Norman S.J. Kennedy

Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease

In chronic heart failure, a diuretic plus an angiotensin-converting enzyme (ACE) inhibitor only partially suppresses aldosterone despite the fact that aldosterone has many harmful effects independent of angiotensin II. These possible harmful effects of aldosterone are magnesium loss, increased cardiac sympathetic activity, and increased ventricular arrhythmias. We have therefore assessed whether adding the aldosterone antagonist, spironolactone, to a loop diuretic and ACE inhibitor reverses any of these potentially harmful effects of residual aldosterone. In a preliminary animal study, we found that exogenous aldosterone reduced myocardial norepinephrine uptake by 24% in anesthetized rats in vivo. In our main study, 42 patients with New York Heart Association II to III congestive heart failure were randomized to spironolactone (50 to 100 mg/day, titrated to blood pressure and plasma potassium) or placebo in a double-blind fashion. Our principal finding is that cardiac norepinephrine uptake as assessed by 123I-metaiodobenzylguanidine scintigraphy increased with spironolactone (p < 0.01). Spironolactone also elevated plasma magnesium (p < 0.05), reduced urinary magnesium excretion (p < 0.05), and caused a reduction in ventricular arrhythmias on 24-hour ambulatory electrocardiography (p < 0.05). Spironolactone increased plasma renin activity, plasma aldosterone (p < 0.01), 24-hour urinary sodium excretion (p < 0.05), and urinary sodium/potassium ratio (p < 0.01). Echocardiographic-determined measurements of left ventricular systolic and diastolic function were unaltered by spironolactone.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma brain natriuretic peptide as an indicator for angiotensin-converting-enzyme inhibition after myocardial infarction

Brain natriuretic peptide (BNP) is a cardiac ventricular hormone that may be a sensitive and specific marker of changes in ventricular function. In a prospective, randomised open trial with 16 patients followed for 6 months after first Q wave anterior myocardial infarction we set out to determine: whether BNP concentrations are raised acutely, the effect on circulating BNP of angiotensin-converting enzyme (ACE) inhibition, how BNP and atrial natriuretic peptide (ANP) concentrations compared as correlates of left-ventricular ejection fraction, and whether plasma BNP concentrations could distinguish patients with low (< 40%) and relatively preserved (> 40%) ejection fractions. Plasma concentrations of BNP measured on days 2, 7, 8, 42, and 180 postinfarction were significantly raised in patients compared with normal controls and to a proportionately greater degree than ANP concentrations. Treatment with placebo (n = 8) or oral captopril (n = 8) from day 8 resulted in significantly lower BNP concentrations at days 42 (p = 0.05) and 180 (p < 0.05) in the captopril-treated group. Compared with ANP, BNP concentrations were much more strongly correlated with radionuclide-measured left-ventricular ejection fraction at days 2, 42, and 180. All 8 patients with baseline (day 2) ejection fractions of 40% or above had plasma BNP concentrations less than 10 pmol/L, whereas the 8 patients with ejection fractions less than 40% had BNP concentrations greater than 10 pmol/L. Our findings suggest that measurements of circulating BNP may identify those patients with significant left-ventricular dysfunction who have been highlighted by the Survival and Ventricular Enlargement study as likely to benefit from long-term ACE inhibition after myocardial infarction.

Comparison of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction

We have directly compared atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and N-terminal pro-ANP (N-ANP) as markers of patients with left ventricular ejection fraction (LVEF) < or = 35%, as measured by radionuclide ventriculography. Venous blood samples were obtained from an unselected group of 87 patients who had been referred for assessment of ventricular function. ANP, BNP, and N-ANP were measured by radioimmunoassay using commercial kits. Receiver-operating characteristic analysis was used for the objective assessment of the diagnostic performance of each assay. There was a weak negative correlation between LVEF and plasma levels of ANP-li (r = -0.50,), BNP-li (r = -0.57), and N-ANP-li (r = -0.49) (p <0.01 for each peptide). Areas under the receiver-operating characteristic curves for BNP (0.880) and N-ANP (0.832) were not significantly different from each other, but were both significantly greater than the value for ANP (0.761): BNP versus ANP, p <0.01; and N-ANP versus ANP, p <0.05. The optimal sensitivity and specificity of each assay for the detection of patients with LVEF < or = 35% were: BNP > 4 pmol/L-sensitivity 1.0, specificity 0.58; N-ANP >200 pmol/L-sensitivity 0.95, specificity 0.35; and ANP >10 pmol/L-sensitivity 0.90, specificity 0.30. Plasma concentrations of BNP and N-ANP provide sensitive indicators of moderate to severe LV dysfunction; both peptides, are objectively superior to ANP for identifying patients with LVEF < or = 35%. These simple tests could be used to screen patients with suspected ventricular dysfunction to reduce the demand for further cardiac investigations.

Prediction of late cardiac events by dipyridamole thallium scintigraphy in patients with intermittent claudication and occult coronary artery disease

Concomitant coronary artery disease often occurs in patients with peripheral vascular disease, but it may be asymptomatic. Despite being asymptomatic, cardiovascular events are the main source of morbidity and mortality in this group of patients. Dipyridamole thallium scintigraphy has been shown to be of prognostic value in patients with peripheral vascular disease and symptomatic coronary artery disease, but its effect on the long-term outcome in the asymptomatic group of patients is less defined. Eighty-four consecutive patients with peripheral vascular disease and no symptoms of coronary artery disease were therefore evaluated by clinical assessment, dipyridamole thallium imaging, radionuclide ventriculography, and cardiac catheterization and followed for a mean of 66 months. Abnormal perfusion patterns were found on thallium scintigraphy in 48 patients (57%); fixed, mixed, and reversible defects were present in 14 (17%), 11 (13%), and 23 (27%) patients, respectively. Significant coronary artery disease was present in 52 patients (69%) and mean left ventricular ejection fraction was 44%. During the follow-up period, 23 patients had a cardiac event (nonfatal myocardial infarction or cardiac death). Univariate analysis of 15 clinical, scintigraphic, radionuclide, and angiographic variables revealed that age, angiographic extent of coronary artery disease, and an abnormal thallium scan were significant predictors of subsequent cardiac events. Multivariate stepwise logistic regression analyses selected fixed and mixed thallium defects and diffuse coronary artery disease as the only significant independent predictors of outcome. Thus, the present study shows the value of dipyridamole thallium scintigraphy as a valuable prognostic indicator for long-term event-free survival in a cohort of patients with peripheral vascular disease and no history or symptoms of coronary artery disease.

B-type natriuretic peptide identifies silent myocardial ischaemia in stroke survivors

Objective: To test the hypothesis that B-type natriuretic peptide (BNP) predicts reversible myocardial ischaemia in stroke survivors who do not have chest pain or previous myocardial infarction. Methods: 56 stroke survivors (mean (SE) age 68 (8) years) underwent tetrofosmin myocardial perfusion scanning with dipyridamole as the stressor. The degree of ischaemia was assessed by a scoring system (out of 64) by an experienced observer blinded to the results of BNP. Results: In the whole cohort, BNP was significantly correlated with the degree of myocardial ischaemia on stress scanning (Spearman’s r  =  −0.475, p < 0.001). BNP also correlated with the degree of reversible ischaemia (stress score − rest score; Spearman’s r  =  0.28, two tailed p  =  0.049). In the cohort who did not have left ventricular systolic dysfunction (n  =  44), BNP remained higher in patients with relevant myocardial ischaemia (mean (SE) BNP 20.9 pg/ml, 95% confidence interval (CI) 15.2 to 26.5 v 12.2 pg/ml, 95% CI 5.95 to 18.5; p  =  0.046); 33 of the 44 patients had no chest pain or history of myocardial infarction. The relation between resting BNP and both inducible ischaemia and dipyridamole stress score remained significant (Spearman’s r  =  0.37 and −0.38, respectively). Conclusions: BNP correlates with the degree of reversible myocardial ischaemia in patients who do not have chest pain or a history of myocardial infarction or evidence of left ventricular systolic dysfunction. Stroke survivors with a high BNP deserve further investigations to rule out significant reversible myocardial ischaemia, in order to reduce their risk of cardiac death.

Spectrum of cardiac abnormalities associated with long QT in stroke survivors

Objectives: To find out what spectrum of cardiac abnormalities are found in those stroke survivors who can be deemed to be at high cardiac risk by their having long QT. Methods: 202 patients with good recovery from a cerebrovascular event occurring at least one month previously were recruited into a prospective epidemiological study. These stroke survivors underwent a battery of cardiac investigations including 12 lead ECG, echocardiography, myocardial perfusion scanning, and heart rate variability assessment. The ECGs were digitised by a single observer blinded to the blood pressure and other investigations of the patients. The maximum heart rate corrected QT interval (QTc max) in the 12 lead ECG was derived by Bazett’s formula. Results: Prolonged QTc max significantly correlated with increasing blood pressure, left ventricular mass index, and depressed heart rate variability. As the number of cardiac abnormalities increased, QTc max became more prolonged. Conclusions: Long QT is significantly associated with left ventricular mass index even after adjustment for both systolic and diastolic blood pressures. Long QT was also associated with the total cardiac disease burden. These two observations may explain why stroke survivors with long QTc max were at greater risk of cardiac death.

Effects of lisinopril on congestive heart failure in normotensive patients with diastolic dysfunction but intact systolic function

This study examined the effects of lisinopril on diastolic function in 12 normotensive patients (mean age 72 years) with symptomatic congestive heart failure, intact left ventricular systolic function and abnormal diastolic function secondary to ischaemic heart disease in a placebo-controlled double blind crossover study, with each treatment dosed orally for 5 continuous weeks. Compared to placebo, lisinopril significantly decreased blood pressure, increased plasma renin activity without altering heart rate or plasma norepinephrine. There was no statistically significant improvement with lisinopril in radionuclide derived peak filling rate and time to peak filling rate, in Doppler echocardiographic measurements of the ratio of peak flow velocity in early diastole to the peak flow velocity of atrial contraction (E:A ratio) and in visual analogue scales of symptoms.Thus, although angiotension converting enzyme inhibitors may have an established role in the treatment of heart failure secondary to left ventricular systolic dysfunction, its use in patients with isolated diastolic dysfunction remains unclear.

Effectiveness of captopril in reversing renal vasoconstriction after Q-wave acute myocardial infarction

The purpose of this investigation was to study whether favorable renal effects might contribute to the influence of captopril in offsetting ventricular dilatation after infarction. Effective renal plasma flow and glomerular filtration rate were estimated by isotope injection methods in 20 patients on days 2, 7, 8, 42 and 180 after a first transmural anterior myocardial infarction. After measurements on day 7, patients were randomized to receive either captopril 25 mg 3 times daily (n = 10) or placebo (n = 10) for the remainder of the study. At baseline (day 7) there were no differences between the 2 treatment groups in radionuclide left ventricular ejection fraction, effective renal plasma flow, glomerular filtration rate or neurohormones. Left ventricular ejection fractions (40 +/- 4% [mean +/- 2 SD] at baseline) were higher in the captopril- than the placebo-treated patients on days 42 (p < 0.05) and 180 (p < 0.01) after infarction. Effective renal plasma flow became significantly higher at all time points after randomization in the captopril-treated group than in the placebo group (p < 0.001). A similar but lesser trend was observed for glomerular filtration rate. Plasma atrial natriuretic factor and aldosterone were significantly higher in the placebo group (p < 0.05). Renal hemodynamic indexes were directly correlated with and neurohumoral indexes inversely correlated with ejection fractions. In a second group of 12 patients with higher baseline ejection fractions (48 +/- 4%) after an inferior infarction, none of these beneficial effects of captopril were demonstrable. It is proposed that in the setting of left ventricular dysfunction after infarction, a prompt and sustained improvement in renal hemodynamics, by reducing inappropriate fluid retention and thus ventricular preload, may be one contributory mechanism by which captopril prevents progression of left ventricular dilatation.

Myocardial ischaemia is associated with an elevated brain natriuretic pepide level even in the presence of left ventricular systolic dysfunction.

Plasma BNP and high‐sensitivity cardiac troponin‐T (hs‐TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD). As a result, it is unknown whether BNP and/or hs‐TnT could be useful biomarkers to identify ischaemia in the presence of LVSD.

139 CARDIAC TROPONIN-T MEASURED BY HIGH SENSITIVITY ASSAY AND ITS ASSOCIATION WITH REVERSIBLE MYOCARDIAL ISCHAEMIA IN PATIENTS WITH AND WITHOUT LV SYSTOLIC DYSFUNCTION

Introduction Detectable levels of cardiac troponin-T by high sensitivity assay (hs-TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD) but it is unknown whether hs-TnT could be a useful biomarker to identify ischaemia either in the presence or the absence of LVSD. Table 1 No ischaemia and LVEF>55% n=290 No ischaemia and LVEF<55% n=61 Ischaemia and LVEF>55% n=66 Ischaemia and LVEF<55% n=36 p Value 3.80 (4.29) 5.48 (8.01) 5.48 (7.81) 8.01 (5.98) <0.01 Methods 500 consecutive patients undergoing a clinically indicated dipyridamole myocardial perfusion scintigraphy were studied. Those with impaired renal functions and history of atrial fibrillation or valvular disease were excluded. The troponin-T levels were measured in serum using a highly sensitive assay on an automated platform (Elecsys E170, Roche Diagnostics, lower limit of detection 3 ng/l). All scans were interpreted by a trained physician blinded to the biomarker data. Patients were divided into four groups based on reversible ischaemia and stress ejection fraction (EF) on gated SPECT imaging. Results Data were available for 453 patients and 97/453 had a reversible ischaemic defect. hsTnT levels were significantly higher in patients with a reversible ischaemia (Median (IQR) 7.2 (3.3–10.9) vs 4.2 (3.0–7.5) pg/ml p<0.001) compared to those without. When analysed according to four groups based on LV function and reversible ischaemia, hsTnT levels were highest in patients with ischaemia and a low EF and lowest in patients with no ischaemia and normal EF (pTREND <0.001) as shown in the table 1. In a multivariate model which included age, gender, cardiovascular co-morbidities, eGFR, haemoglobin, BNP, and LV ejection fraction, hs-TnT remained an independent predictor of reversible perfusion defect (p=0.026). Conclusions Baseline hs-cTnT levels are an independent predictor of reversible myocardial ischaemia and this is still the case in the presence of LVSD. Figure 1