Risk factors and predictors of Torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving Dofetilide.

The purpose of this study was to identify risk factors of Torsade de pointes (TdP) ventricular tachycardia in patients medicated with a class III antiarrhythmic drug (dofetilide) and left ventricular systolic dysfunction with heart failure (HF) or recent myocardial infarction (MI). The 2 Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) studies enrolled patients with HF (DIAMOND-HF) or MI (DIAMOND-MI) and left ventricular systolic dysfunction. The present analysis includes only patients treated solely with dofetilide. The incidence of TdP was 2.1% (32 of 1,511). Twenty-five of the incidences occurred in the DIAMOND-HF study and 7 cases in the DIAMOND-MI study (p = 0.0015). TdP was more frequent in women than in men (47% vs 28%, p = 0.02). Risk factors for developing TdP were female gender (odds ratio 2.2, 95% confidence interval [CI] 1.0 to 5.0), MI within 8 weeks (odds ratio 0.3, 95% CI 0.1 to 0.7), being in New York Heart Association class III or IV (odds ratio 3.2, 95% CI 1.2 to 8.6), and baseline QTc duration (odds ratio 1.14, 95% CI 1.00 to 1.30) per 10 ms. Women with chronic HF, QTc duration >400 ms. and New York Heart Association class III or IV had a risk of TdP of 10%, whereas no TdP episodes were observed in patients with QTc duration <400 ms. In conclusion, severity of HF, female gender, and QTc duration make it possible to identify patients with a high risk of early TdP when treated with dofetilide. Patients with recent MI less often had TdP compared with patients with chronic HF.

Atrial fibrillation, ischaemic heart disease, and the risk of death in patients with heart failure.

AIMS: Atrial fibrillation (AF) is a risk factor for death in patients with a myocardial infarction, but highly variable results are reported in patients with heart failure. We studied the prognostic impact of AF in heart failure patients with and without ischaemic heart disease. METHODS AND RESULTS: During a period of 2 years, 3587 patients admitted to hospital because of heart failure were included in this study. All patients were examined by echocardiography and the presence of AF was recorded. Follow-up was available for 8 years. Twenty four percent of those discharged alive from hospital had AF. After 4 and 8 years of follow-up, mortality was higher in patients with AF than in patients without, 56 vs. 52% and 77 vs. 73%, respectively. Cox multivariable regression analysis showed a small but significant importance of AF for long-term mortality [hazard ratio (HR) 1.12, 95% confidence limits (CI), 1.02-1.23, P=0.018]. There was a significant interaction between the importance of AF and the presence of ischaemic heart disease (P=0.034). In patients with AF at the time of discharge and ischaemic heart disease, HR was 1.25 (95% CI: 1.09-1.42) and P<0.001; in patients with AF at discharge and without ischaemic heart disease, HR was 1.01 (95% CI: 0.88-1.16) and P=0.88. CONCLUSION: AF is associated with increased risk of death only in patients with ischaemic heart disease. This finding may explain the variable results of studies of the prognosis associated with AF in heart failure.

Pulmonary blood volume and transit time in cirrhosis: relation to lung function.

BACKGROUND/AIMS: In cirrhosis a systemic vasodilatation leads to an abnormal distribution of the blood volume with a contracted central blood volume. In addition, the patients have a ventilation/perfusion imbalance with a low diffusing capacity. As the size of the pulmonary blood volume (PBV) has not been determined separately we assessed PBV and pulmonary transit time (PTT) in relation to lung function in patients with cirrhosis and in controls. METHODS: Pulmonary and cardiac haemodynamics and transit times were determined by radionuclide techniques in 22 patients with alcoholic cirrhosis and in 12 controls. The lung function including diffusing capacity for carbon monoxide (DL, CO) was determined by conventional single breath technique. RESULTS: In the patients, PTT was shorter, 3.9+/-1.2 vs 5.7+/-1.0 s in the controls, P<0.001, and the PBV was lower, 362+/-151 vs 587+/-263 ml, in the controls, P<0.005. Both PTT and PBV were lowest in patients with advanced disease. DL, CO was reduced in the patients and correlated significantly with PTT (r=0.58, P=0.007) and PBV (r=0.49, P<0.03). CONCLUSIONS: The results suggest that the reduced PBV contributes to the reduced effective blood volume in cirrhosis. The relation between PBV and PTT and the low diffusing capacity suggests the pulmonary vascular compartment as an important element in the pathophysiology of the lung dysfunction in cirrhosis.

The reliability of echocardiographic left ventricular wall motion index to identify high-risk patients for multicenter studies.

OBJECTIVE: To study whether the use of echocardiographic left ventricular (LV) wall motion index (WMI) is a dependable parameter for identifying patients with LV dysfunction to be enrolled in multicenter trials. METHODS: Videotaped echocardiographic examinations from 200 randomly selected patients that were screened for inclusion into the DIAMOND-CHF and DIAMOND-MI trials were reevaluated by an external expert echocardiographer. WMI was calculated using the 16-segment LV model. RESULTS: The external echocardiographer systematically found lower values of WMI than the core laboratory. The average difference in WMI was 0.18 (SD: 0.33) in the DIAMOND-CHF trial and 0.09 (SD: 0.33) in the DIAMOND-MI trial. The difference in WMI exceeded 0.33 in 34% of the patients in both trials. The cutoff value for inclusion into the DIAMOND trials was WMI < or = 1.2. There was an agreement on WMI dichotomized to below or above 1.2 in 82% of the patients in both trials (kappa coefficient 0.66 for the DIAMOND-CHF and 0.55 for the DIAMOND-MI). CONCLUSIONS: Despite substantial interlaboratory variation in WMI in individual patients and a systematic lower WMI score by the external echocardiographer there was an acceptable overall agreement for identifying patients with severe impairment of LV function. This not only underscores the value of LV-WMI as a useful tool for selecting high-risk patients to be included in multicenter studies but also serves to warn against the use of rigid cutoff values for WMI in the treatment of individual patients.

Different prognostic impact of systolic function in patients with heart failure and/or acute myocardial infarction.

AIMS: To study the prognostic importance of left ventricular systolic function in patients with heart failure (HF) and acute myocardial infarction (AMI) with respect to the presence of prior heart failure and known ischemic heart disease. METHODS: In 13,084 consecutive patients diagnosed with either AMI or HF, a medical history and an echocardiographic assessment of left ventricular systolic function by wall motion index (WMI) were obtained. Patients were divided into four groups: AMI with or without a history of HF, and primary HF (no recent AMI) with or without a history of ischemic heart disease (IHD). Mortality was assessed after nine years of follow-up. RESULTS: WMI stratified patients according to all-cause mortality in all four groups of patients (p<0.0001). For a decrease in WMI of 0.3 (corresponding to a decrease in left ventricular ejection fraction of 0.1), the hazard ratio was 1.61 (95% CI: 1.48-1.76) for AMI patients without prior HF, 1.43 (1.38-1.48) for AMI patients with prior HF, 1.26 (1.22-1.30) for primary HF patients with IHD and 1.23 (1.18-1.27) for HF patients without IHD. CONCLUSION: WMI stratifies patients with IHD and/or HF according to risk of all-cause death. The presence of HF attenuates the prognostic power of WMI.

Effect of obesity and being overweight on long-term mortality in congestive heart failure: influence of left ventricular systolic function.

AIMS: Previous studies have suggested that a high body mass index (BMI) is associated with an improved outcome in congestive heart failure (CHF). However, the studies addressing this problem have not included enough patients with non-systolic heart failure to evaluate how left ventricular systolic function interacts with obesity on prognosis in CHF. The aim of this study was to evaluate how BMI influences mortality in patients hospitalized with CHF, and to address in particular whether the effect of BMI is influenced by left ventricular (LV) systolic function. METHODS AND RESULTS: Retrospective analysis of baseline and survival data for 4700 hospitalized CHF patients for whom BMI was available. LV systolic function, as assessed by wall motion index was available for 95% of the patients. Follow-up time ranged from 5 to 8 years. In the total population, the risk of death decreased steadily with increasing BMI from the underweight to the obese. Compared with normal weight, and adjusted for sex and age, risk ratios (RR) and 95% confidence limits were: underweight 1.56 (1.33-1.84), overweight 0.90 (0.83-0.97), obese 0.77 (0.70-0.86). Being underweight conferred a greater risk in CHF patients with normal systolic function [RR 1.66 (1.29-2.14), compared with normal weight] than in patients with reduced systolic function [RR 1.11 (0.87-1.42), P for interaction 0.03]. In patients with systolic dysfunction, obesity was associated with increased risk compared with normal weight [RR 1.21 (1.01-1.45)]. CONCLUSION: Increasing BMI in CHF is associated with a lower mortality, but the influence is complex and depends on left ventricular systolic function. Hence, in patients with systolic dysfunction obesity may indicate an increased risk.

Effect of age on short and long-term mortality in patients admitted to hospital with congestive heart failure.

AIMS: To describe the association between age and risk factors in patients hospitalised with congestive heart failure (CHF) and to determine the effect of age on mortality. METHODS AND RESULTS: Consecutive patients admitted to 34 hospitals with CHF during a period of 2 years were registered. Mean age was 71.7+/-10.2 years, 60% were male and 63% were in NYHA class III-IV. Moderate to severe left ventricular (LV) systolic dysfunction was present in 41%. Short and long-term survival status was obtained after 30 days and 5-8 years, respectively. Older patients less frequently had LV systolic dysfunction, were under treated with ACE-inhibitors and were more often female. The prevalence of hypertension, diabetes and ischaemic heart disease increased with age, until the oldest age group (>80 years). Age was an independent predictor of short-term mortality (risk ratio (RR) per 10-year increase was 1.23 (95% CI 1.04-1.47)). Advancing age significantly increased long-term mortality (RR 1.55 (1.50-1.61)). Age interacted with the LV ejection fraction (P = 0.003). In patients with LV systolic dysfunction, the RR per 10-year increase was 1.29 (1.19-1.39) whereas in patients with preserved systolic function the RR was 1.57 (1.43-1.72, multivariate analyses). CONCLUSION: The clinical characteristics of CHF patients vary considerably with age. Elderly patients hospitalised with CHF face a very grave prognosis, particularly if their heart failure symptoms are caused by LV systolic dysfunction.

Influence of diabetes and diabetes-gender interaction on the risk of death in patients hospitalized with congestive heart failure.

OBJECTIVES: The purpose of this study was to investigate the influence of diabetes on long-term mortality in a large cohort of patients hospitalized with heart failure (HF). BACKGROUND: Diabetes is common in HF patients, but information on the prognostic effect of diabetes is sparse. METHODS: The study is an analysis of survival data comprising 5,491 patients consecutively hospitalized with new or worsening HF and screened for entry into the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND). Screening, which included obtaining an echocardiogram in 95% of the patients, took place at Danish hospitals between 1993 and 1995. The follow-up time was five to eight years. RESULTS: A history of diabetes was found in 900 patients (16%), 41% of whom were female. Among the diabetic patients, 755 (84%) died during follow-up, compared with 3,200 (70%) among the non-diabetic patients, resulting in a risk ratio (RR) of death in diabetic patients of 1.5 (95% confidence interval [CI] 1.4 to 1.6, p < 0.0001). In a multivariate analysis, the RR of death in diabetic patients was 1.5 (CI 1.3 to 1.76, p < 0.0001), but a significant interaction between diabetes and gender was found. Diabetes increased the mortality risk more in women than in men, with the RR for diabetic men being 1.4 (95% CI 1.3 to 1.6, p < 0.0001) and 1.7 for diabetic women (95% CI 1.4 to 1.9, p < 0.0001). The effect of diabetes on mortality was similar in patients with depressed and normal left ventricular systolic function. CONCLUSIONS: Diabetes is a potent, independent risk factor for mortality in patients hospitalized with HF. The excess risk in diabetic patients appears to be particularly prominent in females.

Female sex is associated with a better long-term survival in patients hospitalized with congestive heart failure.

AIMS: Results of previous studies on the influence of gender on prognosis in heart failure have been conflicting and most studies have been conducted in selected populations. The aim of this study was determine whether mortality risk in women and men hospitalized with congestive heart failure is different. METHODS AND RESULTS: Survival analysis of 5491 consecutive patients admitted with congestive heart failure to 34 Danish hospitals between 1993-1996. Follow-up time was 5-8 years. Forty percent of the patients were female. Females were older, had less evidence of ischaemic heart disease and their left ventricular systolic function was preserved to a greater extent than in males. Men were more often treated with ACE inhibitors. During the follow-up period 1569 women (72%) and 2386 (72%) of the men died. When the age difference between men and women was adjusted for, male gender was associated with an increased risk of death (RR 1.25 (1.17-1.34)) and the increased risk was confirmed in a multivariate model containing several covariates. CONCLUSIONS: In patients hospitalized with congestive heart failure male gender is an independent predictor of mortality. Female heart failure patients may be under-treated with ACE inhibitors.

Insulin resistance and maximal oxygen uptake.

BACKGROUND: Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown. HYPOTHESIS: This study was undertaken to determine the relationship between insulin resistance, maximal oxygen uptake, and the presence of either diabetes or ischemic heart disease. METHODS: The study population comprised 33 patients with and without diabetes and ischemic heart disease. Insulin resistance was measured by a hyperinsulinemic euglycemic clamp; maximal oxygen uptake was measured during a bicycle exercise test. RESULTS: There was a strong correlation between maximal oxygen uptake and insulin-stimulated glucose uptake (r = 0.7, p = 0.001), and maximal oxygen uptake was the only factor of importance for determining insulin sensitivity in a model, which also included the presence of diabetes and ischemic heart disease. CONCLUSION: Maximal oxygen uptake may be a more important determinant for insulin sensitivity than ischemic heart disease and type 2 diabetes.

The angiotensin converting enzyme inhibitor trandolapril has neutral effect on exercise tolerance or functional class in patients with myocardial infarction and reduced left ventricular systolic function.

AIMS: To study the effect of angiotensin-converting enzyme (ACE) inhibitor trandolapril on exercise tolerance time (ETT) and New York Heart Association (NYHA) classification in patients with reduced left ventricular systolic dysfunction (LVSD) after acute myocardial infarction (AMI). METHODS AND RESULTS: The TRAndolapril Cardiac Evaluation (TRACE) was a randomized controlled study designed to evaluate the effect of trandolapril on mortality in 1749 consecutive Danish patients with LVSD after AMI. NYHA class was recorded every 3 months in all patients. In a prospective sub-study, 254 patients underwent exercise tolerance tests at 1, 3 and 12 months. The two treatment arms showed equal improvement in NYHA class both in the entire and exclusively symptomatic population over 4 years of follow-up (P=ns). ETT increased equally in both treatment arms at 1, 3, 12 months (P=ns). A mean of 12mg/day of furosemide was spared in trandolapril arm (P=0.001). CONCLUSIONS: Trandolapril had a mild diuretic-sparing effect. These results emphasis the importance of explaining to patients that ACE inhibitors provide protection against death and hospitalisation for heart failure but do not have any significant effect upon symptoms.

Long-term survival in patients hospitalized with congestive heart failure: relation to preserved and reduced left ventricular systolic function.

AIMS: The purpose of this study was to evaluate the influence of left ventricular systolic function on the survival in a large consecutive cohort of patients hospitalized with congestive heart failure and to determine how left ventricular systolic function interacts with co-morbid conditions in terms of prognosis. METHODS AND RESULTS: Analysis of survival data from 5491 patients admitted for new or worsening heart failure to 34 departments of cardiology or internal medicine in Denmark from 1993-1996 was carried out. A standardized echocardiogram was available for 95% of the patients, and left ventricular systolic function was estimated using wall motion index score. Follow-up time was 5-8 years. Patients with preserved systolic function were older, more frequently female, and had less evidence of ischemia than patients with systolic dysfunction. After 1 year, 24% of the patients had died. Low wall motion index was a potent independent predictor of death (risk ratio for one unit increase, 0.60 (0.56-0.64)), and was of greater prognostic significance in younger patients and patients with a history of myocardial ischemia. However, even in patients with preserved systolic function, mortality was high (1 year mortality, 19%). CONCLUSION: In hospitalized heart failure patients, particularly in younger patients with ischemic heart disease, mortality risk is inversely related to left ventricular systolic function.

QT interval dynamics predict mortality in high-risk patients after myocardial infarction.

OBJECTIVE: The purpose of this study was to evaluate the prognostic properties of the QT/RR relationship in survivors of myocardial infarction with severe left ventricular dysfunction. DESIGN: The QT/RR interval slope was assessed from 24-h electrocardiographic recordings obtained from 241 patients representative of survivors of an acute myocardial infarction with an ejection fraction < or =35%. During a median follow-up of 752 days, 63 patients died. RESULTS: In a multivariate analysis QT/RR at night-time was an independent predictor of all-cause mortality. A linear all-cause mortality predictor score was calculated from age, ejection fraction, QRS duration and QT/RR night, allowing identification of a high-risk one-third of the patients with a relative risk of death at 4.0. CONCLUSION: This study demonstrates independent prognostic information of night-time QT/RR dynamics in patients at high risk after myocardial infarction. A linear predictor score calculated from age, ejection fraction, QRS duration and QT/RR night identifies a high-risk one-third of the patients with a 1-year mortality of 36% vs 9% in the remaining patients.