaline infusion, the haemodynamic response was markedly attenuated and very little myocyte necrosis was noted. In the model of heterologous desensitisation occurring in hypothyroidism, isoprenaline challenge produced markedly diminished haemodynamic response and little cardiac myocyte necrosis. CONCLUSIONS: In both homologous and heterologous models of beta adrenoceptor desensitisation, the susceptibility of the myocardium to isoprenaline induced cytotoxicity is markedly reduced.

An analytical method to separate inotropic and vasodilatory drug effects in patients with heart failure.

A recently proposed analytical technique to determine whether an inotropic agent improves cardiac pumping performance via its vasodilatory or its positive inotropic effects was adopted to evaluate the pharmacological properties of a positive inotropic agent, dobutamine, and a vasodilatory calcium antagonist, felodipine, in patients with severe heart failure. This technique used a new principle of pump-load interaction, which states that for a given change in vascular input impedance unaccompanied by any direct alteration in the pumping characteristics all possible values of pump power output due to the change in impedance per se are confined within two calculated limits. When dobutamine was infused at 10 micrograms.kg-1.min-1 seven out of 10 patients had power output values above the defined limits, implying that the technique can identify correctly in vivo the direct positive inotropic effects of dobutamine in the presence of its vasodilating activity. In contrast, when 5-10 mg of felodipine was given to 10 patients the consequent power outputs were all within the defined limits, implying that the effects can be explained by vasodilatation alone. In conclusion, this study showed that the analytical technique can be applied clinically to detect the presence of drug induced positive inotropic effects in the midst of vasodilatation and therefore may be useful in determining whether inotropic agents actually improve cardiac function via their positive inotropic effects.

Assessment of myocardial performance in ischaemic heart disease: from changes in left ventricular power output produced by graded-dose isoprenaline infusion.

Current clinical indices of myocardial contractility derive from concepts of muscle mechanics developed from isolated muscle experiments. Numerous simplifying assumptions are needed to apply these concepts to contractility studies in the whole heart. An alternative is to consider the heart as a pump which generates both pressure (P) and flow (Q) and to estimate its performance from the power output of its ventricles (P X Q). A method is described for measuring peak left ventricular power output in patients during routine cardiac catheterisation. The measurements have been made at rest and following inotropic challenge with gradient infusions of isoprenaline intravenously. Results from 13 patients with coronary artery disease and severe angina pectoris, who were clinically indistinguishable from one another, are reported. The patients could be grouped according to their left ventricular peak power responses to isoprenaline, although no difference could be demonstrated between them at rest. The patients who showed no increase in left ventricular power response to isoprenaline had a poor prognosis.

Central haemodynamic changes during lower body positive pressure in patients with congestive cardiac failure.

Fifteen patients with moderately severe and severe chronic congestive heart failure were studied to determine the central haemodynamic results of short term increases in lower body positive pressure. Central haemodynamic variables were determined by Swan-Ganz thermodilution catheterisation and arterial cannulation. Graded increases in lower body positive pressure were applied to supine patients using Medical Anti-Shock Trousers (MAST). Increasing lower body positive pressure by 25 mm Hg and 55 mm Hg caused increases in mean right atrial pressure (6.0 to 13.2 to 17.9 mm Hg; p less than 0.001 and p less than 0.0001 respectively) and mean pulmonary artery pressure (26.8 to 35.5 to 41.3 mm Hg; p less than 0.05 and p less than 0.01 respectively). No significant changes were seen in left heart filling pressures or in pulmonary vascular resistance. Furthermore, there were no significant increases in indices of cardiac work (cardiac index, left ventricular stroke work index, right ventricular stroke work index or cardiac power output) despite the increased right heart filling pressures. These results show that in patients with longstanding severe congestive heart failure, short term increases in cardiac return may increase right heart pressures but do not appear to cause either beneficial or detrimental changes in left heart haemodynamic indices.

Is low VO2max/kg in obese heart failure patients indicative of cardiac dysfunction?

PURPOSE: Low peak O2 consumption (VO2max/kg) has been widely used as an indirect indicator of poor cardiac fitness, and often guides management of patients with severe heart failure (HF). We hypothesized that it should be as good an indicator of cardiac dysfunction in obese and non-obese HF patients. METHODS: We compared the cardiopulmonary exercise performance and non-invasive hemodynamics of 152 obese (BMI>34 kg.m(-2)) and 173 non-obese (BMI≤32) male HF patients in NYHA classes II and III, with reference to 101 healthy male controls. Their physical and cardiac functional reserves were measured during treadmill exercise testing with standard respiratory gas analyses and CO2 rebreathing to measure cardiac output non-invasively during peak exercise. Data are given as mean ± SD. RESULTS: Obese HF patients with BMI 40.9 ± 7.5 kg·m(-2) (age 56.1 ± 14.0 years, NYHA 2.5 ± 0.5) exercised to acceptable cardiopulmonary limits (peak RER=1.07 ± 0.12), and achieved a mean VO2max/kg of 18.6 ± 5.2 ml·kg(-1)·min(-1), significantly lower than in non-obese HF counterparts (19.9 ± 5.6 ml·kg(-1)·min(-1), P=0.02, age 55.8 ± 10.6 years, BMI 26.6 ± 3.1, NYHA 2.4 ± 0.5, peak RER=1.07 ± 0.09), with both lower than controls (38.5 ± 9.7 ml·kg(-1)·min(-1), P<10(-6)). In contrast, the uncorrected VO2max was higher in obese (2.31 ± 0.69 ml·min(-1)) than non-obese HF patients (1.61 ± 0.49 ml·min(-1), P<10(-6)). When cardiac dysfunction was evaluated directly, peak cardiac power was significantly greater in obese than non-obese HF patients (4.11 ± 1.21 W vs 2.73 ± 0.82 W, P<10(-6)), with both lower than controls (5.42 ± 1.04 W, P<10(-6)). CONCLUSION: These results demonstrate that VO2max/kg is not a generally reliable indicator of cardiac fitness in all patients. Instead, we found that despite having lower VO2max/kg, obese HF patients had stronger hearts capable of generating greater cardiac power than non-obese HF patients of equivalent clinical HF status.

Impacts of valve intervention on the Functional REServe of the Heart: The FRESH-valve pilot study.

PURPOSE: Severe valve lesions require corrective interventions to avoid progression to heart failure (HF) and premature demise. We tested the hypothesis that despite operative risks, corrective valvular interventions will lead to significant improvements in overall cardiac pump function, especially before the onset of cardiac decompensation. METHODS: We compared the cardiopulmonary exercise performance and non-invasive haemodynamics of 46 consecutive patients with severe valvular disease before and after valvular intervention with reference to 101 healthy male and 139 female controls without cardiovascular disease. Cardiac and physical functional reserves were measured with standard respiratory gas analyses and CO2 rebreathing to measure cardiac output non-invasively during peak treadmill exercise. Data are given as mean ± SD and statistical significance accepted at P<0.05. RESULTS: The entire patient cohort showed no significant improvement in peak O2 consumption (V˙O2max, P=0.74) or in peak cardiac power (CPOmax, P=0.34) after valvular intervention, but we found instead a dichotomous outcome depending on preoperative cardiac function: (i) the pre-operative cardiac decompensatory subgroup (LoW, n=26) showed increased CPOmax (2.63 ± 0.67 to 3.42 ± 0.98 W, P<0.0001) and V˙O2max (1.38 ± 0.55 to 1.56 ± 0.59 L·min(-1), P<0.01); and (ii) the pre-operative non-decompensatory subgroup (HiW) showed reduced CPOmax (4.58 ± 0.96 to 3.84 ± 0.92 W, P<0.001) and V˙O2max (2.29 ± 0.72 to 1.97 ± 0.75 L·min(-1), P<0.01). Changes in NYHA class were found to be discrepant with these objective measurements. CONCLUSION: This investigation found an unexpected finding that valvular interventions performed in routine clinical practice do not consistently improve cardiac function, especially in those without pre-operative cardiac decompensation. Assessing cardiac functional gains would open up new avenues for future trials of valvular interventions.

Restoration of sinus rhythm results in early and late improvements in the functional reserve of the heart following direct current cardioversion of persistent AF: FRESH-AF.

BACKGROUND: The improvement in cardiac physiological parameters after restoration of sinus rhythm in patients with persistent atrial fibrillation (AF) can be challenging to quantify. Overall cardiac function assessment is better assessed by peak cardiac power output (CPOpeak), rather than indirect measures of cardiac performance such as peak oxygen consumption (VO2peak). CPO was used to quantify improvement in cardiac function early and later following electrical cardioversion. METHODS AND RESULTS: 29 patients with persistent AF underwent maximal treadmill cardiopulmonary exercise (CPEx) testing within 14days (±3) 8weeks (±3) following electrical cardioversion (DCCv). This enabled measurement of VO2peak, cardiac output (COpeak) and calculation of CPOpeak. Quality of life (QoL) data (EQ5D) was also recorded. Three patients attended for 2 CPEx tests and 3 were lost to follow-up (total n=26). Fourteen were successfully cardioverted and 12 remained in AF. In patients successfully cardioverted exercise duration increased significantly between all tests. CPOpeak, VO2peak, CO peak and QoL were improved significantly between Tests 1 and 2 (p<0.02) and Tests 1 and 3 (p<0.05). QoL improved by 15%. CONCLUSIONS: Restoration of SR confers significant, early and sustained cardiac functional improvement following DCCv with a significant 14% increase in the calculated peak power output of the heart. Such increase in functional reserve suggests that pursuit of a rhythm control strategy in the treatment of AF may be warranted in terms of both improving quality of life and cardiac function with objective improvement of cardiac function.

Left ventricular volume reduction without ventriculectomy.

Partial left ventriculectomy (the Batista procedure) to achieve left ventricular volume reduction (LVVR) has been advocated as an alternative to cardiac transplantation in patients with end-stage dilated left ventricles. Here, we describe a new technique of LVVR that uses realignment of the papillary muscles, thus avoiding ventriculectomy, and report preliminary results. Eight patients (all male, mean age 49.3 [range 38 to 70] years) underwent LVVR between October 1998 and March 2000 as an adjunct to surgical coronary revascularization. Five were assessed with echocardiography and cardiopulmonary exercise testing before and after (mean follow-up time 267 [range 94 to 416] days) the operation. LVVR significantly improved left ventricular end-diastolic volume (254 +/- 32 to 218 +/- 36 mL, p = 0.03), left ventricular ejection fraction (20.14% +/- 1.36% to 31.28% +/- 2.32%, p = 0.007), and exercise duration (from 394 +/- 88 to 611 +/- 79 seconds, p = 0.03). A nonsignificant improvement in maximal oxygen consumption was also observed. This technique of LVVR is relatively simple to perform and is accomplished through a small apical cardiotomy. Preliminary results show an encouraging functional improvement following surgery. Future controlled studies are required to assess this novel technique further.

Physiological cardiac reserve: development of a non-invasive method and first estimates in man.

OBJECTIVE: To investigate whether physiological cardiac reserve can be measured in man without invasive procedures and whether it is a major determinant of exercise capacity. DESIGN: Development of method of measurement and an observational study. SETTING: A regional cardiothoracic centre. SUBJECTS: 70 subjects with a wide range of cardiac function, from heart failure patients to athletes. METHODS: Subjects underwent treadmill, symptom limited cardiopulmonary exercise tests to measure aerobic exercise capacity (represented by VO2max) and cardiac reserve. Cardiac output was measured non-invasively using the CO2 rebreathing technique. RESULTS: Cardiac power output (CPOmax) at peak exercise was found to be significantly related to aerobic capacity: CPOmax (W) = 0.35 + 1.5 VO2max (1/min), r = 0.87, p < 0.001. It also correlated well with exercise duration (r = 0.62, p < 0.001), suggesting that cardiac reserve is a major determinant of exercise capacity. In the study, cardiac reserve ranged from 0.27 to 5.65 W, indicating a 20-fold difference between the most impaired cardiac function and that of the fittest subject. CONCLUSIONS: A non-invasive method of estimating physiological cardiac reserve was developed. The reserve was found to be a major determinant of exercise capacity in a population of normal subjects and patients with heart disease. This method may thus be used to provide a clearer definition of the extent of cardiac impairment in patients with heart failure.

Safety and efficacy of computerized closed-loop delivery of arbutamine: a new pharmacologic myocardial stress modality for the assessment of coronary artery disease. The European Arbutamine Study Group.

This study evaluated the efficacy of computer-controlled closed-loop delivery of a new synthetic catecholamine, arbutamine, when given to induce myocardial ischemia detected by electrocardiography and echocardiography with a high (10 beats/min/min) and low (6 beats/min/min) rate of increase in heart rate (heart rate slope) in 70 patients with coronary artery disease. The electrocardiographic sensitivity for the detection of myocardial ischemia was 52% for the low slope and 51% for the high slope. The corresponding figures for echocardiographic sensitivity were 83% and 79% for the low and high slopes, respectively. There were no significant differences in changes from baseline to maximum in pharmacodynamic variables, although the mean times to reach maximum heart rate and systolic blood pressure were 1.4 minutes shorter (p = 0.001) and 3.7 minutes shorter (p < 0.05), respectively, for the high-slope regimen. The duration of the infusion was shorter (p < 0.001) for the high slope. In this study, closed-loop arbutamine administration was effective and safe in the detection of coronary artery disease for both heart rate slope regimens.

Comparison of the haemodynamic effects of dopexamine and dobutamine in patients with severe congestive heart failure.

Dopexamine hydrochloride is a novel compound with properties of DA1-dopaminergic and beta 2-adrenergic receptor agonism and neuronal noradrenaline uptake inhibition. It has been shown to produce beneficial renal and haemodynamic effects in patients with severe heart failure. We compared the haemodynamic effects of dopexamine (0.5 to 6 micrograms/kg/min) with those of dobutamine (5 to 25 micrograms/kg/min) in 9 patients with severe congestive heart failure. The two drugs were similar in their effects at peak infusion rates: heart rate increased (dopexamine 87 +/- 17 to 100 +/- 14; dobutamine 91 +/- 18 to 103 +/- 17 min-1), cardiac index increased (dopexamine 1.7 +/- 0.5 to 2.8 +/- 1.1; dobutamine 1.8 +/- 0.5 to 3.0 +/- 1.1 l.min-1.m-2) and systemic vascular resistance decreased (dopexamine 1553 +/- 221 to 1117 +/- 432; dobutamine 1721 +/- 347 to 1280 +/- 433 dyne.s.cm-5). Neither drug affected pulmonary artery wedge pressure (dopexamine 24 +/- 6 to 22 +/- 6; dobutamine 25 +/- 9 to 24 +/- 10 mm Hg). Dopexamine had significantly lower peak effects on left ventricular stroke work index (dopexamine 20 +/- 9, dobutamine 27 +/- 15 g.m.m-2, P less than 0.05) and cardiac power output (dopexamine 0.71 +/- 0.36, dobutamine 0.93 +/- 0.46 W, P less than 0.05). These haemodynamic effects, due largely to vasodilatation but with some contributory positive inotropy, indicate that dopexamine will be useful in the acute treatment of congestive heart failure.

From CONSENSUS to CHARM--how do ACEI and ARB produce clinical benefits in CHF?

Two decades of research from CONSENSUS to CHARM using modulators of the renin-angiotensin-aldosterone system (RAAS) in chronic heart failure (CHF) patients have shown convincing clinical benefits, but the majority of clinicians prescribing these drugs are still unclear about what mechanisms are responsible for the observed benefits. Of the candidate mechanisms hitherto proposed, there emerges a theme that best fits the spectrum of known factors from pathophysiology of heart failure to how the drugs enhance longevity of patients. This concept can be summarised as follows: after the onset of heart failure, neurohormones are activated resulting in raised levels of angiotensin, aldosterone and catecholamines, which are all known cardiotoxic agents. Cumulatively over time, they are responsible for accelerated cardiomyocyte attrition, manifesting as a faster reduction of cardiac pumping reserve, leading to worsening heart failure, more neurohormonal activation, thus propagating a vicious cycle spiralling towards an earlier fatality. The vicious cycle can be interrupted by dampening the excessive neurohormonal activities, thereby minimising cardiomyocyte losses and preserving cardiac functional reserve for longer. This culminates in maintenance of a reasonable quality of life and enhanced longevity. Such a mechanistic understanding would enable clinicians to have a better perspective on how to apply data from various clinical trials involving these drugs into clinical practice, to optimise and tailor therapy to the individual patient so that each patient can gain maximal benefits.

Disparate results of ACE inhibitor dosage on exercise capacity in heart failure: a reappraisal of vasodilator therapy and study design.

Despite manifest benefits of angiotensin converting enzyme (ACE) inhibitors on the prognosis of patients with heart failure, there is a lack of consistency in the results of trials investigating the effects of ACE inhibitors on exercise capacity. The inconsistencies cannot be readily explained by variations in effects on known neurohumoral or conventional haemodynamic factors. Drawing on insights from physiology of pump-load interactions, in a normal circulation there is an optimal extent of systemic vasodilation at which the delivery of hydraulic energy from the cardiac pump is maximal (the 'impedance matchpoint'). In heart failure, the vasoconstrictive effects shift the operating point towards mismatch at higher resistances, and optimal vasodilatory therapy would reshift the operating point to the matchpoint. Excessive dosage, however, would cause overvasodilatation leading to a reduction in cardiac power output and consequently compromising exercise ability. High levels of ACE inhibitors may not therefore improve exercise ability. Another potential reason for the observed inconsistencies is that the often used parallel-group study design (ideal for mortality studies) may not be suitable for investigating drug effects on exercise capacity because dropouts from such studies would introduce occult selection biases, thereby confounding treatment effects. In conclusion, this reappraisal of the conflicting observations reported on ACE inhibitor effects on exercise capacity has highlighted a proposition that there is an optimal dosage of ACE inhibitors which will most enhance exercise capacity, and this will require further well designed cross-over studies to elucidate.

Which exercise test variables are of prognostic importance post-myocardial infarction?

The prognostic value of parameters noted on pre-discharge exercise testing was assessed in 300 survivors of acute myocardial infarction. Exercise testing was performed at a mean of 9 days post-infarction. Each patient's data were studied for the presence of ST-segment depression or elevation greater than or equal to 0.1 mV in any of the 12 leads recorded, angina pectoris, exertional hypotension and duration of exercise. The patients were followed for a mean of 12 months and the incidence of death, reinfarction, angina pectoris, heart failure and coronary revascularization procedures was noted. All variables studied, other than the presence of exercise-induced ST-segment elevation, were significantly associated with the occurrence of subsequent cardiac events (P less than 0.001). Exercise-induced ST-segment depression identified 80% of patients who developed complications and was significantly more sensitive than any of the other variables as a prognostic marker (P less than 0.05). The finding of angina pectoris, an abnormal blood pressure response or a limited exercise tolerance in association with exercise-induced ST-segment depression heightened the prognostic implications of this variable.