David Aguilar

Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction

OBJECTIVES The aim of this study was to evaluate the prevalence and prognostic impacts of noncardiac comorbidities in patients with heart failure (HF) with preserved ejection fraction (HFpEF) compared with those with HF with reduced ejection fraction (HFrEF). BACKGROUND There is a paucity of information on the comparative prognostic significance of comorbidities between patients with HFpEF and those with HFrEF. METHODS In a national ambulatory cohort of veterans with HF, the comorbidity burden of 15 noncardiac comorbidities and the impacts of these comorbidities on hospitalization and mortality were compared between patients with HFpEF and those with HFrEF. RESULTS The cohort consisted of 2,843 patients with HFpEF and 6,599 with HFrEF with 2-year follow-up. Compared with patients with HFrEF, those with HFpEF were older and had higher prevalence of chronic obstructive pulmonary disease, diabetes, hypertension, psychiatric disorders, anemia, obesity, peptic ulcer disease, and cancer but a lower prevalence of chronic kidney disease. Patients with HFpEF had lower HF hospitalization, higher non-HF hospitalization, and similar overall hospitalization compared with those with HFrEF (p < 0.001, p < 0.001, and p = 0.19, respectively). An Increasing number of noncardiac comorbidities was associated with a higher risk for all-cause admissions (p < 0.001). Comorbidities had similar impacts on mortality in patients with HFpEF compared with those with HFrEF, except for chronic obstructive pulmonary disease, which was associated with a higher hazard (1.62 [95% confidence interval: 1.36 to 1.92] vs. 1.23 [95% confidence interval: 1.11 to 1.37], respectively, p = 0.01 for interaction) in patients with HFpEF. CONCLUSIONS There is a higher noncardiac comorbidity burden associated with higher non-HF hospitalizations in patients with HFpEF compared with those with HFrEF. However, individually, most comorbidities have similar impacts on mortality in both groups. Aggressive management of comorbidities may have an overall greater prognostic impact in HFpEF compared to HFrEF.

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Diabetes, left ventricular systolic dysfunction and chronic heart failure

Chronic heart failure (HF) and diabetes mellitus (DM) commonly coexist. Each condition increases the likelihood of developing the other, and when they occur together in the same patient the risk of morbidity and mortality increases markedly. We discuss the epidemiological overlap and consider the complex patho-physiological pathways linking the two diseases. The treatment of each condition is made more problematic by the presence of the other. We review the evidence-based treatment strategies and discuss the common problems faced by physicians when treating patients with both conditions. This article forms a comprehensive overview of a fascinating intersection between two common diseases.

Relationship of Hemoglobin A1C and Mortality in Heart Failure Patients With Diabetes

OBJECTIVES This study was designed to examine the relationship between glycosylated hemoglobin (HbA1C) and adverse outcomes in diabetic patients with established heart failure (HF). BACKGROUND Despite the common coexistence of diabetes and HF, previous studies examining the association between HbA1C and outcomes in this population have been limited and have reported discrepant results. METHODS We assessed the association between increasing quintiles (Q1 to Q5) of HbA1C and risk of death or risk of HF hospitalization by conducting a retrospective study in a national cohort of 5,815 veterans with HF and diabetes treated in ambulatory clinics at Veterans Affairs medical centers. RESULTS At 2 years of follow-up, death occurred in 25% of patients in Q1 (HbA1C < or =6.4%), 23% in Q2 (6.4% < HbA1c < or =7.1%), 17.7% in Q3 (7.1% < HbA1c < or =7.8%), 22.5% in Q4 (7.8% < HbA1c < or =9.0%), and 23.2% in Q5 (HbA1c >9.0%). After adjustment for potential confounders, the middle quintile (Q3) had reduced mortality when compared with the lowest quintile (risk-adjusted hazard ratio: 0.73, 95% confidence interval: 0.61 to 0.88, p = 0.001). Hospitalization rates for HF at 2 years increased with increasing quintiles of HbA1C (Q1: 13.3%, Q2: 13.1%, Q3: 15.5%, Q4: 16.4%, and Q5: 18.2%), but this association was not statistically significant when adjusted for potential confounders. CONCLUSIONS The association between mortality and HbA1C in diabetic patients with HF appears U-shaped, with the lowest risk of death in those patients with modest glucose control (7.1% < HbA1C < or =7.8%). Future prospective studies are necessary to define optimal treatment goals in these patients.

The potential effects of anti-diabetic medications on myocardial ischemia–reperfusion injury

Heart disease and stroke account for 65% of the deaths in people with diabetes mellitus (DM). DM and hyperglycemia cause systemic inflammation, endothelial dysfunction, a hypercoagulable state with impaired fibrinolysis and increased platelet degranulation, and reduced coronary collateral blood flow. DM also interferes with myocardial protection afforded by preconditioning and postconditioning. Newer anti-diabetic agents should not only reduce serum glucose and HbA1c levels, but also improve cardiovascular outcomes. The older sulfonylurea agent, glyburide, abolishes the benefits of ischemic and pharmacologic preconditioning, but newer sulfonylurea agents, such as glimepiride, may not interfere with preconditioning. GLP-1 analogs and sitagliptin, an oral dipeptidyl peptidase IV inhibitor, limit myocardial infarct size in animal models by increasing intracellular cAMP levels and activating protein kinase A, whereas metformin protects the heart by activating AMP-activated protein kinase. Both thiazolidinediones (rosiglitazone and pioglitazone) limit infarct size in animal models. The protective effect of pioglitazone is dependent on downstream activation of cytosolic phospholipase A2 and cyclooxygenase-2 with subsequent increased production of 15-epi-lipoxin A4, prostacyclin and 15-d-PGJ2. We conclude that agents used to treat DM have additional actions that have been shown to affect the ability of the heart to protect itself against ischemia–reperfusion injury in preclinical models. However, the effects of these agents in doses used in the clinical setting to minimize ischemia–reperfusion injury and to affect clinical outcomes in patients with DM have yet to be shown. The clinical implications as well as the mechanisms of protection should be further studied.

Case Report: Evidence of Autochthonous Chagas Disease in Southeastern Texas

Autochthonous transmission of Trypanosoma cruzi in the United States is rarely reported. Here, we describe five newly identified patients with autochthonously acquired infections from a small pilot study of positive blood donors in southeast Texas. Case-patients 1-4 were possibly infected near their residences, which were all in the same region ∼100 miles west of Houston. Case-patient 5 was a young male with considerable exposure from routine outdoor and camping activities associated with a youth civic organization. Only one of the five autochthonous case-patients received anti-parasitic treatment. Our findings suggest an unrecognized risk of human vector-borne transmission in southeast Texas. Education of physicians and public health officials is crucial for identifying the true disease burden and source of infection in Texas.

Rationale, design, and baseline characteristics in evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo

BACKGROUND Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Furthermore, patients with T2DM and acute coronary syndrome (ACS) have a particularly high risk of CV events. The glucagon-like peptide 1 receptor agonist, lixisenatide, improves glycemia, but its effects on CV events have not been thoroughly evaluated. METHODS ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of lixisenatide in patients with T2DM and a recent ACS event. The primary aim is to evaluate the effects of lixisenatide on CV morbidity and mortality in a population at high CV risk. The primary efficacy end point is a composite of time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Data are systematically collected for safety outcomes, including hypoglycemia, pancreatitis, and malignancy. RESULTS Enrollment began in July 2010 and ended in August 2013; 6,068 patients from 49 countries were randomized. Of these, 69% are men and 75% are white; at baseline, the mean ± SD age was 60.3 ± 9.7 years, body mass index was 30.2 ± 5.7 kg/m(2), and duration of T2DM was 9.3 ± 8.2 years. The qualifying ACS was a myocardial infarction in 83% and unstable angina in 17%. The study will continue until the positive adjudication of the protocol-specified number of primary CV events. CONCLUSION ELIXA will be the first trial to report the safety and efficacy of a glucagon-like peptide 1 receptor agonist in people with T2DM and high CV event risk.

Comparison of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction Among Those With Versus Without Diabetes Mellitus

Heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and diabetes commonly coexist, but the impact of diabetes on HF outcomes in patients with HF and preserved LVEF has not been well studied. We assessed the risk of HF death or hospitalization for worsening HF associated with diabetes by studying 987 patients with HF and preserved LVEF enrolled in the Digitalis Investigation Group (DIG) ancillary study. Diabetics (n = 285, 28.9%) were younger, had a larger body mass index, faster heart rate, and higher pulse pressure than nondiabetics. Diabetics were also more likely to be women, have a history of hypertension, ischemic cause for HF, and were more likely to be treated with diuretics. During the mean follow-up of 37 months, 88 (30.9%) diabetics and 133 (19.0%) nondiabetics developed the primary outcome of HF hospitalization or HF death. After adjustments for baseline differences, diabetes was associated with a 68% increased risk of HF hospitalization or HF death (adjusted hazard ratio 1.68, 95% confidence interval 1.26 to 2.25, p <0.001). In conclusion, in patients with HF and preserved LVEF, diabetes is associated with significantly increased risk of developing adverse HF outcomes.

Alcohol consumption and risk of heart failure: the Atherosclerosis Risk in Communities Study

AIM Alcohol is a known cardiac toxin and heavy consumption can lead to heart failure (HF). However, the relationship between moderate alcohol consumption and risk for HF, in either men or women, remains unclear. METHODS AND RESULTS We examined 14 629 participants of the Atherosclerosis Risk in Communities (ARIC) study (54 ± 6 years, 55% women) without prevalent HF at baseline (1987-89) who were followed for 24 ± 1 years. Self-reported alcohol consumption was assessed as the number of drinks/week (1 drink = 14 g of alcohol) at baseline, and updated cumulative average alcohol intake was calculated over 8.9 ± 0.3 years. Using multivariable Cox proportional hazards models, we examined the relation of alcohol intake with incident HF and assessed whether associations were modified by sex. Overall, most participants were abstainers (42%) or former drinkers (19%), with 25% reporting up to 7 drinks per week, 8% reporting ≥7 to 14 drinks per week, and 3% reporting ≥14-21 and ≥21 drinks per week, respectively. Incident HF occurred in 1271 men and 1237 women. Men consuming up to 7 drinks/week had reduced risk of HF relative to abstainers (hazard ratio, HR 0.80, 95% CI 0.68-0.94, P = 0.006); this effect was less robust in women (HR 0.84, 95% CI 0.71-1.00, P = 0.05). In the higher drinking categories, the risk of HF was not significantly different from abstainers, either in men or in women. CONCLUSION In the community, alcohol consumption of up to 7 drinks/week at early-middle age is associated with lower risk for future HF, with a similar but less definite association in women than in men. These findings suggest that despite the dangers of heavy drinking, modest alcohol consumption in early-middle age may be associated with a lower risk for HF.

Associations Between Metabolomic Compounds and Incident Heart Failure Among African Americans: The ARIC Study

Heart failure is more prevalent among African Americans than in the general population. Metabolomic studies among African Americans may efficiently identify novel biomarkers of heart failure. We used untargeted methods to measure 204 stable serum metabolites and evaluated their associations with incident heart failure hospitalization (n = 276) after a median follow-up of 20 years (1987-2008) by using Cox regression in data from 1,744 African Americans aged 45-64 years without heart failure at baseline from the Jackson, Mississippi, field center of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for established risk factors, we found that 16 metabolites (6 named with known structural identities and 10 unnamed with unknown structural identities, the latter denoted by using the format X-12345) were associated with incident heart failure (P < 0.0004 based on a modified Bonferroni procedure). Of the 6 named metabolites, 4 are involved in amino acid metabolism, 1 (prolylhydroxyproline) is a dipeptide, and 1 (erythritol) is a sugar alcohol. After additional adjustment for kidney function, 2 metabolites remained associated with incident heart failure (for metabolite X-11308, hazard ratio = 0.75, 95% confidence interval: 0.65, 0.86; for metabolite X-11787, hazard ratio = 1.23, 95% confidence interval: 1.10, 1.37). Further structural analysis revealed X-11308 to be a dihydroxy docosatrienoic acid and X-11787 to be an isoform of either hydroxyleucine or hydroxyisoleucine. Our metabolomic analysis revealed novel biomarkers associated with incident heart failure independent of traditional risk factors.