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Aims: According to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, the definition of chronic kidney disease (CKD) requires the presence of abnormal kidney structure or function for >3 months with implications for health. CKD in patients with heart failure (HF) has not been defined using this definition, and less is known about the true health implications of CKD in these patients. The objective of the current study was to identify patients with HF who met KDIGO criteria for CKD and examine their outcomes. Methods and results: Of the 1 419 729 Veterans with HF not receiving kidney replacement therapy, 828 744 had data on ≥2 ambulatory serum creatinine >90 days apart. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (n = 185 821) or urinary albumin‐to‐creatinine ratio (uACR) >30 mg/g (n = 32 730) present twice >3 months apart. Normal kidney function (NKF) was defined as eGFR ≥60 ml/min/1.73 m2, present for >3 months, without any uACR >30 mg/g (n = 365 963). Patients with eGFR <60 ml/min/1.73 m2 were categorized into four stages: 45–59 (n = 72 606), 30–44 (n = 74 812), 15–29 (n = 32 077), and <15 (n = 6326) ml/min/1.73 m2. Five‐year all‐cause mortality occurred in 40.4%, 57.8%, 65.6%, 73.3%, 69.7%, and 47.5% of patients with NKF, four eGFR stages, and uACR >30mg/g (albuminuria), respectively. Compared with NKF, hazard ratios (HR) (95% confidence intervals [CI]) for all‐cause mortality associated with the four eGFR stages and albuminuria were 1.63 (1.62–1.65), 2.00 (1.98–2.02), 2.49 (2.45–2.52), 2.28 (2.21–2.35), and 1.22 (1.20–1.24), respectively. Respective age‐adjusted HRs (95% CIs) were 1.13 (1.12–1.14), 1.36 (1.34–1.37), 1.87 (1.84–1.89), 2.24 (2.18–2.31) and 1.19 (1.17–1.21), and multivariable‐adjusted HRs (95% CIs) were 1.11 (1.10–1.12), 1.24 (1.22–1.25), 1.46 (1.43–1.48), 1.42 (1.38–1.47), and 1.13 (1.11–1.16). Similar patterns were observed for associations with hospitalizations. Conclusion: Data needed to define CKD using KDIGO criteria were available in six out of ten patients, and CKD could be defined in seven out of ten patients with data. HF patients with KDIGO‐defined CKD had higher risks for poor outcomes, most of which was not explained by abnormal kidney structure or function. Future studies need to examine whether CKD defined using a single eGFR is characteristically and prognostically different from CKD defined using KDIGO criteria. [ABSTRACT FROM AUTHOR]

Aims To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Methods and results Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction =35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n=748; enalapril, n=696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n=486; enalapril, n=528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). Conclusion In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. [ABSTRACT FROM AUTHOR]

Antihypertensive monotherapy is often insufficient to control blood pressure (BP). Several recent guidelines advocate for initial combination drug therapy in many patients. This meta-analysis of seven randomized, double-blind studies (N = 5888) evaluated 8 weeks of olmesartan medoxomil (OM)-based single-pill dual-combination therapy (OM+amlodipine/azelnidipine or hydrochlorothiazide) vs OM monotherapy in adults with hypertension. BP-lowering efficacy, goal achievement, and adverse events were assessed in the full cohort and subgroups (elderly/nonelderly and patients with and without chronic kidney disease). In the full cohort at week 8, for dual therapy vs monotherapy, seated BP was lower (137.5/86.1 mm Hg vs 144.4/89.9 mm Hg), and the mean change from baseline in BP and BP goal achievement (<140/90 mm Hg) were greater (-22.7/-15.0 mm Hg vs -16.0/-11.3 mm Hg and 51.2% vs 34.7%, respectively). Adverse events were similar between groups. BP-lowering efficacy among subgroups mirrored the findings in the full cohort whereby changes were significantly greater following OM dual-combination therapy vs OM monotherapy. [ABSTRACT FROM AUTHOR]

Aims: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.Methods and Results: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population.Conclusion: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population. [ABSTRACT FROM AUTHOR]

In this multicenter trial, the effects of nebivolol added to an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) were assessed in patients with hypertension (diastolic blood pressure [DBP] 80-110 mm Hg) and prediabetes (fasting blood glucose 100-125 mg/dL and/or 2-hour oral glucose tolerance test [OGTT] 140-199 mg/dL). After a 4-week run-in period (in which lisinopril [10 mg/d] or losartan [50 mg/d] treatment was initiated), patients with DBP 90-110 mm Hg were randomized (2:2:1) to 12-week, double-blind treatment with nebivolol (n=223; 5-40 mg/d), hydrochlorothiazide (HCTZ; n=212; 12.5-25 mg/d), or placebo (n=102), titrated to achievement of 130/80 mm Hg. The primary outcome measure was DBP (last observation carried forward, intent to treat population); secondary measures included systolic blood pressure (SBP) and glucose levels. At baseline, overall mean values for body mass index, triglycerides, and high-density lipoprotein cholesterol were 32.3 kg/m2, 1.7 mmol/L, and 1.3 mmol/L, respectively. At week 12, nebivolol and placebo groups demonstrated a decrease of −9.4 and −5.0 mm Hg, respectively ( P<.001) for DBP and −10.4 and −7.8 mm Hg for SBP ( P=.147). The mean changes in area under the curve OGTT were 0.0 mg/dL (nebivolol), 6.9 mg/dL (HCTZ; P=.024 vs nebivolol), and −1.0 mg/dL (placebo). Adverse event-related discontinuation rates were 10.3%, 6.6%, and 2.0%, respectively. Nebivolol, added to an ACE inhibitor or ARB, provides additional blood pressure reduction with little or no effect on glucose metabolism in hypertensive patients with prediabetes. [ABSTRACT FROM AUTHOR]

J Clin Hypertens (Greenwich). 2012; 14:415-421. ©2012 Wiley Periodicals, Inc. The authors previously reported that addition of valsartan ameliorated the negative metabolic effects of hydrochlorothiazide in obese hypertensive patients through an enhanced postprandial insulin response. In this secondary analysis, the authors tested whether this enhanced insulin response to valsartan/hydrochlorothiazide was influenced by serum potassium levels, which were reduced to a lesser extent, when compared with amlodipine/hydrochlorothiazide. Results showed that the early insulin response with valsartan plus hydrochlorothiazide occurred regardless of serum potassium levels. Heightened insulin response was, however, not significantly different when patients with normal potassium (>3.9 mEq/L) at baseline and low potassium (≤3.9 mEq/L) at the end of the study were compared with the amlodipine/hydrochlorothiazide group. Despite the influence of serum potassium on insulin secretory response to a glucose challenge, the addition of valsartan maintained normoglycemia in patients given hydrochlorothiazide. Thus, the metabolic response to hydrochlorothiazide was improved with addition of valsartan through an enhanced insulin response that was not greatly affected by changes in potassium levels. [ABSTRACT FROM AUTHOR]

Aims To determine independent associations of diabetes mellitus with outcomes in a propensity-matched cohort of patients with acute myocardial infarction (AMI) and systolic heart failure (HF). Methods and results In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, hospitalized AMI patients complicated by left ventricular ejection fraction ≤40% and symptoms of HF receiving standard therapy were randomized 3–14 days post-AMI to receive eplerenone 25–50 mg/day (n = 3319) or placebo (n = 3313). Of the 6632 patients, 2142 (32%) had a history of diabetes, who were older and sicker. Using propensity scores for diabetes, we assembled a cohort of 1119 pairs of patients with and without diabetes who were balanced on 64 baseline characteristics. Incident fatal or nonfatal recurrent AMI occurred in 136 (12%) and 87 (8%) of matched patients with and without diabetes, respectively, during 2.5 years of follow-up [hazard ratio (HR) when diabetes was compared with no-diabetes, 1.61; 95% confidence interval (CI), 1.23–2.10; P = 0.001]. Diabetes was associated with nonfatal AMI (HR, 1.68; 95% CI, 1.23–2.31; P = 0.001) but not with fatal AMI (HR, 1.42; 95% CI, 0.88–2.28; P = 0.146). Hazard ratios (95% CIs) for the association of diabetes with all-cause mortality, cardiovascular mortality, all-cause hospitalization, and cardiovascular hospitalization were 1.12 (0.93–1.37; P = 0.224), 1.11 (0.90–1.37; P = 0.318), 1.13 (1.00–1.27; P = 0.054), and 1.20 (1.01–1.44; P = 0.042), respectively. Conclusion In post-AMI patients with systolic HF, diabetes mellitus is a significant independent risk factor for recurrent short-term nonfatal AMI, but had no association with fatal AMI. [ABSTRACT FROM PUBLISHER]

Aims Obesity is paradoxically associated with survival benefit in patients with chronic heart failure (HF). However, obesity complicates the management of diabetes mellitus (DM), which is common in HF. Yet, little is known about the impact of obesity in HF patients with DM. Therefore, we examined the association between obesity and outcomes in propensity-matched cohorts of HF patient with and without DM. Methods and results Of the 7788 participants with chronic mild to moderate HF in the Digitalis Investigation Group trial, 7379 were non-cachectic [body mass index (BMI) ≥20 kg/m2] at baseline. Of these, 2153 (29%) had DM, of whom 798 (37%) were obese (BMI ≥30 kg/m2). Of the 5226 patients without DM, 1162 (22%) were obese. Propensity scores for obesity were used to separately assemble 636 pairs of obese and non-obese patients with DM and 770 pairs of obese and non-obese patients without DM, who were balanced on 32 baseline characteristics. Among matched patients with DM, all-cause mortality occurred in 38 and 39% of obese and non-obese patients, respectively [hazard ratio (HR) when obesity was compared with no obesity 0.99; 95% confidence interval (CI) 0.80–1.22; P = 0.915]. Among matched patients without DM, all-cause mortality occurred in 23 and 27% obese and non-obese patients, respectively (HR associated with obesity 0.77; 95% CI 0.61–0.97; P = 0.025). Conclusion In patients with chronic mild to moderate HF and DM, obesity confers no paradoxical survival benefit. Whether intentional weight loss may improve outcomes in these patients needs to be investigated in future prospective studies. [ABSTRACT FROM AUTHOR]

Hypertension frequently coexists with diabetes and the cardiometabolic syndrome. β-Blockers have been a mainstay for controlling blood pressure for nearly 4 decades. However, β-blockers are perceived to cause glucose and lipid metabolism dysregulation, including hypoglycemia masking, reduced glycemic control, insulin resistance, and dyslipidemia. It should be noted, however, that β-blockers are diverse in their effects on glucose and lipid metabolism. Potential mechanisms that contribute to these metabolic effects include hemodynamic differences, anti-inflammatory and anti-oxidative pathways, and/or weight changes. Traditional β-blockers decrease cardiac output while peripheral vascular resistance increases or remains unchanged, which may result in glucose and lipid abnormalities. In contrast, vasodilating β-blockers reduce peripheral vascular resistance but have little effect on cardiac output. Vasodilating β-blockers may therefore result in less impact on insulin sensitivity and glycemic control, a reduced new-onset diabetes risk, and improved dyslipidemia compared with traditional β-blockers. Because of these effects, vasodilating β-blockers may represent a favorable option in the treatment of high-risk patients with hypertension. [ABSTRACT FROM AUTHOR]

Hypertensive patients with the cardiometabolic syndrome (CMS) are at increased risk for type 2 diabetes and cardiovascular disease. The authors examined effects of valsartan and hydrochlorothiazide (HCTZ) combined and alone on insulin sensitivity (using homeostasis model assessment-insulin resistance [HOMA-IR]), and inflammatory/metabolic biomarkers in prediabetic hypertensive persons with CMS. Eligible patients entered 16-week therapy with valsartan 320 mg/d (n=189), HCTZ 25 mg/d (n=190), or valsartan/HCTZ 320/25 mg/d (n=187). At the end point, there were no statistically significant differences in HOMA-IR among the 3 groups. HCTZ significantly increased hemoglobin A(1c) and triglyceride concentrations and lowered serum potassium levels vs valsartan. HCTZ also increased plasma aldosterone and C-reactive protein levels. Blood pressure reduction and blood pressure control rates were highest with valsartan/HCTZ. There were no differences between combination valsartan/HCTZ or monotherapies on a measure of insulin sensitivity; however, the negative metabolic effects of HCTZ (increase in triglyceride and hemoglobin A(1c) values) were absent with valsartan/HCTZ, indicating an ameliorating effect of valsartan on these measures. [ABSTRACT FROM AUTHOR]

Background: Exercise microvolt T-wave alternans (TWA) identifies sudden cardiac death (SCD) risk. TWA can be measured from ambulatory ECGs (AECGs) using modified moving average (MMA) method. Whether MMA TWA from AECGs predicts SCD in post-MI patients with left ventricular dysfunction (LVD) is unknown. Methods: EPHESUS enrolled hospitalized post-MI patients with heart failure and/or diabetes with LVD. Before randomization to drug treatment, AECGs were obtained in 493 patients. Of them, 46 died of cardiovascular causes, including 18 of SCD. Patients alive at end of follow-up (N = 92) were matched with 46 nonsurvivors based on age, gender, and diabetes. MMA TWA was analyzed using MARSPC system (GE Healthcare, Milwaukee, WI, USA). The three highest TWA values from artifact-free periods were averaged for AECG channels corresponding to leads V1 and V3. SCD prediction was tested with a prespecified 47 μV cutpoint and at a cutpoint maximizing the separation between SCD patients versus survivors or non-SCD. Results: TWA in either lead was higher for patients with SCD (P ≤ 0.05) versus survivors or non-SCD. TWA ≥ 47 μV was associated with RR = 5.2 (95%CI = 1.8–13.6, P = 0.002) in V1 and RR = 5.5 (95% CI = 2.2–13.8, P < 0.001) in V3 for SCD. The optimal cutpoint for TWA in V1 was ≥43 μV (RR = 5.9 [95%CI = 2.2–15.8, P < 0.001]). The optimal cutpoint in V3 was ≥47 μV. TWA greater than the optimal cutpoint in either lead was associated with RR = 7.1 (95%CI = 2.7–18.3, P < 0.001) for SCD, with 11 out of 18 patients dying of SCD. Conclusions: AECG-based TWA measured with MMA is a powerful predictor of SCD in high-risk post-MI patients with LV dysfunction. [ABSTRACT FROM AUTHOR]

This post-hoc analysis of the Treating to New Targets (TNT) study evaluated the joint effects of managing low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on cardiovascular outcomes. Patients (N=9739) with clinically evident, stable coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/d. The primary end point was occurrence of a first major cardiovascular event. At 3 months' follow-up, patients were stratified according to SBP (<140 mm Hg vs ≥140 mm Hg) and tertiles of LDL-C. At 4.9 years' median follow-up, the rate of major cardiovascular events was reduced most in patients with lower LDL-C (P <.001) and in patients with SBP <140 mm Hg (P =.014). A 42% relative risk reduction was observed for patients in the lowest LDL-C tertile with an SBP <140 mm Hg, compared with patients in the highest LDL-C tertile with an SBP ≥140 mm Hg. The effect of lower SBP on stroke was most pronounced in the lowest LDL-C tertile. [ABSTRACT FROM AUTHOR]

The identification and treatment of high-risk patients for cardiovascular disease reduces the risk of morbidity and mortality. Significant risk factors for cardiovascular events in hypertensive patients over and above dyslipidemia, smoking, and obesity include coronary heart disease, peripheral arterial disease, cerebrovascular/carotid artery disease, and diabetes. Treatment options for the reduction of cardiovascular events in hypertensive patients include diuretics, β-blockers, α-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists. All of these agents, in various combinations, have been found to reduce the risk of cardiovascular events, even in high-risk patients. The use of ACE inhibitors or ARBs (usually in combination with a diuretic) has proven especially effective in reducing cardiovascular events in diabetes and, although both classes of drugs target the renin-angiotensin-aldosterone system, each has a different mechanism of action. Some investigators believe that combination therapy with an ACE inhibitor and ARB, usually given with other medications, may be more effective than either agent alone with other drugs. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) is evaluating the cardioprotective effect of an ACE inhibitor (ramipril) plus an ARB (telmisartan) in high-risk patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with systolic heart failure (SHF) often have concomitant diastolic dysfunction (DD). SHF is associated with decreased heart rate variability (HRV), but the impact of degree of DD on HRV in SHF is unclear. Methods and results: HRV was measured in 139 patients, aged 64±12 years, 74% male, LVEF 30±8%. Patients had stable NYHA class II–III CHF on ACE inhibitors or ATII receptor blockers, with LVEF≤40% and BNP≥200 pg/ml. Subjects underwent 2-D echocardiography with Doppler assessment and 24-h Holters. Patients were categorized as having impaired relaxation (E-deceleration time>2 SD above age-adjusted normal values (AANV), E/A≤1, systolic/diastolic pulmonary vein flow≥1; N =30), pseudonormal (E-deceleration time within 2 SD of AANV, E/A=1–2, systolic/diastolic pulmonary vein flow <1; N =25) or restrictive filling patterns (E-deceleration time>2 SD below AANV or/and E/A ratio≥2; N =84) Differences were adjusted for clinical covariates using UNIANOVA, p <0.05. HRV was reduced and BNP higher in pseudonormal patients compared to impaired relaxation, but this difference was only significant for restrictive vs. impaired filling. Differences remained significant after adjustment for covariates. Conclusion: Significantly more abnormal HRV, reflecting greater cardiac autonomic dysfunction, is associated with restrictive DD compared to impaired relaxation. [Copyright &y& Elsevier]

Background: Coronary artery disease (CAD) is associated with a small but measurable amount of electrical disorganization, which may appear as temporal electrical heterogeneity on the electrocardiogram and is not visible with the low resolution, 12-lead electrocardiogram. A newly developed, multilead, high-fidelity variance cardiograph captures the heterogeneity component of the electrocardiograph signal. The subsequent analysis produces an electrical heterogeneity index (EHI) by quantifying phase-invariant electrical disorganization, which represents cardiac abnormalities that are modulated onto the measured high frequency electrocardiogram. A prospective investigation was conducted to determine the predictive accuracy of the variance cardiograph to detect clinically important CAD. Methods: Sixty-five patients (group I) with documented CAD were given the variance cardiography test, as well as 21 normal volunteers (group II). An EHI >; 75 from the variance cardiograph was determined to best represent a positive test for clinically important CAD. Results: Group I had a mean EHI of 89.5 ± 19.7, while group II had a mean EHI of 61.1 ± 19.1 (P < 0.001). The variance cardiograph had a sensitivity of 79%, a specificity of 76%, a positive predictive value of 91%, and a negative predictive value of 55%. Conclusions: These results demonstrate that analysis of the temporal electrical heterogeneity component of the electrocardiographic signal obtained by the variance cardiograph provides a new and reliable stress-free test For the detection of CAD. [ABSTRACT FROM AUTHOR]

A response by Phyllis K. Stein and Prakash Deedwania to a letter to the editor about their article "Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI Patients with left ventricular dysfunction in the EPHESUS Study" is presented.