Henry Dargie

Captopril in heart failure. A double blind controlled trial.

The effect of the converting enzyme inhibitor captopril as long term treatment was investigated in 14 patients with severe congestive heart failure in a double blind trial. Captopril reduced plasma concentrations of angiotensin II and noradrenaline, with a converse increase in active renin concentration. Effective renal plasma flow increased and renal vascular resistance fell; glomerular filtration rate did not change. Serum urea and creatinine concentrations rose. Both serum and total body potassium contents increased; there were no long term changes in serum concentration or total body content of sodium. Exercise tolerance was appreciably improved, and dyspnoea and fatigue lessened. Left ventricular end systolic and end diastolic dimensions were reduced. There was an appreciable reduction in complex ventricular ectopic rhythms. Adverse effects were few: weight gain and fluid retention were evident in five patients when captopril was introduced and two patients initially experienced mild postural dizziness; rashes in two patients did not recur when the drug was reintroduced at a lower dose; there was a significant reduction in white cell count overall, but the lowest individual white cell count was 4000 X 10(6)/l. Captopril thus seemed to be of considerable value in the long term treatment of severe cardiac failure.

Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state.

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.

Mortality in heart failure: clinical variables of prognostic value.

One hundred and fifty two patients with chronic heart failure caused primarily by left ventricular dysfunction were followed prospectively in an open study for a mean period of 21 months. The effects of several clinical variables on subsequent outcome were examined, including the effects of treatment, which was determined by the clinician caring for the patient and was not randomly allocated. In order of importance, frequent ventricular extrasystoles, non-treatment with amiodarone, low mean arterial pressure, and a diagnosis of coronary artery disease were associated with a poor prognosis, with each of these variables providing extra predictive information independently of the others. Initial serum potassium concentration and treadmill exercise time also carried further weak but independent prognostic information. Neither treatment with angiotensin converting enzyme inhibitors nor digoxin appeared to affect outcome. Left ventricular function (as reflected by M mode echocardiography) and the dose of diuretic also failed to predict outcome. There did, however, appear to be a reduction in the frequency of sudden death when angiotension converting enzyme inhibitors were given. Further studies are required to confirm the adverse prognostic significance of ventricular arrhythmias in patients with heart failure and the possible benefit associated with amiodarone treatment.

Plasma alpha natriuretic peptide in cardiac impairment.

Regional plasma alpha human atrial natriuretic peptide concentrations were measured, and their relation to intracardiac pressures assessed, in an unselected series of 45 patients undergoing diagnostic cardiac catheterisation. Arteriovenous gradients in plasma concentrations of alpha human atrial natriuretic peptide were consistent with its cardiac secretion and its clearance by the liver and kidneys. Plasma concentrations of the peptide in the pulmonary artery, aorta, and superior vena cava correlated closely with the mean right atrial and pulmonary arterial pressures, and similar, though weaker, positive relations were seen with the left ventricular end diastolic and pulmonary artery wedge pressures. Concentrations of both atrial natriuretic peptide and renin showed significant inverse relations with serum sodium concentrations. Plasma concentrations of alpha human atrial natriuretic peptide are an additional objective indicator of the severity of haemodynamic compromise in patients with cardiac impairment.

The national heart failure audit for England and Wales 2008–2009

Objectives To obtain national data on the clinical characteristics, investigation, management and outcome of patients hospitalised with a diagnosis of heart failure. Method A survey was carried out of the first 10 patients hospitalised with a primary diagnosis of heart failure each month in 86 hospitals providing services for acute medical admissions in England and Wales from April 2008 until March 2009. The main outcome measures were rates of investigations, treatments and specialist management, length of hospital stay and mortality. Results The 86 hospitals enrolled 6170 patients with a median age of 78u2005years (IQR 70–85u2005years), including 2639 (43%) women. At admission, only 30% of patients were breathless at rest, while 43% had peripheral oedema. Echocardiograms were recorded in 75% of patients and left ventricular ejection fraction (LVEF) was ≤40% in 78%. Natriuretic peptides were rarely measured. Allowing for missing data, >90% of patients were treated with loop diuretics at discharge, 80% with ACE inhibitors or angiotensin receptor blockers, 50% with β-blockers and 30% with aldosterone antagonists. Patients with an LVEF <40% were more likely to receive these agents. Median hospital stay was 9u2005days (IQR 5–17) and in-patient mortality was 12%. Patients admitted to general medicine rather than cardiology wards were more likely to die (HR=2.5, 95% CI 2.0 to 3.3, p<0.001) even after adjusting for differences (HR=1.9, 95% CI 1.5 to 2.5, p<0.001). Projected 1-year mortality below and above age 75u2005years was 26% and 56%, with higher rates if managed on general medicine rather than cardiology wards (HR=1.4, 95% CI 1.2 to 1.6, p<0.001). Conclusion The prognosis of patients hospitalised with heart failure remains poor and investigation and treatment suboptimal. Specialist services are associated with higher rates of investigation and treatment and improved outcome.

Severe hypotension after first dose of enalapril in heart failure.

The new, long acting converting enzyme inhibitor enalapril was given to 26 patients with moderate to severe heart failure. In 23 cases the mean systolic blood pressure fell from 120 (SD 22) to 108 (25) mm Hg without adverse effects. Profound hypotension with severe bradycardia and sweating, however, occurred in three patients, most pronounced two to four hours after the first dose. The haemodynamic and biochemical changes in these patients were similar to those seen in patients with severe symptomatic hypotension after the first dose of the converting enzyme inhibitor captopril, except that with enalapril the changes occurred later and were longer lasting. Evidence of myocardial damage and reversible renal failure was seen in one patient, and acute reversible deterioration in renal function occurred in one other. In patients with heart failure converting enzyme inhibitors should be administered initially under strict medical supervision with appropriate facilities available for dealing with occasional profound hypotension.

The index of microcirculatory resistance measured acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction.

OBJECTIVESnThis study investigated the relationship between the index of microcirculatory resistance (IMR) with myocardial injury and microvascular obstruction (MVO) assessed by contrast-enhanced cardiac magnetic resonance (ceCMR) imaging in a broad range of ST-segment elevation myocardial infarction (STEMI) patients undergoing emergency percutaneous coronary intervention (PCI).nnnBACKGROUNDnContrast-enhanced cardiac magnetic resonance imaging is the gold standard for assessment of microvascular obstruction (MVO), left ventricular (LV) ejection fraction, and infarct volumes in ST-segment elevation myocardial infarction (STEMI). However, ceCMR is not available acutely. The index of microcirculatory resistance is a simple invasive measure of microvascular function available at the time of emergency PCI. We investigated the relationship between IMR with myocardial injury and MVO assessed by ceCMR in STEMI patients undergoing emergency PCI.nnnMETHODSnFifty-seven patients with STEMI were included and 53 (93%) and 47 (82%) patients had complete ceCMR scans 2 days and 3 months following MI, respectively. Microvascular obstruction was defined as a dark core of hypoenhancement within the area of hyperenhanced infarct tissue 10 to 15 min following intravenous gadolinium (0.1 mmol/kg).nnnRESULTSnThe median IMR (interquartile range [IQR]) was 35 (24 to 63) U. Twenty-seven patients (46%) had MVO. We found that IMR (median [IQR]) was higher in patients with MVO (38 [29 to 55] U) than in patients without MVO (27 [18 to 36] U); p = 0.003). The index of microcirculatory resistance was a negative multivariable predictor of LV ejection fraction, (p < or = 0.001) and infarct volume (p = 0.01) on the ceCMR scan 2 days after MI, and IMR was a multivariable predictor of LV ejection fraction (p = 0.028) and infarct volume (p = 0.048) at 3 months.nnnCONCLUSIONSnThe index of microcirculatory resistance measured acutely was higher in patients with MVO on ceCMR, and IMR independently predicted LV function and infarct volume. This easily measured physiological parameter provides important prognostic information at the time of emergency PCI.

Clinical, haemodynamic, and antiarrhythmic effects of long term treatment with amiodarone of patients in heart failure.

Twenty two patients with heart failure were studied in a double blind crossover trial to compare amiodarone (200 mg/day) with placebo. Each agent was given for three months. Extrasystoles and complex ventricular arrhythmias were common during ambulatory electrocardiographic monitoring and during exercise testing at entry to the study. Breathlessness and tiredness as assessed by visual analogue scores and duration of treadmill exercise did not become worse during amiodarone treatment. During the placebo and amiodarone phases of the study left ventricular ejection fraction and cardiac index determined by first pass radionuclide ventriculography were similar, both at rest and during upright bicycle exercise. Exercise induced ventricular tachycardia was abolished and simple and complex ventricular arrhythmias observed on 24 hour ambulatory monitoring were greatly diminished during amiodarone treatment. Three patients died, all suddenly, during the placebo phase. In two patients amiodarone was withdrawn after a further myocardial infarction in one and a worsening of symptoms of ventricular arrhythmia in the other. In contrast with other antiarrhythmic agents amiodarone is effective in suppressing ventricular arrhythmias in heart failure without causing adverse haemodynamic effects. Because frequent ventricular arrhythmias are known to be associated with a poor prognosis in heart failure, these data suggest that amiodarone may improve the poor prognosis in patients with heart failure.

Declining Risk of Sudden Death in Heart Failure

Background The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin‐converting–enzyme inhibitors, angiotensin‐receptor blockers, beta‐blockers, and mineralocorticoid‐receptor antagonists. We sought to examine this trend in detail. Methods We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter–defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization. Results Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer‐standing diagnosis. Conclusions Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence‐based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.)

EndothelinBreceptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction

OBJECTIVES n nThis study was designed to assess the functional importance of endothelin (ET)Breceptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ETAand ETBagonist, with ET-3, a selective ETBreceptor agonist. n nBACKGROUND n nKnowledge of the functional importance of ETBreceptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ETAand ETBreceptors are required to fully prevent vasoconstriction to endogenously produced ET-1. n nMETHODS n nWe infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. n nRESULTS n nEndothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean ± SEM 100 ± 3 to 105 ± 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 ± 142 to 2,055 ± 164 dyn/s/cm−5, p < 0.001) and a fall in cardiac index (2.44 ± 0.21 to 2.22 ± 0.20 liters/min/m2, p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 ± 6 to 105 ± 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 ± 210 to 1,918 ± 245 dyn/s/cm−5, p < 0.01) and a fall in cardiac index (2.66 ± 0.28 to 2.42 ± 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group. n nCONCLUSIONS n nBoth ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ETBreceptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.