Recombinant human annexin A5 inhibits proinflammatory response and improves cardiac function and survival in mice with endotoxemia.

OBJECTIVES: Annexin A5 is a 35-kDa protein with high affinity binding to negatively charged phospholipids. However, its effects on sepsis are not known. Our aim was to study the effects of annexin A5 on myocardial tumor necrosis factor-α expression, cardiac function, and animal survival in endotoxemia. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Mice were challenged with lipopolysaccharide (4 or 20 mg/kg, i.p.) to induce endotoxemia with and without recombinant human annexin A5 treatment (5 or 10 µg/kg, i.v.). Cytokine expression and cardiac function were assessed, and animal survival was monitored. MEASUREMENTS AND MAIN RESULTS: Treatment with annexin A5 inhibited myocardial mitogen-activated protein kinase, and nuclear factor-κB activation in mice with endotoxemia. Furthermore, annexin A5-treated animals showed significant reductions in myocardial and plasma levels of tumor necrosis factor-α and interleukin-1ß while cardiac function was significantly improved during endotoxemia. Additionally, 5-day animal survival was significantly improved by either an immediate or a 4-hour delayed annexin A5 treatment after lipopolysaccharide challenge. Importantly, annexin A5 dose-dependently inhibited lipopolysaccharide binding to a toll-like receptor-4/myeloid differentiation factor 2 fusion protein. CONCLUSIONS: Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis.

Rhythm control versus rate control for atrial fibrillation and heart failure.

BACKGROUND: It is common practice to restore and maintain sinus rhythm in patients with atrial fibrillation and heart failure. This approach is based in part on data indicating that atrial fibrillation is a predictor of death in patients with heart failure and suggesting that the suppression of atrial fibrillation may favorably affect the outcome. However, the benefits and risks of this approach have not been adequately studied. METHODS: We conducted a multicenter, randomized trial comparing the maintenance of sinus rhythm (rhythm control) with control of the ventricular rate (rate control) in patients with a left ventricular ejection fraction of 35% or less, symptoms of congestive heart failure, and a history of atrial fibrillation. The primary outcome was the time to death from cardiovascular causes. RESULTS: A total of 1376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup. CONCLUSIONS: In patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes, as compared with a rate-control strategy. (ClinicalTrials.gov number, NCT00597077.)

Left atrial remodelling in patients with myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALIANT Echo study.

AIMS: To assess the relationship between left atrial (LA) size and outcome after high-risk myocardial infarction (MI) and to study dynamic changes in LA size during long-term follow-up. METHODS AND RESULTS: The VALIANT Echocardiography study prospectively enrolled 610 patients with left ventricular (LV) dysfunction, heart failure (HF), or both following MI. We assessed LA volume indexed to body surface area (LAVi) at baseline, 1 month, and 20 months after MI. Baseline LAVi was an independent predictor of all-cause death or HF hospitalization (P = 0.004). In patients who survived to 20 months, LAVi increased a mean of 3.00 +/- 7.08 mL/m(2) from baseline. Hypertension, lower estimated glomerular filtration rate, and LV mass were the only baseline independent predictors of LA remodelling. Changes in LA size were related to worsening in MR and increasing in LV volumes. LA enlargement during the first month was significantly greater in patients who subsequently died or were hospitalized for HF than in patients without events. CONCLUSION: Baseline LA size is an independent predictor of death or HF hospitalization following high-risk MI. Moreover, LA remodelling during the first month after infarction is associated with adverse outcome.

Disruption of phospholipase Cgamma1 signalling attenuates cardiac tumor necrosis factor-alpha expression and improves myocardial function during endotoxemia.

AIMS: Lipopolysaccharide (LPS) induces tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes, which contributes to myocardial dysfunction during sepsis. The purpose of this study was to investigate the role of phosphatidylinositol (PI) phospholipase Cgamma1 (PLCgamma1) in cardiac TNF-alpha expression, and myocardial dysfunction during endotoxemia. METHODS AND RESULTS: In cultured mouse neonatal cardiomyocytes, LPS increased PLCgamma1 phosphorylation. Knockdown of PLCgamma1 with specific siRNA or inhibition of PLCgamma1 with U73122 attenuated TNF-alpha expression induced by LPS. This action of PLCgamma1 was mediated through inositol-1,4,5-trisphosphate (IP3)/IP3 receptor (IP3R) pathways since blocking either IP3 or IP3R decreased LPS-induced TNF-alpha expression. In contrast, neither diacylglycerol agonist nor antagonist had any evident effect on LPS-induced TNF-alpha expression in cardiomyocytes. To investigate the role of PLCgamma1 in endotoxemia in vivo, wild-type and heterozygous PLCgamma1 knockout (PLCgamma1(+/-)) mice were pre-treated with either U73122, or its inactive analog U73343, or vehicle for 15 min, followed by LPS for 4 h. Inhibition of PLCgamma1 by U73122 or by heterozygous deletion of the PLCgamma1 gene decreased cardiac TNF-alpha expression. More importantly, LPS-induced myocardial dysfunction was also attenuated in PLCgamma1(+/-) mice or by U73122 treatment. CONCLUSION: PLCgamma1 signalling induces cardiac TNF-alpha expression and myocardial dysfunction during LPS stimulation. The action of PLCgamma1 on TNF-alpha expression is mediated through IP3/IP3R pathways. The present results suggest that PLCgamma1 may be a potential therapeutic target for myocardial dysfunction in sepsis.

Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease. METHODS AND RESULTS: We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 mug/mg for men and <25 mug/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality (P<0.001) and cardiovascular death (P=0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 mug/mg, P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82). CONCLUSIONS: Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial.

BACKGROUND: Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents. METHODS: Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170924. FINDINGS: 186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29). INTERPRETATION: Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.

Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study.

BACKGROUND: Elevated plasma homocysteine levels are reported to be associated with higher rates of vascular diseases. Plasma homocysteine increases in chronic kidney disease (CKD) and could contribute to the increased cardiovascular risk in CKD. METHODS: Participants aged 55 years or older with CKD, defined as estimated GFR<60 ml/min and at high cardiovascular risk, were randomly assigned to the combination of folic acid, 2.5 mg, vitamin B6, 50 mg and vitamin B12, 1 mg (n = 307) or placebo (n = 312) daily for 5 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction and stroke. RESULTS: Mean baseline plasma homocysteine was 15.9 +/- 7.3 micromol/l in the active treatment group and 15.7 +/- 5.7 micromol/l in placebo group and decreased to 11.9 +/- 3.3 micromol/l (P < 0.001) on active treatment (15.5 +/- 4.5 on placebo). Primary outcome events occurred in 90 participants (29.3%) on active therapy and in 80 (25.6%) on placebo (relative risk, 1.19; 95% confidence interval, 0.88-1.61; P = 0.25). There were no significant treatment benefits on death from cardiovascular causes (1.24; 0.84-1.83), myocardial infarction (1.10; 0.76-1.61) and stroke (1.00; 0.54-1.85). More participants in the active treatment group were hospitalized for heart failure (1.98; 1.21-3.26; P = 0.007) and for unstable angina (1.70; 1.02-2.83; P = 0.04). Incidence of primary outcome increased with decreasing GFR. CONCLUSIONS: Active treatment with B vitamins lowered homocysteine levels in participants with CKD but did not reduce cardiovascular risk.

Augmentation index and central aortic stiffness in middle-aged to elderly individuals.

BACKGROUND: Increased aortic stiffness contributes to systolic hypertension and increased cardiovascular risk. The augmentation index (AI), ie, the percentage of central pulse pressure attributed to reflected wave overlap in systole, was proposed as a noninvasive indicator of increased arterial stiffness. We evaluated this hypothesis by investigating relations between AI and other direct measures of aortic stiffness. METHODS: Tonometric carotid- and femoral-pressure waveforms, Doppler aortic flow, and aortic-root diameter were assessed in 123 individuals with uncomplicated systolic hypertension and 29 controls of comparable age and sex. Carotid-femoral pulse-wave velocity (PWV) was assessed from the carotid-femoral time delay and body-surface measurements. Aortic PWV was assessed from the ratio of the upstroke of carotid pressure and aortic flow velocity and was used to calculate proximal aortic compliance as [aortic area]/[1.06 x (aortic PWV)(2)]. RESULTS: Partial correlations (adjusted for age, sex, presence of hypertension, height, weight, and systolic ejection period) showed no association between AI and carotid-femoral PWV (R = -0.05, P = .54). The AI was significantly though weakly related directly with aortic compliance (R = 0.21, P = .012) and inversely with aortic PWV (R = -0.198, P = .017). However, higher stiffness (lower compliance and higher PWV) was associated with lower AI. CONCLUSIONS: Increased AI is not a reliable surrogate for increased aortic stiffness. Decreasing AI with decreasing compliance (increasing aortic stiffness) may be attributable to impedance matching and reduced wave reflection at the interface between the aorta and the muscular arteries.

Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension.

BACKGROUND: We have previously demonstrated that ramipril reduces vascular events and new diagnoses of diabetes when given for a 4.5-year period. However, it is not known whether the benefits are observed in subgroups of patients at varying risk or on other proven therapies and whether the benefits are sustained beyond the current trial. The 2 aims of this investigation were to assess whether the benefits observed during the HOPE trial were (1) maintained after trial cessation during an additional 2.6 years of follow-up and (2) observed in subgroups based on risk and ancillary treatments. METHODS AND RESULTS: Of the initial 267 study centers and 9297 patients, 174 centers and 4528 patients agreed to further follow-up. The rates of use of angiotensin-converting-enzyme inhibitors (ACEIs) in the 2 groups (72% ramipril versus 68% placebo) were similar after the end of the trial. During the posttrial follow-up, patients allocated to ramipril had a 19% further lower relative risk (RR) of myocardial infarction (95% confidence interval [CI], 0.65 to 1.01), a 16% lower RR (95% CI, 0.70 to 0.99) of revascularization, and a 34% lower RR of a new diagnosis of diabetes (95% CI, 0.46 to 0.95). Similar RR reductions in vascular events were observed during and after the active phase of the trial, regardless of baseline risk (RR of 0.76, 0.89, and 0.83 for low-, medium-, and high-risk patients, respectively) or ancillary treatments (RR of 0.90 for aspirin, 0.76 for beta-blockers, and 0.84 for lipid-lowering medication). CONCLUSIONS: The benefits of ramipril observed during the active period of the HOPE trial were maintained during posttrial follow-up for cardiovascular death, stroke, and hospitalization for heart failure. Additional reductions in myocardial infarction, revascularization, and the development of diabetes were observed during the follow-up phase despite similar rates of ACEI use in the 2 randomized groups. These benefits were consistent regardless of patient risk or ancillary treatments.

Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone. METHODS AND RESULTS: Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates. CONCLUSIONS: Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.

Rationale and design: the VALsartan In Diastolic Dysfunction (VALIDD) Trial: evolving the management of diastolic dysfunction in hypertension.

BACKGROUND: Although 50% of hypertensive patients in the community are estimated to have diastolic dysfunction, there is no specific guideline for diastolic dysfunction therapy at present despite the condition's clear association with increased cardiovascular risk. Although the efficacy of angiotensin II receptor blockers (ARBs) in hypertension and left ventricular hypertrophy regression has been established, the effect of angiotensin II receptor blockade on intrinsic parameters of diastolic function has not been evaluated in large-scale studies. METHODS: The VALIDD Trial is an investigator-initiated randomized, controlled, double-blind clinical trial on approximately 350 patients designed to explore whether antihypertensive therapy with the ARB valsartan, in addition to standard therapy, would improve intrinsic diastolic properties of the myocardium in patients with hypertension and evidence of diastolic dysfunction. The result of such therapy will be compared with placebo after 38 weeks of treatment. The primary efficacy variable is change in early diastolic lateral mitral annular relaxation velocity measured by tissue Doppler imaging on week 38. CONCLUSIONS: We expect the VALIDD Trial to provide novel insights into the specific effects of ARBs on diastolic dysfunction, as assessed by tissue Doppler imaging, in hypertensive patients. The trial may provide clinically useful data on whether such therapy can directly improve diastolic function in patients with hypertension.

Pulsatile hemodynamic effects of candesartan in patients with chronic heart failure: the CHARM Program.

BACKGROUND: Abnormal large artery function and increased pulsatile load are exacerbated by excess angiotensin-II acting through the AT1 receptor and contribute to the pathogenesis and progression of chronic heart failure (CHF). AIMS: To evaluate effects of the AT1 receptor blocker candesartan (N = 30) or placebo (N = 34) on pulsatile hemodynamics in participants with CHF in the CHARM program. METHODS AND RESULTS: Noninvasive hemodynamics were assessed following 6 and 14 months of treatment and averaged. Using calibrated tonometry and aortic outflow Doppler, characteristic impedance was calculated as the ratio of the change in carotid pressure and aortic flow in early systole. Total arterial compliance was calculated by the diastolic area method. Brachial blood pressure, cardiac output and peripheral resistance did not differ between groups. Lower central pulse pressure in the candesartan group (57+/-20 vs. 67+/-17 mmHg, P = 0.043) was accompanied by lower characteristic impedance (200+/-78 vs. 240+/-74 dyne s/cm5, P = 0.039) and higher total arterial compliance (1.87+/-0.70 vs. 1.47+/-0.48 ml/mmHg, P = 0.008). Similar favorable differences were seen when analyses were stratified for ejection fraction (< or = 0.40 vs. >0.40) and baseline angiotensin converting enzyme inhibitor use. CONCLUSIONS: Candesartan has a favorable effect on large artery function in patients with chronic heart failure.

Treating the right patient at the right time: access to heart failure care.

Heart failure affects over 500,000 Canadians, and 50,000 new patients are diagnosed each year. The mortality remains staggering, with a five-year age-adjusted rate of 45%. Disease management programs for heart failure patients have been associated with improved outcomes, the use of evidence-based therapies, improved quality of care, and reduced costs, mortality and hospitalizations. Currently, national benchmarks and targets for access to care for cardiovascular procedures or office consultations do not exist. The present paper summarizes the currently available data, particularly focusing on the risk of adverse events as a function of waiting time, as well as on the identification of gaps in existing data on heart failure. Using best evidence and expert consensus, the present article also focuses on timely access to care for acute and chronic heart failure, including timely access to heart failure disease management programs and physician care (heart failure specialists, cardiologists, internists and general practitioners).

Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.

Heart failure remains a common diagnosis, especially in older individuals. It continues to be associated with significant morbidity and mortality, but major advances in both diagnosis and management have occurred and will continue to improve symptoms and other outcomes in patients. The Canadian Cardiovascular Society published its first consensus conference recommendations on the diagnosis and management of heart failure in 1994, followed by two brief updates, and reconvened this consensus conference to provide a comprehensive review of current knowledge and management strategies. New clinical trial evidence and meta-analyses were critically reviewed by a multidisciplinary primary panel who developed both recommendations and practical tips, which were reviewed by a secondary panel. The resulting document is intended to provide practical advice for specialists, family physicians, nurses, pharmacists and others who are involved in the care of heart failure patients. Management of heart failure begins with an accurate diagnosis, and requires rational combination drug therapy, individualization of care for each patient (based on their symptoms, clinical presentation and disease severity), appropriate mechanical interventions including revascularization and devices, collaborative efforts among health care professionals, and education and cooperation of the patient and their immediate caregivers. The goal is to translate best evidence-based therapies into clinical practice with a measureable impact on the health of heart failure patients in Canada.

Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study.

BACKGROUND: Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure. METHODS AND RESULTS: We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death (P<0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; P<0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91; P=0.024 for interaction of group by treatment). CONCLUSION: Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events.

Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study.

OBJECTIVES: We sought to determine the predictors of heart failure (HF) development in long-term survivors of myocardial infarction (MI). BACKGROUND: Modern strategies of acute MI care have resulted in an increasing proportion of survivors at heightened risk of future non-fatal events, including HF. METHODS: We assessed the risk of developing HF in 3860 stable MI patients without a previous history of HF, who were enrolled in the Cholesterol And Recurrent Events (CARE) trial a median of 10 months post MI. Baseline characteristics of patients who did or did not develop HF during the five years of observation were assessed. RESULTS: A total of 243 patients (6.3%) developed HF in a linear pattern at a rate of 1.3%/year. Heart failure development markedly increased the risk of death (hazard ratio 10.2, 95% confidence interval 7.7 to 13.5). Fifty-seven patients (23.5%) who developed HF had a recurrent MI between enrollment and the onset of HF, increasing the risk fivefold. The most important predictors of HF were age and left ventricular ejection fraction. Other predictors included diabetes, history of hypertension, previous MI, and baseline heart rate. Moderate exercise three or more times per week was independently associated with a 30% lower risk of HF. CONCLUSIONS: Heart failure post MI occurs in a time-dependent fashion, which is usually not a direct consequence of a detectable interim MI. Patients who experience late-onset HF have a 10-fold increased risk of death compared with other MI survivors. Baseline characteristics can risk stratify patients at high risk of subsequent HF.

Pilot study to determine the impact of a multidisciplinary educational intervention in patients hospitalized with heart failure.

BACKGROUND: Patients with heart failure (HF) face challenges complying with multidrug regimens. OBJECTIVES: To examine the impact of a compliance enhancing intervention on medication compliance and morbidity in HF. DESIGN: Patients were randomized to either usual care or an inhospital educational intervention delivered by a multidisciplinary team (Intervention). SETTING: Acute medical and surgical units at a teaching hospital. PATIENTS: One hundred thirty four patients with a clinical diagnosis of HF and a left ventricular ejection fraction of < 40% requiring long-term medical treatment. MAIN OUTCOME MEASURES: A validated HF-specific instrument provided a measure of knowledge. We characterized patients as noncompliant if pharmacy refill data suggested they had taken < or = 0.80 of their medication. We measured quality of life using the Minnesota Living with Heart Failure Questionnaire and the Short Form 36 and conducted a time to first event analysis of a composite end point including mortality, readmissions, and emergency department visits. RESULTS: The Intervention group showed higher knowledge scores at discharge and 1 year (P = .05). The risk of noncompliance in Intervention patients varied from 0.78 (95% CI 0.33-1.89) for ACE-I (13% Intervention, 17% Control) to 1.02 (0.49-2.12) for diuretics (23% Intervention, 23% Control). Quality of life improved in both groups over time; the only difference between groups favored the Intervention (Minnesota Living with Heart Failure Questionnaire, P = .04). The composite end point occurred in 67% of control and 60% of Intervention patients (hazard ratio 0.85, 95% CI 0.55-1.30). CONCLUSIONS: An inhospital educational intervention improved knowledge and, possibly, quality of life and may be useful as part of a comprehensive compliance enhancing strategy in patients with HF.

Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.

CONTEXT: Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. OBJECTIVE: To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. INTERVENTION: Daily dose of natural source vitamin E (400 IU) or matching placebo. MAIN OUTCOME MEASURES: Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. RESULTS: Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. CONCLUSION: In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.

Effects of enalaprilat on venoconstriction to norepinephrine: role of prostaglandins.

OBJECTIVE: Most patients with cardiovascular disease continue to receive both aspirin and an angiotensin-converting enzyme (ACE) inhibitor. This is despite the fact that ACE inhibition also inhibits the enzyme kininase II and leads to accumulation of bradykinin which increases prostaglandins. We hypothesized that in normal veins, vasodilator prostaglandins contribute significantly to ACE inhibitor dilation of norepinephrine-induced venoconstriction, and this would be blocked by cyclooxygenase inhibition. METHODS: The study was performed using the in vivo dorsal hand vein technique for measuring vascular responses directly. Venoconstriction to norepinephrine infusions (0.5-1024 ng/min) was assessed in eight normal subjects (46+/-5 years, mean+/-S.E.M.) during coinfusion of saline in one hand (control) and enalaprilat (1000 microg/min) in the contralateral hand. On a second morning (7+/-1 days apart, mean+/-S.E.M., random order), the same procedure was repeated with indomethacin (3 microg/min) coinfusion in both hands. RESULTS: Enalaprilat shifted the norepinephrine dose-response curve to the right (P=0.024) and increased the norepinephrine log ED(50) (dose required to cause 50% venoconstriction) from 1.70+/-0.08 to 2.31+/-0.11 log ng/min (P=0.001). Indomethacin shifted the norepinephrine dose-response curve to the left (P=0.018) and decreased the norepinephrine log ED(50) from 1.70+/-0.08 to 1.09+/-0.18 log ng/min (P=0.002). In the presence of indomethacin, enalaprilat caused only a small but significant increase in the norepinephrine log ED(50), from 1.09+/-0.18 to 1.29+/-0.18 log ng/min (P=0.041). CONCLUSIONS: The results suggest that vasodilator prostaglandins contribute significantly to the attenuation of sympathetic venoconstriction by enalaprilat. This may have clinical relevance in patients receiving aspirin and ACE inhibitors in the setting of increased sympathetic activity.