Prognostic value of cardiovascular screening in potential renal transplant recipients: a single-center prospective observational study.

We assessed the outcome of pretransplant cardiac assessment in a single center. Three hundred patients with end-stage renal disease underwent electrocardiogram, Bruce exercise testing (ETT) and ventricular assessment by cardiac MRI. Patients with high index of suspicion of coronary artery disease (CAD) underwent coronary angiography and percutaneous coronary intervention (PCI) if indicated. Two hundred and twenty-two patients were accepted onto the renal transplant waiting list; 80 patients were transplanted during the follow-up period and 60 died (7 following transplantation). Successful transplantation was associated with improved survival (mean survival 4.5 +/- 0.6 years vs. listed not transplanted 4.1 +/- 1.4 years vs. not listed 3.1 +/- 1.7 years; p < 0.001). Ninety-nine patients underwent coronary angiography; 65 had normal or low-grade CAD and 34 obstructive CAD. Seventeen patients (5.6%) were treated by PCI. There was no apparent survival difference between patients who underwent PCI or coronary artery bypass graft compared to those who underwent angiography without intervention or no angiography (p = 0.67). Factors associated with nonlisting for renal transplantation included burden of preexisting cardiovascular disease, poor exercise tolerance and severity of CAD. Pretransplant cardiovascular screening provides prognostic information and information that can be used to restrict access to transplantation. However, if the aim is to identify and treat CAD, the benefits are far from clear.

B-type natriuretic peptide predicts cardiac morbidity and mortality after major surgery.

BACKGROUND: The objective of this study was to determine whether measurement of B-type natriuretic peptide (BNP) concentration before operation could be used to predict perioperative cardiac morbidity. METHODS: A prospective derivation study was performed in high-risk patients undergoing major non-cardiac surgery, with a subsequent validation study. A venous blood sample was taken the day before surgery for measurement of plasma BNP concentration. Screening for cardiac events (non-fatal myocardial infarction and cardiac death) was performed using clinical criteria, cardiac troponin I analysis and serial electrocardiography. RESULTS: Forty-one patients were recruited to the derivation cohort and 149 to the validation cohort. In the derivation cohort, the median (interquartile range) BNP concentration in the 11 patients who had a postoperative cardiac event was 210 (165-380) pg/ml, compared with 34.5 (14-70) pg/ml in those with no cardiac complications (P < 0.001). In the validation cohort, the median BNP concentration in the 15 patients who had a cardiac event was 351 (127-1034) pg/ml, compared with 30.5 (11-79.5) pg/ml in the remainder (P < 0.001). BNP concentration remained a significant outcome predictor in multivariable analysis (P < 0.001). Using receiver-operator curve analysis it was calculated that a BNP concentration of 108.5 pg/ml best predicted the likelihood of cardiac events, with a sensitivity and specificity of 87 per cent each. CONCLUSION: Preoperative serum BNP concentration predicted postoperative cardiac events in patients undergoing major non-cardiac surgery independently of other risk factors.

NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension.

Right ventricular systolic dysfunction (RVSD) at baseline (pre-treatment) predicts early death in patients with pulmonary hypertension (PH). However, RVSD can only be detected reliably by prohibitively invasive or expensive techniques. N-terminal B-type natriuretic peptide concentration ([NT-proBNP]) correlates with RV function in PH; however, an [NT-proBNP] threshold that indicates RVSD in individual patients has not previously been determined. Twenty-five patients with PH (pulmonary arterial hypertension (n = 19) or chronic thromboembolic PH (n = 6)) underwent cardiovascular magnetic resonance (CMR) imaging and NT-proBNP measurement at baseline. [NT-proBNP] was correlated against RV dimensions and ejection fraction (RVEF) measured directly by CMR imaging. The ability of NT-proBNP to detect RVSD (defined as a CMR-derived RVEF >2 SDS below control values) was tested and predictors of [NT-proBNP] identified. [NT-proBNP] correlated negatively with RVEF. RVSD was present in nine out of 25 patients. An [NT-proBNP] threshold of 1,685 pg.mL(-1) was sensitive (100%) and specific (94%) in detecting RVSD. RVEF and RV mass index independently predicted [NT-proBNP]. In pulmonary hypertension, a baseline N-terminal B-type natriuretic peptide concentration of >1,685 ng.L(-1) suggests right ventricular systolic dysfunction, and thus an increased risk of early death. N-terminal B-type natriuretic peptide could prove useful as an objective, noninvasive means of identifying patients with pulmonary hypertension who have right ventricular systolic dysfunction at presentation.

Vascular function in patients with end-stage renal disease and/or coronary artery disease: a cardiac magnetic resonance imaging study.

Decreased arterial compliance in end-stage renal disease (ESRD) is associated with increased cardiovascular risk. Our aim was to examine aortic compliance in patients with ESRD using cardiac magnetic resonance imaging (MRI) and to compare these with patients with advanced atherosclerotic disease who are known to be at high cardiovascular risk. We examined a total of 83 subjects matched for age: 24 had ESRD and were on dialysis therapy for 3+/-6 years, 24 had severe coronary artery disease (CAD), 11 had both ESRD and CAD (4+/-5 years on dialysis therapy), and 24 healthy subjects with no evidence of CAD. Vascular and cardiac function was assessed using cardiac MRI. Aortic compliance was significantly reduced in patients with CAD compared to control subjects (11.3+/-6.3 ml x 10(-3)/mm Hg vs 15.6+/-6.0 ml x 10(-3)/mm Hg, P=0.009). Patients with ESRD also exhibited significantly reduced aortic compliance compared to healthy controls (12.4+/-5.8 ml x 10(-3)/mm Hg vs 15.6+/-6.0 ml 10(-3)/mm Hg, P=0.012), whereas there was no significant difference in aortic compliance between patients with CAD and ESRD. Even in the absence of symptomatic CAD, patients with ESRD have significantly reduced aortic compliance compared to normal subjects. Patients with ESRD have equivalent aortic compliance to patients with advanced CAD. These findings suggest that a significantly reduced aortic compliance is one of many mechanisms promoting premature cardiovascular events in patients with ESRD compared to age-matched controls from the general population.

Redefinition of uremic cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging.

Patients with end stage renal failure (ESRF) have an increased risk of premature cardiovascular disease. Left ventricular (LV) abnormalities, so called 'uremic cardiomyopathy', are associated with poorer outcome. Cardiac magnetic resonance imaging (CMR) accurately defines LV dimensions and identifies underlying myocardial pathology. We studied the relationship between LV function and myocardial pathology in ESRF patients with CMR. A total of 134 patients with ESRF underwent CMR. LV function was assessed with further images acquired after gadolinium-diethylentriaminepentaacetic acid (DTPA). The presence of myocardial fibrosis was indicated by late gadolinium enhancement (LGE). Two main myocardial pathologies were identified. A total of 19 patients (14.2%) displayed 'subendocardial LGE' representing myocardial infarction, which was associated with conventional cardiovascular risk factors including a history of ischemic heart disease (IHD) (P < 0.001), hypercholesterolemia (P < 0.05), and diabetes (P < 0.01). Patients with subendocardial LGE had greater LV mass (P < 0.05), LV dilation (P < 0.01), and LV systolic dysfunction (P < 0.001) compared to patients with no evidence of LGE. The second pattern, 'diffuse LGE', seen in 19 patients (14.2%) appeared to represent regional areas of diffuse myocardial fibrosis. Diffuse LGE was associated with greater LV mass compared to patients without LGE (P < 0.01) but not systolic dysfunction. In total, 28.4% of all patients exhibited evidence of myocardial fibrosis demonstrated by LGE. In contrast to published literature describing three forms of uremic cardiomyopathy - left ventricular hypertrophy (LVH), dilation, and systolic dysfunction, we have shown that LVH is the predominant cardiomyopathy specific to uremia, while LV dilation and systolic dysfunction are due to underlying (possibly silent) ischemic heart disease.

Comparison of the dual receptor endothelin antagonist enrasentan with enalapril in asymptomatic left ventricular systolic dysfunction: a cardiovascular magnetic resonance study.

OBJECTIVE: To compare the effect of the dual endothelin A/B receptor antagonist enrasentan with enalapril on left ventricular (LV) remodelling. METHODS: Multicentre, randomised, double blind, parallel group study of 72 asymptomatic patients with LV dysfunction. Patients received enrasentan (60-90 mg/day) or enalapril (10-20 mg/day). The primary end point was the change in LV end diastolic volume index (EDVI) after six months' treatment. RESULTS: LV EDVI increased with enrasentan but decreased with enalapril (3.9 (1.8) v -3.4 (1.4) ml/m2, p = 0.001). Enrasentan increased resting cardiac index compared with enalapril (0.11 (0.07) v -0.10 (0.07) l/m2, p = 0.04), as well as LV mass index (0.67 (1.6) v -3.6 (1.6) g/m2, p = 0.04). Other variables were comparable between groups. Enalapril lowered brain natriuretic peptide more than enrasentan (-19.3 (9.4) v -5.8 (6.9) pg/ml, p = 0.005). Noradrenaline (norepinephrine) (p = 0.02) increased more with enrasentan than with enalapril. Enrasentan was associated with more serious adverse events compared with enalapril (six (16.7%) patients v one (2.8%), p = 0.02); the rate of progression of heart failure did not differ. CONCLUSION: In asymptomatic patients with LV dysfunction, LV EDVI increased over six months with enrasentan compared with enalapril treatment, with adverse neurohormonal effects. This suggests that enrasentan at a dose of 60-90 mg/day over six months causes adverse ventricular remodelling despite an increase in the resting cardiac index.

NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies.

Many studies have shown that the B-type natriuretic peptides (BNP and NT-proBNP) are proven diagnostic markers for heart failure due to left ventricular systolic dysfunction. The manner in which they are to be used is still being unravelled; most single centre studies have chosen the best concentration of the peptide on ROC analysis as their cut-point resulting in numerous different values for both BNP and NT-proBNP appearing in the literature. We report a different approach of defining an age and sex corrected abnormal concentration for NT-proBNP, derived from normal individuals within a large sample of 3051 subjects pooled from three European epidemiology studies and applying that to the entire population to detect HF and LVD. Three thousand and fifty one subjects were studied. Of these 10% (305) had significant LVD and 3.1% (94) had HF. The median concentrations of NT-proBNP (IQR) in normals, those with LVD and in heart failure subjects were 20 pg/ml (10.30), 117.3 pg/ml (28.145) and 269.6 pg/ml (54.323), P<0.001, respectively. The area under the ROC curve for NT-proBNP for the detection of 'heart failure' was 0.85 and 0.69 for LVD. NT-proBNP was an independent predictor of the presence of HF on multivariate analysis. An abnormal NT-proBNP was defined as being >95th centile for normals, age and sex corrected, and diagnosed HF with a sensitivity of 75% and a negative predictive value of 99%. In an additional analysis in a breathless subgroup of our population, in 30% a raised NT-proBNP concentration could be explained by HF due to LVD, in another 64% the high BNP level was associated with some other structural of functional cardiac abnormality or renal impairment. We were unable to assign a possible cause to the high NT-proBNP values in 5.9% of this breathless subgroup of the population. An abnormal NT-proBNP concentration is an accurate diagnostic test both for the exclusion of HF in the population and in ruling out LVD in breathless subjects. An elevated NT-proBNP merely indicates the presence of 'cardio-renal distress' and should prompt referral for further investigation.

The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease.

OBJECTIVES: Excess iron stores have been postulated to enhance the risk of ischaemic heart disease. This study aims to determine whether the two major mutations of the haemochromatosis (HFE) gene (C282Y and H63D) are associated with ischaemic heart disease (IHD) or myocardial infarction (MI). DESIGN: Cross sectional case-control study. SETTING: The geographical area studied by the MONICA (monitoring trends and determinants in cardiovascular disease) heart attack register for North Glasgow in Scotland, UK. PATIENTS: 1009 control subjects chosen at random from general practitioner registers were studied. Additionally, 924 subjects who had survived a first MI sustained between 1985 and 1992 were identified from the MONICA register. MAIN OUTCOME MEASURES: C282Y and H63D mutations, previous MI, and presence or absence of IHD. RESULTS: Mutant gene prevalences in the whole control population were as follows: C282Y: homozygote 0.9%, heterozygote 17.7%; H63D: homozygote 2.1%, heterozygote 25.5%; and compound heterozygote: 2.4%. Analysis by chi(2) test and logistic regression analysis did not identify any significant difference in genotype prevalence between normal control, IHD control, and MI survivor groups. CONCLUSIONS: The C282Y homozygote and heterozygote prevalences are among the highest reported worldwide. No association between IHD or MI and HFE genotype was identified. However, these results need to be interpreted in the light of the cross sectional case-control nature of the study.

The value of routine non-invasive tests to predict clinical outcome in stable angina.

BACKGROUND: Chronic stable angina is a common condition, but considerable differences exist in the likelihood of acute coronary events such as CHD death, non-fatal myocardial infarction (MI) and unstable angina between individual patients. Effective risk prediction is necessary for optimum management. The aim of this study was to identify clinical features and non-invasive test parameters associated with high risk of these coronary events in stable angina and compose a clinically useful model to predict adverse outcomes in this population. METHODS: Six hundred and eighty-two patients with stable angina and a positive exercise test (1mm ST depression) from the Total Ischaemic Burden European Trial (TIBET) study, were studied. Resting ECG, exercise tolerance testing and echocardiography were performed at baseline, off anti-anginal therapy. The patients were then randomised to treatment with atenolol, nifedipine or a combination of both. Clinical follow up continued for an average of 2 years (range 1-3 years). RESULTS AND CONCLUSIONS: Prior MI or prior CABG were the clinical parameters associated with adverse outcome in patients with stable angina and a positive exercise test. On the ECG, left ventricular hypertrophy was predictive, and on echocardiogram, increased left ventricular dimensions were predictive of adverse events. When combined with time to ischaemia on exercise testing in a simple clinically applicable table these factors could be used to predict of 2 year probability of events for an individual patient.

Morphine for the relief of breathlessness in patients with chronic heart failure--a pilot study.

BACKGROUND: Chronic heart failure (CHF) patients can experience significant breathlessness despite maximum medication for their heart failure. Morphine has long been used to relieve symptoms in acute failure, but there is little evidence about this potentially useful palliative therapy in CHF. AIMS: To determine the efficacy of morphine for the relief of breathlessness in patients with CHF. METHOD: Ten out-patients with NYHA III/IV CHF entered a randomised, double-blind, placebo controlled, crossover pilot study. The active arm was 4 days of 5 mg oral morphine four times daily (2.5 mg morphine if creatinine > 200 micromol/l). There were 2 days wash-out between active and placebo arms. RESULTS: 6/10 patients indicated that morphine improved their breathlessness. On morphine, the median breathlessness score fell by 23 mm (P = 0.022) by day 2. The improvement was maintained. Sedation scores increased until day 3 (P = 0.013), reducing on day 4. Four patients developed constipation (P = 0.026). On placebo, there was no significant difference in breathlessness or sedation. One patient had constipation. There were no significant differences in either arm in nausea, quality of life scores, blood pressure, pulse, respiratory rate, or catecholamines. Brain natriuretic peptide fell in both arms; significantly in the morphine arm. CONCLUSION: Morphine relieves breathlessness due to CHF. A larger study is indicated.

Randomised controlled trial of continuous positive airway pressure and standard oxygen therapy in acute pulmonary oedema; effects on plasma brain natriuretic peptide concentrations.

AIMS: The study aim was to compare the effects of continuous positive airway pressure (CPAP) on clinical outcomes and plasma neurohormonal concentrations in patients with acute pulmonary oedema. METHODS AND RESULTS: In addition to standard therapy, 58 consecutive patients were randomized to receive 60% inhaled oxygen with or without CPAP at 7.5 cmH(2)O pressure. Clinical variables, symptoms and oxygenation were monitored and plasma epinephrine, norepinephrine and brain natriuretic peptide (BNP) concentrations estimated at 0, 1, 6 and 24 h. CPAP was associated with less breathlessness at 1 h (P<0.001), no treatment failures and more rapid resolution in respiratory rate (P<0.001), heart rate (P<0.001) and acidosis (P<0.005). Length of hospital stay was similar but there was a trend for a reduction in overall hospital mortality in the CPAP group (0.10>P>0.05). Plasma BNP concentrations rose progressively (P<0.001) before falling below admission concentrations at 24 h. Plasma neurohumoral concentrations were unaffected by CPAP treatment but were elevated in patients who died or had acute myocardial infarction. CONCLUSION: CPAP produces a more rapid clinical and symptomatic improvement in patients with acute pulmonary oedema, particularly within the first hour. CPAP is a useful adjunctive treatment in the early management of acute heart failure.

A comparison of physiological responses and rating of perceived exertion in two modes of aerobic exercise in men and women over 50 years of age.

OBJECTIVES: To compare the physiological responses and ratings of perceived exertion to aerobic dance and walking sessions completed at a self selected pace. METHODS: Six women and six men with a sample mean (SD) age of 68 (7) years completed aerobic dance and walking sessions in random order. A treadmill test was performed by each subject from which peak oxygen uptake (.VO(2)) and maximum heart rates (HRmax) were determined. During the aerobic dance and walking sessions, heart rate and .VO(2) were measured continuously throughout. Rate of perceived exertion (RPE) was measured every three minutes throughout the session. RESULTS: The sample means (SD) for %peak .VO(2) were 67 (17)% for the aerobic dance sessions and 52 (10)% for the walking sessions, and the %HRmax sample means (SD) were 74 (12)% for the aerobic dance sessions and 60(8)% for walking sessions. The sample mean (SD) RPE for the aerobic dance sessions was 11(2), and for the walking sessions it was 10(2). CONCLUSIONS: %peak .VO(2), %HRmax, and RPE were significantly higher for aerobic dance than for walking. However, both the aerobic dance and walking sessions were of adequate intensity to improve aerobic fitness in most subjects. Further investigation into the relation between RPE and %peak .VO(2) in a field setting over representative exercise time periods would be useful.

Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population.

OBJECTIVE: To report the mortality of left ventricular systolic dysfunction (LVD), assessed objectively by echocardiography, and its association with natriuretic peptide hormones in a random sample of 1640 men and women aged 25-74 years from a geographical, urban population. METHODS: Left ventricular function was measured by echocardiography in 1640 attendees studied in 1992-3. LVD was defined as a left ventricular ejection fraction (LVEF) 30% (p < 0.001). The median (interquartile range) BNP concentration in those who died was 16.9 pg/ml (8.8-27) and 7.8 pg/ml (3.4-13) in survivors (p < 0.0001). Similarly, N-ANP had a median concentration of 2.35 ng/ml (1.32-3.36) in those with a fatal outcome and 1.27 ng/ml (0.9-2.0) in those alive at four years (p < 0.0001). Subjects with an LVEF /= 17.9 pg/ml compared with 6.8% if their BNP was below this concentration (p = 0.013). Multivariate analysis revealed the independent predictors of four year all cause mortality to be increasing age (p < 0.001), a BNP concentration >/= 17.9 pg/ml (p = 0.006), the presence of ischaemic heart disease (p = 0.03), and male sex (p = 0.04). CONCLUSIONS: LVD is associated with a considerable mortality rate in this population. BNP also independently predicts outcome. In addition to its role as a diagnostic aid in chronic heart failure and LVD, it provides prognostic information and clarifies the meaning of a given degree of LVD.

Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.

BACKGROUND: The beneficial effects of beta-blockers on long-term outcome after acute myocardial infarction were shown before the introduction of thrombolysis and angiotensin-converting-enzyme (ACE) inhibitors. Generally, the patients recruited to these trials were at low risk: few had heart failure, and none had measurements of left-ventricular function taken. We investigated the long-term efficacy of carvedilol on morbidity and mortality in patients with left-ventricular dysfunction after acute myocardial infarction treated according to current evidence-based practice. METHODS: In a multicentre, randomised, placebo-controlled trial, 1959 patients with a proven acute myocardial infarction and a left-ventricular ejection fraction of

ADEPT: Addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial: hemodynamic and neurohormonal effects.

BACKGROUND: Persistent activation of the renin-angiotensin-aldosterone-system (RAAS) is known to occur in patients with chronic heart failure (CHF) despite treatment with angiotensin-converting enzyme inhibitor (ACE) therapy. When added to ACE inhibitors, angiotensin II type 1 (AT1) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone. METHODS: Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were randomly assigned in a double-blind manner to receive either eprosartan, a specific competitive AT1 receptor antagonist (400 to 800 mg daily, n = 18) or placebo (n = 18) for 8 weeks. The primary outcome measure was left ventricular ejection fraction (LVEF) as measured by radionuclide ventriculography, and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects. RESULTS: There was no change in LVEF with eprosartan therapy (mean relative LVEF percentage change [SEM] +10.5% [9.3] vs +10.1% [5.0], respectively; difference, 0.4; 95% confidence interval [CI], -20.8 to 21.7; P =.97). Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo (-7.3 mm Hg [95% CI, -14.2 to -0.4] diastolic; -8.9 mm Hg [95% CI, -18.6 to 0.8] systolic). No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo. A trend toward an increase in plasma renin activity was noted with eprosartan therapy. Eprosartan was well tolerated, with an adverse event profile similar to placebo, whereas kidney function remained unchanged. CONCLUSIONS: When added to an ACE inhibitor, eprosartan reduced arterial pressure without increasing heart rate. There was no change in LVEF after 2 months of therapy with eprosartan.