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Background: Inflammation may play a role in the pathophysiology of heart failure with preserved ejection fraction. We examined whether circulating levels of interleukin-6 identify patients at greater risk of adverse outcomes following hospitalization with heart failure with preserved ejection fraction. Methods: We assessed relationships between interleukin-6 (IL-6) tertiles (T1-3) and all-cause death, cardiovascular death, and subsequent heart failure hospitalization (sHFH) in 286 patients recently hospitalized with heart failure with preserved ejection fraction. Associations between IL (interleukin)-6 and outcomes were examined in a Cox-regression model adjusted for risk factors including BNP (B-type natriuretic peptide). Biomarkers including hsCRP (high-sensitivity C-reactive protein) were assessed. Results: The range of IL-6 (pg/mL) in each tertile was T1 (0.71–4.16), T2 (4.20–7.84), and T3 (7.9–236.32). Compared with T1, patients in the highest IL-6 tertile were more commonly male (56% versus 35%) and had higher creatinine (117±45 versus 101±36 μmol/L), hsCRP (11.6 [4.9–26.6]mg/L versus 2.3[1.1–4.2] mg/L). In univariable analysis, rates of all-cause death, cardiovascular death, and sHFH were higher in T3 versus T1. All-cause and cardiovascular death rates remained higher in T3 versus T1 after adjustment ( P Conclusions: In patients recently hospitalized with heart failure with preserved ejection fraction, IL-6 is an independent predictor of all-cause mortality, cardiovascular death, and sHFH after adjustment for risk factors including BNP. These findings are of particular relevance in the context of current anti–IL-6 drug development.

Background: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium–glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Methods: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. Results: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3–91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57–0.86]; hazard ratio, 0.77 [95% CI, 0.61–0.98]; hazard ratio, 0.62 [95% CI, 0.46–0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P P P Conclusions: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03036124.

Background: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT-proBNP. Methods: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and a NT-proBNP level ≥600 pg/mL (≥600 ng/L; ≥400 pg/mL if hospitalized for HF within the previous 12 months or ≥900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Results: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857–2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, −303 pg/mL [95% CI, −457 to −150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88–0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27–0.67), 0.77 (0.56–1.04), 0.78 (0.60–1.01), and 0.78 (0.64–0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement (≥5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score ( P for interaction=0.99) and decreased the proportion with a deterioration ≥5 points ( P for interaction=0.87) across baseline NT-proBNP quartiles. Conclusions: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.

Over the last three decades, trials of coronary revascularization have taken into account whether populations did or did not have diabetes. What has not been considered is whether or not patients with diabetes in these studies have type 1 or type 2 diabetes. 'Diabetes' appears to be largely used as a synonym for type 2 diabetes. The number of patients with type 1 diabetes has not been reported in most trials. Many questions remain unanswered. Do patients with type 1 diabetes have the same response to various modes of revascularization as those with type 2 diabetes? We know type 2 diabetes affects coronary endothelial function and the coronary artery wall but to what extent does type 1 diabetes affect these? Any response to revascularization does not just depend on the coronary artery but also on the myocardium. How does type 1 diabetes affect the myocardium? To what extent do patients with type 1 diabetes have viable or ischaemic myocardium or scar? What does 'diabetic cardiomyopathy' refer to in the context of type 1 diabetes? This manuscript reviews the evidence for revascularization in type 1 diabetes. We conclude that there has been a near absence of investigation of the pros and cons of revascularization in this population. Investigations to establish both the nature and extent of coronary and myocardial disease in these populations are necessary. Clinical trials of the pros and cons of revascularization in type 1 diabetes are necessary; many will declare that these will be too challenging to perform.

Introduction: Predicting outcomes in patients with heart failure (HF) is challenging. We compared the performance of the recently developed PREDICT-HF score with the established MAGGIC risk score in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods: The MAGGIC risk score is the most commonly used risk score in heart failure and was derived using data from 39,372 patients enrolled in 30 clinical trials and cohort studies and includes 13 clinical variables. PREDICT-HF (www.predict-hf.com) incorporates demographic, comorbidity and laboratory variables, including natriuretic peptides, and was developed using data from PARADIGM-HF. The performance of both models was tested in in DAPA-HF i.e. in symptomatic patients with HFrEF receiving contemporary standard care. The outcomes examined included all-cause death and cardiovascular (CV) death at 1 and 2 years. Model discrimination and calibration were assessed by Harrell’s C statistic. For the PREDICT-HF model participants with missing values, median values from the derivation cohort were imputed. Results: The mean age of the 4744 patients in DAPA-HF was 66 years and 77% were male; 68% were in NYHA functional class II and 24% in class III. During a median follow-up of 18 months, 605 patients died, and 500 experienced CV death. Using PREDICT-HF, the C statistic at 1 and 2 years was 0.71 and 0.70 for all-cause death, and 0.73 and 0.72 for CV death, respectively. The MAGGIC risk score was available for 4740 patients in DAPA-HF. The C-statistic for all cause death at 1 and 2 years was 0.63 and 0.63, respectively. Model discrimination for PREDICT-HF and MAGGIC are shown in Table 1. Conclusions: PREDICT-HF performed well, and significantly better than the MAGGIC risk score, in predicting mortality in a contemporary cohort of patients receiving evidence-based treatment.

No abstract available.

Supplemental Digital Content is available in the text., The rationale for our study was to investigate the pathophysiology of microvascular injury in patients with acute ST-segment–elevation myocardial infarction in relation to a history of hypertension. We undertook a cohort study using invasive and noninvasive measures of microvascular injury, cardiac magnetic resonance imaging at 2 days and 6 months, and assessed health outcomes in the longer term. Three hundred twenty-four patients with acute myocardial infarction (mean age, 59 [12] years; blood pressure, 135 [25] / 79 [14] mm Hg; 237 [73%] male, 105 [32%] with antecedent hypertension) were prospectively enrolled during emergency percutaneous coronary intervention. Compared with patients without antecedent hypertension, patients with hypertension were older (63 [12] years versus 57 [11] years; P

Background: A metabolic shift in energy expenditure toward a catabolic state upon high sodium (Na + ) diet, ultimately favouring endogenous water accrual and body fluid preservation, has recently been described in a rodent model. Objective: To investigate the impact of high Na + intake on renal Na + /water handling and metabolic signatures in a large real-life cohort of patients. Methods and Results: We analysed biochemical data from 767 hypertensive patients (429 males, 55.9%; age 47 ± 13 years; BMI 25.6 [23.0-29.0] kg/m 2 ) in washout from drugs affecting the renin-angiotensin-aldosterone system at the time of screening for secondary causes and with a conclusive diagnosis of essential hypertension (2012-2017). Classes of Na + intake ( L ow ≤2.3g/d; M edium 2.3-5g/d; H igh >5g/d) were defined based on urinary 24h Na + excretion (uNaV). The fractional excretion (FE) of Na + increased with increasing Na + intake (L: 0.39% [0.30-0.47] vs H: 0.81% [0.73-0.98], p < 0.001), while FE of free water decreased (L: 1.13% [0.73-1.72] vs H: 0.89% [0.69-1.12], p = 0.015). uNaV was an independent predictor of glomerular filtration rate (GFR, estimated by creatinine clearance; H: 130 ± 33 vs M: 111 ± 52 and L: 96 ± 39 ml/min/1.73m 2 ; p < 0.001 for comparisons) after correction for age, sex, BMI, renin, aldosterone and uKV (p = 0.001). This resulted in a marked increase in the 24h tubular Na + reabsorption and, accordingly, in the estimated energy expenditure (Δ H vs L= 18 [12-24] kcal/d, p < 0.001). At non-targeted LC/MS metabolomics (n = 67), metabolites increased (p < 0.05) in H vs L Na + intake mostly entailed intermediates or end products of the urea cycle and products of protein catabolism. Urinary 24h cortisol excretion, as a potential determinant of catabolism, increased with Na + intake (n = 137; L: 63 [36-72] nmol, M: 60 [47-86] nmol, H: 86 [75-139] nmol; p < 0.001), but its strongest predictor at multivariate regression analysis was GFR (p = 0.001). Conclusions: Kidneys can effectively dissociate Na + and water handling upon high Na + diet, at the cost of glomerular hyperfiltration, enhanced glomerulotubular balance, increased tubular energy expenditure and, ultimately, protein catabolism from endogenous or excess exogenous sources. This has broad implications on global cardiovascular risk.

Background: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials. Methods: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function). Results: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years’ follow-up (median [interquartile range], 744 [570–853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months. Conclusions: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01895751.

Background: The STICH trial (Surgical Treatment for Ischemic Heart Failure) demonstrated a survival benefit of coronary artery bypass grafting in patients with ischemic cardiomyopathy and left ventricular dysfunction. The Society of Thoracic Surgeons (STS) risk score and the EuroSCORE-2 (ES2) are used for risk assessment in cardiac surgery, with little information available about their accuracy in patients with left ventricular dysfunction. We assessed the ability of the STS score and ES2 to evaluate 30-day postoperative mortality risk in STICH and a contemporary cohort (CC) of patients with a left ventricle ejection fraction ≤35% undergoing coronary artery bypass grafting outside of a trial setting. Methods and Results: The STS and ES2 scores were calculated for 814 STICH patients and 1246 consecutive patients in a CC. There were marked variations in 30-day postoperative mortality risk from 1 patient to another. The STS scores consistently calculated lower risk scores than ES2 (1.5 versus 2.9 for the CC and 0.9 versus 2.4 for the STICH cohort), and underestimated postoperative mortality risk. The STS and ES2 scores had moderately good C statistics: CC (0.727, 95% CI: 0.650–0.803 for STS, and 0.707, 95% CI: 0.620–0.795 for ES2); STICH (0.744, 95% CI: 0.677–0.812, for STS and 0.736, 95% CI: 0.665–0.808 for ES2). Despite the CC patients having higher STS and ES2 scores than STICH patients, mortality (3.5%) was lower than that of STICH (4.8%), suggesting a possible decrease in postoperative mortality over the past decade. Conclusions: The 30-day postoperative mortality risk of coronary artery bypass grafting in patients with left ventricular dysfunction varies markedly. Both the STS and ES2 score are effective in evaluating risk, although the STS score tend to underestimate risk. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00023595.

At variance with the classic physiology concept of constant balance between salt intake and excretion, hypertonic Na + accumulation has been shown to occur in peripheral tissues, particularly in the skin. In humans, higher 23 Na MR signal from skin and skeletal muscle has been associated with aging, hypertension, CKD and diabetes.In a rodent model of aging and hypertension, we recently identified an increase in absolute Na + content and concentration in the myocardium, but paralleled by water accrual and an associated decrease in K + , thus pointing to an overall isotonic accumulation. To further investigate the phenomenon, we developed a mathematical model for expected chemical composition of tissues, as a function of extracellular volume fraction (ECV%) and the amount of fluid isotonic to the extracellular space added to the system (i.e. edema; fig, closed circles ).Total Na + concentration is higher in tissues with larger ECV%; the opposite occurs relative to K + ( fig A, open symbols ). The proportional increase in Na + concentration due to different degrees of edema is higher than the increase in water content in tissues where ECV% is < 45% (3-4 times higher for skeletal muscle and myocardium, where ECV% is 18-30%; fig B, black ). When absolute Na + content is assessed, similarly to 23 Na MR signal analysis, the proportionally higher increase occurs across the whole spectrum of ECV% ( fig B, red ).We conclude that Na + is more sensitive than water to detect edema. This could justify some of the recent evidence of high tissue Na + content in multiple conditions, including hypertension, CKD and diabetes, and holds the broad potential for early diagnosis of subclinical congestion and localised edema.

Background Invasive measures of microvascular resistance in the culprit coronary artery have potential for risk stratification in acute ST‐segment–elevation myocardial infarction. We aimed to investigate the pathological and prognostic significance of coronary thermodilution waveforms using a diagnostic guidewire. Methods and Results Coronary thermodilution was measured at the end of percutaneous coronary intervention, (PCI) and contrast‐enhanced cardiac magnetic resonance imaging (MRI) was intended on day 2 and 6 months later to assess left ventricular (LV) function and pathology. All‐cause death or first heart failure hospitalization was a pre‐specified outcome (median follow‐up duration 1469 days). Thermodilution recordings underwent core laboratory assessment. A total of 278 patients with acute ST‐segment elevation myocardial infarction EMI (72% male, 59±11 years) had coronary thermodilution measurements classified as narrow unimodal (n=143 [51%]), wide unimodal (n=100 [36%]), or bimodal (n=35 [13%]). Microvascular obstruction and myocardial hemorrhage were associated with the thermodilution waveform pattern ( P =0.007 and 0.011, respectively), and both pathologies were more prevalent in patients with a bimodal morphology. On multivariate analysis with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction (odds ratio [95% confidence interval]=5.29 [1.73, 16.22];, P =0.004) and myocardial hemorrhage (3.45 [1.16, 10.26]; P =0.026), but the relationship was not significant when index of microvascular resistance (IMR) >40 or change in index of microvascular resistance (5 per unit) was included. However, a bimodal thermodilution waveform was independently associated with all‐cause death and hospitalization for heart failure (odds ratio [95% confidence interval]=2.70 [1.10, 6.63]; P =0.031), independent of index of microvascular resistance>40, ST‐segment resolution, and TIMI (Thrombolysis in Myocardial Infarction) Myocardial Perfusion Grade. Conclusions The thermodilution waveform in the culprit coronary artery is a biomarker of prognosis and may be useful for risk stratification immediately after reperfusion therapy.

Background Interatrial shunt device (IASD) effects have been described in patients with heart failure and ejection fractions (EFs) ≥40%. However, baseline characteristics that correlate with greatest hemodynamic effects are unknown. On the basis of fundamental principles, we hypothesized that larger pressure gradients between left and right atria would yield greater shunt flow and greater hemodynamic effects. Methods and Results REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a multicenter study that investigated IASD safety and performance. Sixty-four patients with EF ≥40% underwent device implantation followed by hemodynamic assessments at rest and exercise, including pulmonary capillary wedge pressure (PCWP, surrogate for left atrial pressure) and central venous pressure (CVP). At 6 months, IASD resulted in an average pulmonary-to-systemic blood flow ratio of 1.27 and increased exercise tolerance. The PCWP-CVP gradient (ie, the driving pressure for shunt flow) decreased at peak exercise from 16.8±6.9 to 11.4±5.5 mm Hg, because of increased CVP (17.5±5.4 to 20.3±7.9 mm Hg; P =0.04) and decreased PCWP (34.1±7.6 to 31.6±8.0 mm Hg; P =0.025). Baseline PCWP-CVP gradient during exercise correlated with changes of both PCWP-CVP and PCWP: Δ(PCWP-CVP)=10.0−0.89·(PCWP-CVP) baseline ( r 2 =0.56) and ΔPCWP=7.54−0.60·(PCWP-CVP) baseline ( P =0.001). Hemodynamics of patients with EF ≥50% and those with EF Conclusions In heart failure patients with EF ≥40%, IASD significantly reduced PCWP and PCWP-CVP at peak exercise. Patients with higher baseline PCWP-CVP gradient had greater reductions in both parameters at follow-up. Results were sustained through 12 months and were independent of whether EF was ≥50% or between 40% and 49%. Additional studies will help further define the baseline hemodynamic predictors of exercise, hemodynamic, and clinical efficacy of the IASD. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01913613.

Supplemental Digital Content is available in the text., Background— Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required. Methods and Results— Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (P

Background— Diabetes and heart failure frequently coexist. Our aim was to assess the association between diabetes and short- and long-term outcomes in all patients admitted to the hospital for the first time with heart failure in Scotland between 1986 and 2003. Methods and Results— A total of 116 556 patients were studied, of whom 13% (n=15 161) had a diagnosis of diabetes. At 30 days, diabetes was associated with a lower case fatality. By 1 year, the association between diabetes and better outcome was reversed, and diabetes was a significant independent predictor of higher case fatality. The longer term risk of death associated with diabetes was greatest in younger patients. In patients aged 65 years or younger, the hazard ratio for mortality at 5 years associated with diabetes was 1.41 (95% CI, 1.31 to 1.52) for men and 1.64 (1.50 to 1.79) for women. The risk associated with diabetes was less in patients aged 75 years or older: a hazard ratio in men 1.16 (1.10 to 1.22) and in women 1.15 (1.10 to 1.20). In the younger age group the risk associated with diabetes was significantly greater in women than in men ( P =0.005 for diabetes-sex interaction). Diabetes was also a significant independent predictor of heart failure readmission, and again the risk was greatest in younger women. Conclusions— Although diabetes was associated with a lower case fatality at 30 days, by 1 year it was a significant independent predictor of higher case fatality. The risk associated with diabetes was greatest in young patients, and in young patients the risk was greatest in women.

Despite recent advances in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) still accounts for ≈50% of all cardiovascular deaths in developed countries, thus accounting for a significant proportion of annual death worldwide.1 Reduction of the incidence of SCD depends on identification of those at most risk. In the present review we will concentrate on the challenges of risk stratification for SCD in chronic heart failure (CHF). We evaluate the utility of microvolt T-wave alternans (MTWA) as a tool for predicting SCD and consider whether MTWA is currently a valid means of selecting which patients should, or should not, receive an implantable cardioverter-defibrillator (ICD). Until recently, attempts to prevent SCD relied on pharmacological therapy. β-Blockers,2 angiotensin-converting enzyme inhibitors,3 angiotensin receptor blockers4 and aldosterone antagonists5 modestly reduce the risk of SCD in patients with CHF and after myocardial infarction (MI), whereas antiarrhythmic therapy has largely failed.6 Despite such treatments, these patients remained at high risk until the advent of the ICD. Although ICDs have further reduced the risk of SCD, they are expensive and can be associated with significant morbidity; therefore, precisely targeting their use is crucial. Implantation of ICDs for secondary prevention is clear. Prior sustained ventricular arrhythmia confers high risk and the benefit/risk balance is clearly favorable.7 Also, the secondary prevention population is relatively small and readily identified, thus the financial costs are not insurmountable. Primary prevention ICD therapy is an entirely different scenario. Large, randomized controlled trials have shown a mortality benefit with ICDs in patients with a low left ventricular ejection fraction (LVEF) and a history of MI or CHF.6,8 However, 2 major concerns have restricted implementation of this strategy. First, although analyses have estimated an acceptable cost-effectiveness profile,9 the immediate cost of implanting devices …

Background— The use of fractional flow reserve (FFR) in acute coronary syndromes is controversial. The British Heart Foundation Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Non-ST-Elevation Myocardial Infarction (FAMOUS-NSTEMI) study (NCT01764334) has recently demonstrated the safety and feasibility of FFR measurement in patients with non–ST-segment–elevation myocardial infarction. We report the findings of the cardiac magnetic resonance (CMR) substudy to assess the diagnostic accuracy of FFR compared with 3.0-T stress CMR perfusion. Methods and Results— One hundred six patients with non–ST-segment–elevation myocardial infarction who had been referred for early invasive management were included from 2 centers. FFR was measured in all major patent epicardial coronary arteries with a visual stenosis estimated at ≥30%, and if percutaneous coronary intervention was performed, an FFR assessment was repeated. Myocardial perfusion was assessed with stress perfusion CMR at 3 T. The mean age was 56.7±9.8 years; 82.6% were men. Mean time from FFR evaluation to CMR was 6.1±3.1 days. The mean±SD left ventricular ejection fraction was 58.2±9.1%. Mean infarct size was 5.4±7.1%, and mean troponin concentration was 5.2±9.2 μg/L. There were 34 fixed and 160 inducible perfusion defects. There was a negative correlation between the number of segments with a perfusion abnormality and FFR ( r =−0.77; P P Conclusions— FFR in patients with recent non–ST-segment–elevation myocardial infarction showed high concordance with myocardial perfusion in matched territories as revealed by 3.0-T stress perfusion CMR. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02073422.

Introduction: Diabetes mellitus (DM), coronary artery disease (CAD) and heart failure commonly coexist. Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with a left ventricular ejection fraction (LVEF) of 35% or less and CAD amenable to CABG. Patients were randomised to CABG and optimal medical therapy (OMT) or OMT alone. Hypothesis: We assessed the hypothesis that patients with DM enrolled in the STICH trial would have greater benefit of CABG than patients without DM. Methods: We compared the characteristics and clinical outcomes of patients with and without DM randomized to CABG and OMT or OMT alone. Cox-proportional hazards analyses were used to assess treatment effect. Results: Diabetes was present in 40.3%. At baseline, patients with DM had more triple vessel CAD (66% v 57%, p Conclusions: Patients with and without DM enrolled in the STICH trial had similar outcomes at 5 years, and CABG did not exert greater benefit in patients with DM.

Background [Pro 11 D -Ala 12 ] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II–generating pathway exists in human dorsal hand veins. Methods and Results Using a modified Aellig technique, we studied the response to Ang I and [Pro 11 D -Ala 12 ] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean±SEM venoconstrictor response of 45±11%, 40±10%, 55±8%, and 4±4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril ( P =0.002). [Pro 11 D -Ala 12 ] Ang I induced a mean venoconstrictor response of 42±9%, 49±9%, 48±10%, and 54±11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro 11 D -Ala 12 ] Ang I. Conclusions We have demonstrated that [Pro 11 D -Ala 12 ] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding −log concentrations of agonist required to effect a 50% response (pD 2 ) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.

Recently, differences in the management of men and women with ischemic heart disease have been highlighted.1 Although at least as great, sex differences in heart failure have received little attention. In this article, we review the evidence that men and women with heart failure may differ with respect to epidemiology, etiology, diagnosis, prognosis, and treatment. To date, most studies of the prevalence and incidence of heart failure have identified cases on clinical grounds and, in some instances, with the aid of an ECG and chest radiograph. Thus, the precise type of heart failure (eg, left ventricular systolic dysfunction, or valvular disease) is unclear in most reports. This is important in view of the evidence that left ventricular systolic dysfunction is less common in women than in men with suspected heart failure (see the “Diagnosis” section below). ### Prevalence With these caveats in mind, the major epidemiological surveys of heart failure (see the Figure⇓)2 3 4 5 show that the overall prevalence rate of heart failure is similar in men and women. This balance, however, reflects a much lower female prevalence

Large epidemiological studies, including the Framingham Heart Study, the National Health and Nutrition Examination Survey, and the Cardiovascular Health Study, have shown that diabetes mellitus is an independent risk factor for the development of heart failure.1–3 Overall, the risk is approximately doubled, but the relative increase may be greater in younger compared with older individuals (and in younger women compared with younger men).1–9 In diabetic individuals, the risk of developing heart failure is greatest in those with an elevated body mass index, poor glycemic control (as indicated by hemoglobin A1c level), nephropathy, retinopathy, and coronary heart disease.1–9 Article p 1371 In this issue of Circulation , Held and colleagues10 have shown that the association between dysglycemia and heart failure extends beyond diabetes mellitus. In a clinical trial cohort of 31 546 subjects with arterial disease, diabetes with end-organ damage, or both who were followed up for a mean of 2.4 years, these investigators found that elevated fasting plasma glucose was an independent predictor of hospitalization for heart failure even in nondiabetic individuals (but unfortunately did not report other cardiovascular outcomes for comparison). These observations support 2 earlier studies. …