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Sphingosine-1-phosphate (S1P) is a bioactive mediator in inflammation. Dysregulated S1P is demonstrated as a cause of heart failure (HF). However, the time-dependent and integrative role of S1P interaction with receptors in HF is unclear after myocardial infarction (MI). In this study, the sphingolipid mediators were quantified in ischemic human hearts. We also measured the time kinetics of these mediators post-MI in murine spleen and heart as an integrative approach to understand the interaction of S1P and respective S1P receptors in the transition of acute (AHF) to chronic HF (CHF). Risk-free 8-12 wk male C57BL/6 mice were subjected to MI surgery, and MI was confirmed by echocardiography and histology. Mass spectrometry was used to quantify sphingolipids in plasma, infarcted heart, spleen of mice, and ischemic and healthy human heart. The physiological cardiac repair was observed in mice with a notable increase of S1P quantity (pmol/g) in the heart and spleen significantly reduced in patients with ischemic HF. The circulating murine S1P levels were increased during AHF and CHF despite lowered substrate in CHF. The S1PR1 receptor expression was observed to coincide with the respective S1P quantity in mice and human hearts. Furthermore, selective S1P1 agonist limited inflammatory markers CCL2 and TNF-alpha and accelerated reparative markers ARG-1 and YM-1 in macrophages in the presence of Kdo2-Lipid A (KLA; potent inflammatory stimulant). This report demonstrated the importance of S1P/S1PR1 signaling in physiological inflammation during cardiac repair in mice. Alteration in these axes may serve as the signs of pathological remodeling in patients with ischemia. NEW & NOTEWORTHY Previous studies indicate that sphingosine-1-phosphate (S1P) has some role in cardiovascular disease. This study adds quantitative and integrative systems-based approaches that are necessary for discovery and bedside translation. Here, we quantitated sphinganine, sphingosine, sphingosine-1-phosphate (S1P) in mice and human cardiac pathobiology. Interorgan S1P quantity and respective systems-based receptor activation suggest cardiac repair after myocardial infarction. Thus, S1P serves as a therapeutic target for cardiac protection in clinical translation.

Objective: There has been a substantial decline in patients presenting for emergent and routine cardiovascular care in the United States after the onset of the coronavirus disease 2019 (COVID-19) pandemic. We sought to assess the risk of adverse clinical outcomes among patients undergoing coronary artery bypass graft (CABG) surgery during the 2020 COVID-19 pandemic period and compare the risks with those undergoing CABG before the pandemic in the year 2019. Methods: A retrospective cross-sectional analysis of the TriNetX Research Network database was performed. Patients undergoing CABG between January 20, 2019, and September 15, 2019, contributed to the 2019 cohort, and those undergoing CABG between January 20, 2020, and September 15, 2020, contributed to the 2020 cohort. Propensity-score matching was performed, and the odds of mortality, acute kidney injury, stroke, acute respiratory distress syndrome, and mechanical ventilation occurring by 30 days were evaluated. Results: The number of patients undergoing CABG in 2020 declined by 35.5% from 5534 patients in 2019 to 3569 patients in 2020. After propensity-score matching, 3569 patient pairs were identified in the 2019 and the 2020 cohorts. Compared with those undergoing CABG in 2019, the odds of mortality by 30 days were 0.96 (95% confidence interval [CI], 0.69-1.33; P = .80) in those undergoing CABG in 2020. The odds for stroke (odds ratio [OR], 1.201; 95% CI, 0.96-1.39), acute kidney injury (OR, 0.76; 95% CI, 0.59-1.08), acute respiratory distress syndrome (OR, 1.01; 95% CI, 0.60-2.42), and mechanical ventilation (OR, 1.11; 95% CI, 0.94-1.30) were similar between the 2 cohorts. Conclusions: The number of patients undergoing CABG in 2020 has substantially declined compared with 2019. Similar odds of adverse clinical outcomes were seen among patients undergoing CABG in the setting of COVID-19 compared with those in 2019.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet pattern has shown some promise for preventing heart failure (HF), but studies have been conflicting. OBJECTIVE: To determine whether the DASH diet pattern was associated with incident HF in a large biracial and geographically diverse population. METHODS: Among participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study of adults aged ≥45 years who were free of suspected HF at baseline in 2003–2007, DASH diet score was derived from the baseline food frequency questionnaire. The main outcome was incident HF defined as the first adjudicated HF hospitalization or HF death through December 31, 2016. We estimated hazard ratios (HR) for the associations of DASH diet score quartiles with incident HF, and incident HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) using the Lunn-McNeil extension to the Cox model. We tested for several pre-specified interactions including with age. RESULTS: Compared to the lowest quartile, individuals in the 2(nd)-4(th) DASH diet score quartiles had lower risk for incident HF after adjustment for sociodemographic and health characteristics: Q2 HR 0.70, 95%CI[0.56–0.87]; Q3 HR 0.65, 95%CI:[0.52–0.81]; Q4 HR 0.67, 95%CI:[0.52–0.85]. When stratifying results by age, quartiles 2–4 had a lower hazard for incident HF among age

Supplemental Digital Content is available in the text., The 2017 American College of Cardiology/American Heart Association high blood pressure (BP) guidelines recommend risk assessment of atherosclerotic cardiovascular disease to inform hypertension treatment in adults with elevated BP or low-risk stage I hypertension. The use of coronary artery calcium (CAC) score to guide hypertension therapy has not been adequately evaluated. Participants free of cardiovascular disease were pooled from Multi-Ethnic Study of Atherosclerosis, Coronary Artery Risk Development in Young Adults, and Jackson Heart Study. The risk for incident cardiovascular events (heart failure, stroke, coronary heart disease), by CAC status (CAC-0 or CAC>0) and BP treatment group was assessed using multivariable-adjusted Cox regression. The 10-year number needed to treat to prevent a single cardiovascular event was also estimated. This study included 6461 participants (median age 53 years; 53.3% women; 32.3% Black participants). Over a median follow-up of 8.5 years, 347 incident cardiovascular events occurred. Compared with those with normal BP, the risk of incident cardiovascular event was higher among those with elevated BP/low-risk stage I hypertension and CAC>0 (hazard ratio, 2.4 [95% CI, 1.7–3.4]) and high-risk stage I/stage II hypertension (BP, 140–160/80–100 mm Hg) with CAC>0 (hazard ratio, 2.9 [95% CI, 2.1–4.0]). A similar pattern was evident across racial subgroups and for individual study outcomes. Among those with CAC-0, the 10-year number needed to treat was 160 for elevated BP/low-risk stage I hypertension and 44 for high-risk stage I or stage II hypertension (BP, 140–160/80–100 mm Hg). Among those with CAC>0, the 10-year number needed to treat was 36 and 22, respectively. Utilization of the CAC score may guide the initiation of hypertension therapy and preventive approaches to personalize cardiovascular risk reduction among individuals where the current guidelines do not recommend treatment.

Aims We sought to compare the generalizability and prognostic implications of heart failure with preserved ejection fraction (HFpEF) scores (HFA-PEFF and H2 FPEF score) in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial participants and matched controls from the Atherosclerosis Risk in Community (ARIC) study. Methods and results Based on the respective scores, the study participants from the TOPCAT (N = 356), RELAX (N = 216), and ARIC (N = 379) studies were categorized as having a low, intermediate, or high likelihood of HFpEF. Age, sex, and race matched controls free of cardiovascular disease who had unexplained dyspnoea were used to evaluate the diagnostic performance. The prognostic value of scores was assessed using multivariable-adjusted Cox regression analyses. The median HFA-PEFF scores in the TOPCAT, RELAX, and ARIC studies were 5.0 [interquartile range (IQR): 5.0-6.0], 4.0 (IQR: 2.0-4.0), and 3.0 (IQR: 2.0-4.0), respectively. The median H2 FPEF scores in the three studies were 5.5 (IQR: 4.0-7.0), 6.0 (IQR: 4.0-7.0), and 3.0 (IQR: 2.0-5.0), respectively. A low HFA-PEFF and H2 FPEF score can rule out HFpEF with high sensitivity (99.5% and 99.6%, respectively) and negative predictive value (95.7% and 98.3%, respectively). A high HFA-PEFF and H2 FPEF score can rule-in HFpEF with good specificity (82.8% and 95.6%, respectively) and positive predictive value (79.9% and 90.4%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA-PEFF and H2 FPEF score was 1.26 (95% confidence interval: 0.98-1.63) and 1.01 (95% confidence interval: 0.88-1.15), respectively. A higher H2 FPEF score was associated with lower peak oxygen intake in RELAX trial participants (adjusted P = 0.01). Conclusions The HFA-PEFF and the H2 FPEF scores are reliable diagnostic tools for HFpEF. The prognostic utility of HFpEF scores requires further validation in larger rigorously phenotyped populations.

Background: Right ventricular (RV) dysfunction is common and associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19). In non-COVID-19 acute respiratory distress syndrome, RV dysfunction develops due to pulmonary hypoxic vasoconstriction, inflammation, and alveolar overdistension or atelectasis. Although similar pathogenic mechanisms may induce RV dysfunction in COVID-19, other COVID-19-specific pathology, such as pulmonary endothelialitis, thrombosis, or myocarditis, may also affect RV function. We quantified RV dysfunction by echocardiographic strain analysis and investigated its correlation with disease severity, ventilatory parameters, biomarkers, and imaging findings in critically ill COVID-19 patients. Methods: We determined RV free wall longitudinal strain (FWLS) in 32 patients receiving mechanical ventilation for COVID-19-associated respiratory failure. Demographics, comorbid conditions, ventilatory parameters, medications, and laboratory findings were extracted from the medical record. Chest imaging was assessed to determine the severity of lung disease and the presence of pulmonary embolism. Results: Abnormal FWLS was present in 66% of mechanically ventilated COVID-19 patients and was associated with higher lung compliance (39.6 vs 29.4 mL/cmH2O, P = 0.016), lower airway plateau pressures (21 vs 24 cmH2O, P = 0.043), lower tidal volume ventilation (5.74 vs 6.17 cc/kg, P = 0.031), and reduced left ventricular function. FWLS correlated negatively with age (r = −0.414, P = 0.018) and with serum troponin (r = 0.402, P = 0.034). Patients with abnormal RV strain did not exhibit decreased oxygenation or increased disease severity based on inflammatory markers, vasopressor requirements, or chest imaging findings. Conclusions: RV dysfunction is common among critically ill COVID-19 patients and is not related to abnormal lung mechanics or ventilatory pressures. Instead, patients with abnormal FWLS had more favorable lung compliance. RV dysfunction may be secondary to diffuse intravascular micro- and macro-thrombosis or direct myocardial damage. Trial Registration: National Institutes of Health #NCT04306393. Registered 10 March 2020, https://clinicaltrials.gov/ct2/show/NCT04306393

BACKGROUND Hypertension is a common condition that increases risk for future cardiovascular disease. N-terminal B-type natriuretic peptide (NT-proBNP) is higher in individuals with hypertension, but studies of its association with hypertension risk have been mixed. METHODS The REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 U.S. Black or White adults aged ≥45 years from 2003 to 2007. A subcohort included 4,400 participants who completed a second assessment in 2013–2016. NT-proBNP was measured by immunoassay in 1,323 participants without baseline hypertension, defined as blood pressure ≥140/90 or self-reported antihypertensive prescriptions. Two robust Poisson regression models assessed hypertension risk, yielding incidence rate ratios (IRRs): Model 1 included behavioral and demographic covariates and Model 2 added risk factors. A sensitivity analysis using a less conservative definition of hypertension (blood pressure ≥130/80 or self-reported antihypertensive prescriptions) was conducted. RESULTS Four hundred and sixty-six participants developed hypertension after mean follow-up of 9.4 years. NT-proBNP was not associated with hypertension (Model 2 IRR per SD log NT-proBNP 1.01, 95% confidence interval 0.92–1.12), with no differences by sex, body mass index, age, or race. Similar findings were seen in lower-threshold sensitivity analysis. CONCLUSIONS NT-proBNP was not associated with incident hypertension in REGARDS; this did not differ by race or sex.

Anemia is a commonly occurring comorbidity among patients of heart failure with preserved ejection fraction (HFpEF) but limited data exists on the cardiovascular phenotype of anemia in HFpEF. We sought to characterize the clinical features, exercise capacity, and outcomes in patients with HFpEF to elucidate the phenotype and pathophysiology of anemia in HFpEF. Post hoc analyses of participants enrolled in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial was performed. Anemia was defined as hemoglobin13 g/dL in men and12 g/dL in women. Multivariate adjusted regression modeling was done to assess for differences in peak oxygen uptake. Adjusted hazard ratios were generated to assess difference in hospitalization events using a Cox proportional hazards model. Anemic HFpEF patients were more likely to be older, male, and have worse renal function (p0.05 for all). N-terminal pro-B-type natriuretic peptide, troponin I, pro-collagen III N-terminal peptide, C-telopeptide for type I collagen, uric acid, cystatin-c, and galectin-3 (p0.05 for all) levels were higher in anemic HFpEF patients. In adjusted models, anemic HFpEF patients had worse exercise capacity (peak oxygen uptake: 11.3 vs 12.1 mL/kg/min; p = 0.004). The hazard for cardiac or renal cause of hospitalization in those with anemia was 2.0 (95% confidence interval: 0.9 to 4.3). Anemic HFpEF patients have worse exercise capacity and are more likely to be hospitalized. A better understanding of the physiologic phenotypes of HFpEF patients may allow for greater personalization of treatment and prognostication in HFpEF patients.

We evaluated the impact of intensive blood pressure control on the incidence of new-onset atrial fibrillation/flutter (AF) and the prognostic implications of preexisting and new-onset AF in SPRINT (Systolic Blood Pressure Intervention Trial) participants. New-onset AF was defined as occurrence of AF in 12-lead electrocardiograms after randomization in participants free of AF at baseline. Poisson regression modeling was used to calculate incident rates of new-onset AF. Multivariable-adjusted Cox proportional hazard models were used to evaluate the risk of adverse cardiovascular events (composite of myocardial infarction, non–myocardial infarction acute coronary syndrome, stroke, heart failure, or cardiovascular death). In 9327 participants, 8.45% had preexisting AF, and 1.65% had new-onset AF. The incidence of new-onset AF was 4.53 per 1000-person years, with similar rates in the standard and intensive treatment arms (4.95 versus 4.11 per 1000-person years; adjusted P =0.14). Participants with preexisting AF (adjusted hazard ratio, 1.83 [95% CI, 1.46–2.31]; P P P =0.001) compared with those with no AF. Intensive blood pressure control does not diminish the incidence of new-onset AF in an older, high-risk, nondiabetic population. Both preexisting and new-onset AF have adverse prognostic implications. In participants with preexisting AF, residual cardiovascular risk is evident even with on-treatment blood pressure Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

Atrial fibrillation (AF) is a common perioperative arrhythmia. However, its occurrence and implications remain poorly defined in the setting of noncardiac procedures. We sought to define the incidence, prevalence, and prognostic implications of AF among patients with atherosclerotic cardiovascular disease (ASCVD) undergoing noncardiac surgery. Using a previously validated approach that employed unique patient-linked variables in the New York State Inpatient Database from January 1, 2012, to December 31, 2014, the frequency of new-onset and pre-existing AF was determined in adults with ASCVD aged ≥18 years undergoing noncardiac surgery. The secondary outcomes were stroke within 1 month and all-cause mortality. Using multivariable logistic regression models, the factors and outcomes associated with new-onset AF after noncardiac surgery were assessed. Nine surgical subgroups of major noncardiac surgery served as exposure. A total of 184,775 patients were identified during the study period. Age ≥65, anemia, history of heart failure, valvular heart disease, and thoracic surgery were predictors of new-onset AF after noncardiac surgery. Among 3,806 patients (2.5%) developed new-onset AF and 31,603 (17.5%) patient had pre-existing AF. After multivariable-adjusted modeling, new-onset AF was associated with increased odds of stroke within 1 month (odds ratio: 1.31, 95% confidence interval: 1.12 to 1.53; p < 0.001)], mortality (odds ratio: 3.74; 95% confidence interval: 3.30 to 4.24; p < 0.001) and longer length of stay in the hospital (10 days; interquartile range: 6 to 16 days; p < 0.001). New-onset AF portends a poor prognosis in patients with ASCVD undergoing noncardiac surgeries. The risk profile of patients that develop new-onset AF differs across patient phenotypes and by surgical procedure.

Objective Recently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair. Methods To define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers. Results Lack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2−/− mice showed lower expression of lipoxygenases (−5, −12, −15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (−1 and −2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1β) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2−/− mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction. Conclusions Lack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation–resolution processes, obesogenic aging, and renal homeostasis., Highlights • Lack of resolution sensor (ALX/FPR2) led to spontaneous, age-related obesity. • Absence of ALX/FPR2 triggered obesogenic cardiomyopathy and renal inflammation. • Deficiency of ALX/FPR2 reduced SPMs in the infarcted heart after cardiac injury. • ALX/FPR2 dysfunction impaired macrophage function and amplified inflammation.

Background: Among patients receiving percutaneous coronary intervention (PCI), the role of a genotype-guided approach for antiplatelet therapy compared with usual care is unclear. We conducted a Bayesian analysis of the entire TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) randomized clinical trial population to evaluate the effect of the genotype-guided antiplatelet therapy post-PCI compared with the usual care on the risk of major adverse cardiovascular events (MACE). Methods: The primary outcome for our study was the composite of MACE (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included cardiovascular death, stroke, myocardial infarction, stent thrombosis, and major/minor bleeding. Bayesian modeling was used to estimate the probability of clinical benefit of genotype-guided therapy using (1) noninformative priors (ie, analyzing the TAILOR-PCI trial) and (2) informative priors derived from the ADAPT, POPular Genetics, IAC-PCI, and PHARMCLO trials (ie, analyzing TAILOR-PCI trial in the context of prior evidence). Risk ratio (RR: ratio of cumulative outcome incidence between genotype-guided and conventional therapy group) and 95% credible interval (CrI) were estimated for the study outcomes, and probability estimates for RR Results: Using noninformative priors, in TAILOR-PCI the RR for MACE was 0.78 (95% CrI, 0.55–1.07) in genotype-guided therapy after PCI, and the probability of RR Conclusions: Bayesian analysis of the TAILOR-PCI trial provides clinically meaningful data on the posterior probability of reducing MACE using genotype-guided P2Y 12 inhibitor therapy after PCI.

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) transitioned their recommendations for lipid management from an approach focused on “titration to goal low-density lipid cholesterol (LDL-C) level” to a “risk-based approach” ([1][1]). Following the

Variable propensity toward cardiovascular disease in the different ethnicities in the United States has been reported. We aimed to characterize the prevalence trends of cardiovascular health, as defined by the American Heart Association's Life's Simple 7 metrics, and cardiovascular diseases amongst Asian-Americans. We used the National Health and Examination Nutrition Survey from 2011 to 2016 to capture self-identified American-born Asian-Americans and foreign-born Asian-Americans. The prevalence trends of cardiovascular health metrics and diseases were evaluated in Asian-Americans and also compared between American-born and foreign-born Asian-Americans. Results were presented as weighted percentages and odds ratios with 95% confidence intervals. From 2011-2012 to 2015-2016, the prevalence of Asian-Americans reporting no physical activity increased from 21.5% to 32.4% (p for linear trend = 0.001) and the prevalence of Asian-American participants reporting a healthy diet decreased from 44.1% to 36.8% (p for quadratic trend = 0.02). There was a concomitant decline in the prevalence of Asian-Americans with normal weight (body mass index25 kg/m

Objective— Increased Lp(a) [lipoprotein(a)] is associated with coronary heart disease risk, but links with stroke are less consistent. Blacks have higher Lp(a) levels and stroke incidence than whites but have been underrepresented in studies. We hypothesized that Lp(a) is a risk factor for ischemic stroke and that risk differs by race. Approach and Results— REGARDS (Reasons for Geographic and Racial Differences in Stroke) recruited 30 239 black and white US adults aged ≥45 in 2003–2007 to study regional and racial differences in stroke mortality. We measured baseline Lp(a) by immunonephelometric assay in 572 cases of incident ischemic stroke and a 967-person cohort random sample. The hazard ratio of stroke by baseline Lp(a) was calculated using Cox proportional hazards models, stratified by race. Lp(a) was modeled in sex- and race-specific quartiles, given known differences in distributions by race and sex. Interactions were tested by including interaction terms in the proportional hazards models, with P P interaction=0.12. Lp(a) was lower in men than women, but associations with stroke in men and women were similar. Conclusions— We confirm that Lp(a) is a risk factor for ischemic stroke. Further research is needed to confirm the role of racial differences of the Lp(a) risk multiplier in ischemic stroke.

Background: A metabolic paradox of lower triglyceride (TG) and higher high-density lipoprotein cholesterol (HDL-C) levels but a higher incidence of diabetes has been described in Blacks. We evaluated the association of genetic ancestry-related variants with the risk of incident diabetes in self-identified Black individuals in the Systolic Blood Pressure (BP) Intervention Trial (SPRINT). Methods: The genetic European ancestry proportions were estimated using 106 biallelic genotype markers in non-diabetic Black participants. Participants were stratified into tertiles (T1-T3) of European ancestry proportions. Multivariable-adjusted association of baseline metabolic syndrome indices (fasting plasma glucose [FPG], TG, HDL-C, body mass index [BMI], and BP) with the ancestry proportion was assessed. Multivariable-adjusted Cox regression was used to assess the risk of incident diabetes (FPG ≥126 mg/dL or self-reported diabetes treatment) across tertiles. Results: In 2,466 participants with median European ancestry 19% (13 - 27%), those in T1 were relatively younger, with lower Framingham risk score, and worse renal function (p Conclusions: Genetic factors may account for racial differences in TG and HDL-C levels. The higher risk of incident diabetes in Blacks may similarly be genetically determined.

Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs‐CRP (high‐sensitivity C‐reactive protein), N‐terminal pro‐B‐type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25‐hydroxyvitamin‐D [25‐OH‐D] ≤25 ng/mL) receiving low‐dose (400 IU/d) versus high‐dose (4000 IU/d) vitamin D3 for 6 months. A meta‐analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25‐OH‐D increased in the high‐dose relative to the low‐dose vitamin D group (+15.5 versus +4.6 ng/mL, P P Conclusions In the DAYLIGHT randomized controlled trial, high‐dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation, or lipids. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01240512.

Background Obese patients have lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels. The prognostic implications of achieving NT‐proBNP levels ≤1000 pg/mL in obese patients with heart failure (HF) receiving biomarker‐guided therapy are not completely known. We evaluated the prognostic implications of obesity and having NT‐proBNP levels (≤1000 pg/mL) in the GUIDE‐IT (Guiding Evidence‐Based Therapy Using Biomarker‐Intensified Treatment in HF) trial participants. Methods and Results The risk of adverse cardiovascular events (HF hospitalization or cardiovascular mortality) was assessed using multivariable‐adjusted Cox proportional hazard models based on having NT‐proBNP ≤1000 pg/mL (taken as a time‐varying covariate), stratified by obesity status. The study outcome was also assessed on the basis of the body mass index at baseline. The predictive ability of NT‐proBNP for adverse cardiovascular events was assessed using the likelihood ratio test. Compared with nonobese patients, obese patients were mostly younger, Black race, and more likely to be women. NT‐proBNP levels were 59.0% (95% CI, 39.5%–83.5%) lower among obese individuals. The risk of adverse cardiovascular events was lower in obese (hazard ratio [HR], 0.48; 95% CI, 0.29–0.59) and nonobese (HR, 0.32; 95% CI, 0.19–0.57) patients with HF who had NT‐proBNP levels ≤1000 pg/mL, compared with those who did not. There was no interaction between obesity and having NT‐proBNP ≤1000 pg/mL on the study outcome ( P >0.10). Obese patients had a greater risk of developing adverse cardiovascular events (HR, 1.39; 95% CI, 1.01–1.90) compared with nonobese patients. NT‐proBNP was the strongest predictor of adverse cardiovascular event risk in both obese and nonobese patients. Conclusions On‐treatment NT‐proBNP level ≤1000 pg/mL has favorable prognostic implications, irrespective of obesity status. NT‐proBNP levels were the strongest predictor of cardiovascular events in both obese and nonobese individuals in this trial. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01685840.

Background Diurnal variation of natriuretic peptide (NP) levels and its relationship with 24-h blood pressure (BP) rhythm has not been established. Obese individuals have a relative NP deficiency and disturbed BP rhythmicity. Objectives This clinical trial evaluated the diurnal rhythmicity of NPs (B-type natriuretic peptide [BNP], mid-regional pro-atrial natriuretic peptide [MR-proANP], N-terminal pro–B-type natriuretic peptide [NT-proBNP]) and the relationship of NP rhythm with 24-h BP rhythm in healthy lean and obese individuals. Methods On the background of a standardized diet, healthy, normotensive, lean (body mass index 18.5 to 25 kg/m2) and obese (body mass index 30 to 45 kg/m2) individuals, age 18 to 40 years, underwent 24-h inpatient protocol involving ambulatory BP monitoring starting 24 h prior to the visit, controlled light intensity, and repeated blood draws for assessment of analytes. Cosinor analysis of normalized NP levels (normalized to 24-h mean value) was conducted to assess the diurnal NP rhythm and its relationship with systolic BP. Results Among 52 participants screened, 40 participants (18 lean, 22 obese; 50% women; 65% Black) completed the study. The median range spread (percentage difference between the minimum and maximum values) over 24 h for MR-proANP, BNP, and NT-proBNP levels was 72.0% (interquartile range [IQR]: 50.9% to 119.6%), 75.5% (IQR: 50.7% to 106.8%), and 135.0% (IQR: 66.3% to 270.4%), respectively. A cosine wave-shaped 24-h oscillation of normalized NP levels (BNP, MR-proANP, and NT-proBNP) was noted both in lean and obese individuals (prhythmicity Conclusions This human physiological trial elucidates evidence of diurnal NP rhythmicity and the presence of an NP-BP rhythm axis. There exists a misalignment of the NP-BP diurnal rhythm in the obese, which may contribute to the disturbed diurnal BP pattern observed among obese individuals. (The Diurnal Rhythm in Natriuretic Peptide Levels; NCT03834168 )

Background Increased pleural pressure affects the mechanics of breathing of people with class III obesity (BMI > 40 kg/m2). Research Question What are the acute effects of CPAP titrated to match pleural pressure on cardiopulmonary function in spontaneously breathing patients with class III obesity? Study design and Methods We enrolled six participants with BMI within normal range (control participants, group I) and 12 patients with class III obesity (group II) divided into subgroups: IIa, BMI of 40 to 50 kg/m2; and IIb, BMI of ≥ 50 kg/m2. The study was performed in two phases: in phase 1, participants were supine and breathing spontaneously at atmospheric pressure, and in phase 2, participants were supine and breathing with CPAP titrated to match their end-expiratory esophageal pressure in the absence of CPAP. Respiratory mechanics, esophageal pressure, and hemodynamic data were collected, and right heart function was evaluated by transthoracic echocardiography. Results The levels of CPAP titrated to match pleural pressure in group I, subgroup IIa, and subgroup IIb were 6 ± 2 cmH2O, 12 ± 3 cmH2O, and 18 ± 4 cmH2O, respectively. In both subgroups IIa and IIb, CPAP titrated to match pleural pressure decreased minute ventilation (IIa, P = .03; IIb, P = .03), improved peripheral oxygen saturation (IIa, P = .04; IIb, P = .02), improved homogeneity of tidal volume distribution between ventral and dorsal lung regions (IIa, P = .22; IIb, P = .03), and decreased work of breathing (IIa, P Interpretation In ambulatory patients with class III obesity, CPAP titrated to match pleural pressure decreased work of breathing and improved respiratory mechanics while maintaining hemodynamic stability, without impairing right heart function. Trial Registry ClinicalTrials.gov; No.: NCT02523352; URL: www.clinicaltrials.gov

Background: The prognostic implications of achieving NT-proBNP concentrations ≤1000 pg/mL among obese patients having heart failure with reduced ejection fraction (HFrEF) are not completely known. We evaluated the prognostic implications of body mass index (BMI), and achievement of target NT-proBNP levels of ≤1000 pg/mL in obese HF patients from the GUIDE-IT trial. Methods: Survival analysis using multivariable-adjusted Cox proportional hazard models was used to evaluate the risk of adverse cardiovascular (CV) events (HF hospitalization or CV mortality) based on the achievement of target NT-proBNP (≤1000 pg/mL), stratified by obesity status (obese [≥30 kg/m 2 ] and non-obese [2 ]). Achievement of NT-proBNP ≤1000 pg/mL was treated as a time-varying measure. We also assessed the risk of the study outcome stratified by baseline obesity status and across BMI quartiles, taking NT-proBNP as a time-varying covariate. Results: Compared to non-obese patients, obese patients were mostly younger, Black, females with 59% (95% CI: 39.5-83.5%) lower adjusted NT-proBNP levels. The risk of adverse CV outcomes was 55% lower in obese (HR: 0.45 [95% CI: 0.28-0.74]) and 70% lower in non-obese (HR: 0.30 [95% CI: 0.17-0.51]) HF patients who achieved the target NT-proBNP, compared to their counterparts who did not achieve the target NT-proBNP ( Figure 1 ). The was no interaction between obesity and achievement of target NT-proBNP on the study outcome (p>0.10). Obese patients at baseline had a greater risk of developing adverse CV events (HR: 1.52 [95% CI: 1.13-2.03]) compared to non-obese patients. Patients in the third (HR: 1.49 [95% CI: 1.03-2.17]) and fourth BMI quartile (HR: 2.04 [95% CI: 1.36-3.01]) had a higher risk of adverse CV events, compared to those in the first quartile. Conclusion: Achievement of NT-proBNP ≤1000 pg/mL has favorable prognostic implications irrespective of obesity status. Obese HF patients had a greater risk of adverse CV events than non-obese patients.

Background: Obese individuals have disturbed blood pressure (BP) rhythmicity and relative natriuretic peptide (NP) deficiency. The relationship of diurnal variation in NP levels and 24h BP rhythm is not known. Furthermore, mechanisms behind difference in circulating NPs in healthy obese and lean individuals has not been explored. We conducted a prospective clinical trial to evaluate 1) the diurnal rhythmicity of NPs and its relationship with 24-hour BP rhythm between healthy lean and obese individuals, and 2) elucidate mechanism behind NP deficiency in obese. Methods: Healthy, normotensive, lean (BMI:18.5-25 kg/m 2 ) and obese (BMI:30-45 kg/m 2 ) individuals aged 18-40 years, underwent 24-hour standardized inpatient protocol involving ambulatory BP monitoring (ABPM), controlled light intensity, and 10 blood draws, following 5-days of standardized diet. NP gene expression was evaluated in a cohort of 37 healthy donor heart tissues obtained from the MAGNet repository. Results: Among 52 participants screened, a total of 40 participants (18 lean; 22 obese) were enrolled. Diurnal variation in MRproANP levels was seen in both lean and obese individuals (p for rhythmicity=0.001). The mesor of the NP rhythm was 15% (8.5-21.6%) lower in obese. The diurnal variation in MRproANP was in antiphase with diurnal variation of systolic BP (pFigure ). Obese participants had lower 24h renin levels (p=0.06) and higher nocturnal sodium excretion (p=0.08). Among obese, there was lower expression of NP production genes ( NPPA, NPPB) (p, and higher expression of clearance gene ( NPR3 ) (p Conclusions: In a mechanistic human trial, we elucidate key neurohormonal differences in rhythm and evidence of poor salt handling in obese. Decreased production and increased clearance may contribute to the NP deficiency in obese. Targeting the diurnal NP-BP rhythm axis may reduce the cardiovascular risk burden, specifically in obese individuals.

Background: The 2017 American College of Cardiology/American Heart Association high blood pressure (BP) guidelines recommend risk assessment of atherosclerotic cardiovascular disease (CVD) to inform hypertension (HTN) treatment in adults with elevated BP or low-risk stage 1 HTN. Use of coronary artery calcium (CAC) score, an excellent imaging risk-prediction tool, to guide HTN therapy has not been well studied. Methods: Participants free of CVD were pooled from three population cohort studies; 1) Multiethnic Study of Atherosclerosis, 2) Coronary Artery Risk Development in Young Adults and 3) Jackson Heart Study. Risk for incident CVD events (heart failure, stroke or cardiovascular mortality) by the CAC status and the BP treatment group was assessed. Multivariable Cox proportional hazards models were used to estimate the hazard ratios. The 10-year number needed to treat to prevent a single CVD event was also estimated. Results: This study included 11,499 participants (mean age 56 years; 55.2% women; 42.1% blacks). CAC score was non-zero in 38.2% of the participants. Over a median follow-up of 8.5 years, 910 incident CVD events occurred. Compared to those with zero CAC, participants with non-zero CAC score had a higher CVD incidence rate (per 1000 person-years) at all BP levels (elevated BP/low-risk stage 1 HTN: 14.5 vs 2.7; high-risk stage 1 or stage 2 HTN: 27.1 vs 8.8). Multivariable adjusted hazards of adverse CVD events displayed similar patterns ( Figure ). Among those with zero CAC, the 10-year number needed to treat to prevent 1 CVD event was 154 for those with elevated BP/low-risk stage 1 HTN and 47 for those with high-risk stage 1 or stage 2 HTN. Among those with non-zero CAC score, the number needed to treat was lower, 33 and 18 respectively. Conclusions: Utilization of CAC score may be an effective precision medicine approach to personalize HTN therapy in elevated BP or low-risk stage 1 HTN when treatment is not recommended by the current guidelines.

NTproBNP ≤1000 has favorable prognostic implications in HF, but the prognosis is worse for Black patients at any level of achieved NTproBNP

Objective To investigate the relative predictive value of circulating immune cell markers for cardiovascular mortality in ambulatory adults without cardiovascular disease. Methods We analyzed data of participants enrolled in the National Health and Nutrition Examination Survey from January 1, 1999, to December 31, 2010, with the total leukocyte count within a normal range (4000-11,000 cells/μL [to convert to cells ×109/L, multiply by 0.001]) and without cardiovascular disease. The relative predictive value of circulating immune cell markers measured at enrollment—including total leukocyte count, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count, monocyte-lymphocyte ratio (MLR), neutrophil-lymphocyte ratio, and C-reactive protein—for cardiovascular mortality was evaluated. The marker with the best predictive value was added to the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to estimate net risk reclassification indices for 10-year cardiovascular mortality. Results Among 21,599 participants eligible for this analysis, the median age was 47 years (interquartile range, 34-63 years); 10,651 (49.2%) participants were women, and 10,713 (49.5%) were self-reported non-Hispanic white. During a median follow-up of 9.6 years (interquartile range, 6.8-13.1 years), there were 627 cardiovascular deaths. MLR had the best predictive value for cardiovascular mortality. The addition of elevated MLR (≥0.3) to the 10-year ASCVD risk score improved the classification by 2.7%±1.4% (P=.04). Elevated MLR had better predictive value than C-reactive protein and several components of the 10-year ASCVD risk score. Conclusion Among ambulatory US adults without preexisting cardiovascular disease, we found that MLR had the best predictive value for cardiovascular mortality among circulating immune markers. The addition of MLR to the 10-year risk score significantly improved the risk classification of participants.

OBJECTIVES: We sought to determine the frequency of unexpectedly low natriuretic peptide (NP) levels in a clinical population. BACKGROUND: Higher NP concentrations are typically observed as a compensatory response to elevated cardiac wall stress. Under these conditions, low NP levels may be indicative of a “NP deficiency.” METHODS: We identified 3 clinical scenarios in which high B-type natriuretic peptide (BNP) levels would be expected: (A) hospitalization for heart failure (HF), (B) abnormal cardiac structure or function, or (C) abnormal hemodynamics. In Vanderbilt’s electronic health record, 47,970 adult patients had BNP measurements. A total of 13,613 patients had at least one of the 3 conditions (hospitalized HF, n=9,153; abnormal cardiac structure/function, n=7,041; abnormal hemodynamics, n=363). We quantified the frequency of low BNP levels. We performed whole exome sequencing of the NPPB gene in a subset of 9 patients. RESULTS: Very low BNP levels (

Background Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m2] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. Methods In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012–2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015–2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. Results The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m2), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m2). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13–0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74). Conclusion Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Natriuretic peptides (NPs) are cardiac derived hormones that are secreted in response to increased wall stress, stretching of the myocardium, volume overload, and angiotensin II stimulation. The principal circulating NPs, atrial and B-type NP (ANP and BNP respectively) are released as precursor molecules (proANP and proBNP) which are processed to active components ANP and BNP, and inactive amino-terminal fragments NT-proANP and NT-proBNP (1).

BACKGROUND: Coronary chronic total occlusion (CTO) using percutaneous coronary intervention (PCI) presents a distinct challenge in the field of cardiology owing to multiple reasons including the increased risk of peri-procedural complications. We sought to explore rates of hospitalization, outcomes, use of mechanical circulatory support devices, and economic burden associated with single-vessel coronary CTO undergoing PCI for stable coronary artery disease (CAD). METHODS: The National Inpatient Sample spanning from 2008 through 2014 was queried to identify hospitalizations associated with single-vessel coronary CTO-PCI for stable CAD by excluding hospitalizations with ST-elevation and non-ST elevation myocardial infarction. Survey-Specific logistic regression was used to analyze adjusted incidence of in-hospital mortality and acute renal failure. RESULTS: A total of 109,094 hospitalizations were identified as having single-vessel coronary CTO-PCI for stable CAD from 2008–2014. An increasing number of coronary CTO-PCI hospitalizations (2,465 to 2,688 per 100,000 PCI procedures, P(trend)

Randomized controlled trials (RCTs) have shown fractional flow reserve-guided (FFR) multivessel stenting to be superior to infarct-related artery (IRA) only stenting in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease. This effect was mainly driven by a reduction in overall repeat revascularization. However, the ability to assess the effect of this strategy on urgent revascularization or reinfarction was underpowered in individual trials.We searched Pubmed, EMBASE, Cochrane CENTRAL, and Web of Science for RCTs of FFR-guided multivessel stenting versus IRA-only stenting in STEMI with multivessel disease. The outcomes of interest were death, reinfarction, urgent, and non-urgent repeat revascularization. Risk ratios (RR) were pooled using the DerSimonian and Laird random-effects model.After review of 786 citations, 2 RCTs were included. The pooled results demonstrated a significant reduction in the composite of death, reinfarction, or revascularization in the FFR-guided multivessel stenting group versus IRA-only stenting group (RR [95%, Confidence Interval]: 0.49 [0.33-0.72], p0.001). This risk reduction was driven mainly by a reduction in repeat revascularization, both urgent (0.41 [0.24-0.71], p=0.002) and non-urgent revascularization (0.31 [0.19-0.50], p0.001). Pooled RR for reinfarction was lower in the FFR-guided strategy, but was not statistically significant (0.71[0.39-1.31], p=0.28).This systematic review and meta-analysis suggests that a strategy of FFR-guided multivessel stenting in STEMI patients reduces not only overall repeat revascularization but also urgent revascularization. The effect on reinfarction needs to be evaluated in larger trials.

Background We sought to estimate the efficacy and safety outcomes of catheter-directed treatment (CDT) for patients with acute pulmonary embolism (PE). Methods We searched SCOPUS for studies reporting outcomes after CDT for acute PE. Studies were categorized in three groups for analyses due to heterogeneity in the classification of acute PE: 1) patients with PE causing right ventricular dysfunction and haemodynamic instability: unstable haemodynamic status, 2) patients with PE causing right ventricular dysfunction where study outcomes were not stratified by haemodynamic status: stable and unstable haemodynamic status, and 3) patients with PE causing right ventricular dysfunction who remained haemodynamically stable: stable haemodynamic status. Efficacy and safety outcomes were estimated and presented as point estimates with 95% confidence intervals. Results In 35 studies with 1253 patients, 1277 CDTs were performed. The in-hospital mortality rates for the unstable haemodynamic status, stable and unstable haemodynamic status, and stable haemodynamic status groups were 18.1% (7.3–38.2%), 7.1% (5.0–10.1%), and 2.6% (0.8–7.3%), respectively. The major bleeding rates across the groups were estimated to be 4.5, 8.5 and 3.9 per 100 CDTs, respectively. Minor bleeding occurred in 6.2, 11.9 and 9.1 per 100 CDTs, respectively. After CDT, all groups had improvements in mean pulmonary artery pressure and right ventricular function. Conclusions We provide descriptive measures of efficacy and safety for patients who underwent CDT for acute PE.

Rationale: Lower NP (natriuretic peptide) levels may contribute to the development of cardiometabolic diseases. Blacks have lower NP levels than middle-aged and older white adults. A high-carbohydrate challenge causes an upregulation of a negative ANP regulator microRNA-425 ( miR-425 ), which reduces ANP (atrial-NP) levels in whites. Objectives: We designed a prospective trial to study racial differences in (1) NP levels among young adults, (2) NP response to a high-carbohydrate challenge, and (3) explore underlying mechanisms for race-based differences. Methods and Results: Healthy self-identified blacks and whites received 3 days of study diet followed by a high-carbohydrate challenge. Gene expression from whole blood RNA was assessed in the trial participants. Additionally, atrial and ventricular tissue samples from the Myocardial Applied Genomics Network repository were examined for NP system gene expression. Among 72 healthy participants, we found that B-type-NP, NT-proBNP (N-terminal-pro-B-type NP), and MRproANP (midregional-pro-ANP) levels were 30%, 47%, and 18% lower in blacks compared with whites ( P ≤0.01), respectively. The decrease in MRproANP levels in response to a high-carbohydrate challenge differed by race (blacks 23% [95% CI, 19%–27%] versus whites 34% [95% CI, 31%–38]; P interaction NPPA/NPPB ) or NP signaling ( NPR1 ) in atrial and ventricular tissues. NP processing ( corin ), clearance ( NPR3 ), and regulation ( miR-425 ) genes were ≈3.5-, ≈2.5-, and ≈2-fold higher in blacks than whites in atrial tissues, respectively. We also found a 2-and 8-fold higher whole blood RNA expression of gene encoding for Neprilysin ( MME ) and miR-425 among blacks than whites. Conclusions: Racial differences in NP levels are evident in young, healthy adults suggesting a state of NP deficiency exists in blacks. Impaired NP processing and clearance may contribute to race-based NP differences. Higher miR-425 levels in blacks motivate additional studies to understand differences in NP downregulation after physiological perturbations. Clinical Trial Registration: URL: https://clinicaltrials.gov/ct2/show/NCT03072602 . Unique identifier: NCT03072602.

Background: Black individuals have lower N-terminal-pro-B-type natriuretic peptide (NTproBNP) levels than whites. Higher NTproBNP levels are associated with increased risk of incident heart failure (HF). Although, the ability of NTproBNP for risk stratification is variable in the setting of obesity and kidney disease. We studied the 1) association of NTproBNP with incident HF stratified by race and 2) tested the predictive ability across body mass index (BMI) and estimated glomerular filtration rate (eGFR) categories. Methods: Using a case-cohort design, NTproBNP levels were measured from the Reasons for Geographic And Racial Differences in Stroke study for 855 participants who subsequently developed incident HF and 3,680 randomly selected participants. Multivariable Cox proportional hazard modeling including all the factors which can affect NTproBNP levels was used to assess 1) the association of NTproBNP with incident HF; 2) interaction by race, and 3) predictive ability of NTproBNP based on percentage contribution in global Wald Chi-square score across BMI and eGFR categories. Results: The mean age of the random sub-cohort was 66.6 (12.1) years, 1,847 (50.2%) were females and 1,775 (48.2%) were blacks. The magnitude and strength of the relationship of NTproBNP with incident HF differed by race (p=0.01 for interaction). A doubling in NTproBNP levels was associated with greater risk of incident HF among whites [(hazard ratio (HR): 1.82; 95% CI: 1.62-2.04] compared with blacks (HR: 1.54; 95% CI: 1.35-1.75). NTproBNP remained a strong predictor (25%-50% Wald score) of incident HF across all BMI and eGFR categories in whites. However, among blacks with obesity (BMI ≥ 30 kg/m 2 ) and eGFR ≤60 mL/min/1.73 m 2 , NTproBNP was a weak predictor of incident HF (Figure ). Conclusions: Higher NTproBNP was more strongly associated with incident HF among whites compared with blacks. The predictive ability of NTproBNP levels with incident HF was preserved with obesity and impaired renal function among whites, but not in blacks.

The burden of cardiovascular events among patients hospitalized with severe sepsis and the association of these events with in-hospital mortality is not well known. We examined the incidence of cardiovascular events and their association with in-hospital mortality among patients with severe sepsis. Patients with severe sepsis from the New York State Inpatient Database from 2012 through 2014 were identified using a validated International Classification of Diseases 9th Revision, Clinical Modification code 995.92. The primary outcome was the incidence of cardiovascular events during the hospitalizations, defined as a composite of ischemic, acute heart failure, or arrhythmic events and the secondary outcome was in-hospital mortality. Multivariable logistic regression models were used to compare the risk of in-hospital mortality among severe sepsis patients with and without cardiovascular events. A total of 117,418 patients (mean age, 70.8 years; 50.4% males, 59.5% whites) with severe sepsis occurred during the study period 2012 to 2014. New-onset (incident) cardiovascular event occurred in 13.1%, ischemic events in 4.5%, acute heart failure events in 2.3%, and arrhythmic events in 8.0% of patients, respectively. An estimated 32.9% of patients with severe sepsis died during their hospitalization. Severe sepsis patients with new-onset cardiovascular events were associated with 30% higher odds for in-hospital mortality (odds ratio: 1.30; 95% CI: 1.23 to 1.37, p0.001) as compared with patients without cardiovascular events in multivariable adjusted model. In conclusion, among patients with severe sepsis, incident cardiovascular events occur frequently. Further research is required to improve recognition and treatment of new-onset cardiovascular events in patients with severe sepsis.

Background: Among patients receiving percutaneous coronary intervention (PCI), the role of a genotype-guided approach for antiplatelet therapy compared with usual care is unclear. We conducted a Ba...

Background The phenotypically heterogeneous syndrome of heart failure with preserved ejection fraction (HFpEF) is challenging to diagnose. The HFA-PEFF and H2FPEF scores were developed to guide HFpEF diagnosis but have not been directly compared. We evaluated the generalizability and prognostic implications of the two scores in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and PDE-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial participants and matched controls from Atherosclerosis Risk in Community (ARIC) study. Methods Participants from TOPCAT, RELAX, and ARIC studies were categorized as having low, intermediate, and high likelihood of HFpEF based on the respective scores. Diagnostic performance was evaluated using age, sex, and race matched controls, free of cardiovascular disease from ARIC study. Multivariable-adjusted Cox regression was used to assess the prognostic value of the scores. Results The median HFA-PEFF score in TOPCAT, RELAX and ARIC was 5.0 (IQR:5.0-6.0), 4.0 (IQR:2.0-4.0) and 3 (IQR:2.0-4.0), respectively. The median H2FPEF score in the three populations was 5.0 (IQR:4.0-7.0), 6.0 (IQR:4.0-7.0), and 2.5 (IQR:2.0-4.0), respectively. High HFA-PEFF scores were seen in 75.8%, 20.4%, and 16.5% of in the three populations, respectively. High H2FPEF scores were seen in 42.3%, 55.3%, and 1.9% of the three populations, respectively. Application of HFA-PEFF score categories to patients categorized using H2FPEF score led to 84.2% of TOPCAT, and 50.5% of RELAX participants being reclassified (Figure 1A,B). Using low HFA-PEFF and H2FPEF scores, HFpEF can be ruled-out with high sensitivity (99.5% and 99.9%, respectively) and high negative predictive value (95.7% and 98.5%, respectively). A high HFA-PEFF and H2FPEF score can rule-in HFpEF with good specificity (83.5% and 98.1%, respectively) and positive predictive value (80.6% and 95.5%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA-PEFF and H2FPEF score was 1.32 (95% CI: 1.03-1.69) and 1.03 (95% CI: 0.91-1.17), respectively (Figure 1 C,D). Conclusion The HFA-PEFF and the H2FPEF scores are reliable diagnostic tools for HFpEF. The scores also provide prognostic value for the risk stratification of HFpEF patients.

This study sought to determine the effect of intensive blood pressure (BP) control on the incidence of new-onset atrial fibrillation/flutter (AF) and to assess the prognostic implications of preexisting and new-onset AF in the randomized, multicenter Systolic Blood Pressure Intervention Trial (

Introduction The relationship between serum galectin-3 and incident cognitive impairment was analyzed in the Reasons for Geographic and Racial Differences in Stroke study. Methods Baseline galectin-3 was measured in 455 cases of incident cognitive impairment and 546 controls. Galectin-3 was divided into quartiles based on the weighted distribution in the control group, and the first quartile was the referent. Results There was an increasing odds of cognitive impairment across quartiles of galectin-3 (odds ratios, 1.00 [0.68–1.46], 1.45 [1.01–2.10], and 1.58 [1.10–2.27] relative to the quartile 1; P trend = .003) in an unadjusted model, which persisted after adjusting for age, sex, and race (P = .004). Adjustment for cardiovascular risk factors greatly attenuated this association (odds ratios, 0.97 [0.60–1.57], 1.52 [0.94–2.46], and 1.27 [0.76–2.12]; P = .15). The association differed by diabetes status (P interaction, .007). Among nondiabetics (293 cases, 411 controls), those with galectin-3 in the fourth compared with first quartile had an odds ratio of 1.6 (0.95–2.99; P trend, .02). In diabetics, the odds ratio was 0.23 (0.04–1.33). Discussion Serum galectin-3 was associated with increased risk of incident cognitive impairment in a large cohort study of blacks and whites but only in nondiabetics.

Background The effects of monthly, high‐dose, long‐term (≥1‐year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. Methods and Results A total of 517 adults (58% male, aged 50–84 years) were recruited into a double‐blinded, placebo‐controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9–1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000‐IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow‐up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25‐hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow‐up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (

We thank Nery et al for their insightful letter to our article.1 We alluded to the age and survival interaction with implantable cardioverter-defibrillator (ICD) use in patients with nonischemic cardiomyopathy (NICM) noted in the DANISH trial (Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure) in our article.1 We agree that similar trends have been observed in other trials.2 However, only 4 of 6 trials included in our meta-analysis (DEFINITE [Defibrillator in Nonischemic Cardiomyopathy Treatment Evaluation], COMPANION [Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure], SCD-HeFT [Sudden Cardiac Death in Heart Failure Trial], and DANISH)1 reported age-stratified outcomes. Two of the 4 trials, SCD-HeFT3 and COMPANION,4 reported outcomes for both ischemic and nonischemic patients, making age-stratified analysis in patients with NICM difficult in the absence of individual patient–level data. Nonetheless, we do agree that this should be recognized as one of the key limitations of the currently available data we have from the randomized controlled trials. In addition, all treatment decisions for ICD placement should be personalized and involve …

Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably alter the lipid profile. We sought to examine the rates of ischaemic stroke and neurocognitive deficits in patients treated with and without PCSK9 inhibitors. Methods and results Randomized controlled trials (RCTs) reporting rates of ischaemic stroke and neurocognitive deficits in patients using PCSK9 inhibitors were identified. Standard meta-analysis techniques were used to compare these outcomes among patients treated with and without PCSK9 inhibitors and the two US Food and Drug Administration-approved PCSK9 inhibitors, evolocumab and alirocumab. The results were presented in terms of risk ratio (RR) with 95% confidence intervals (CIs). Sixteen RCTs with 39 104 patients were included. Evolocumab was used in six RCTs with 33 450 patients, whereas alirocumab was used in 10 RCTs with 5654 patients. We observed a significantly lower risk of ischaemic stroke among those treated with PCSK9 inhibitors (RR 0.77, 95% CI 0.64-0.93) when compared with those without. We did not observe any difference in the risk of neurocognitive deficits between the aforementioned groups (RR 1.11, 95% CI 0.93-1.32). The lower stroke risk in the PCSK9 inhibitors group was driven by evolocumab studies. We observed no difference in the risk of neurocognitive deficits among evolocumab and alirocumab when compared with no PCSK9 inhibitors group. Conclusion Treatment with PCSK9 inhibitors significantly lowers the risk of ischaemic stroke, without any increased risk of neurocognitive deficits. PCSK9 inhibitors are neuroprotective due to the decrease in ischaemic-mediated neurovascular events and should be considered cognitively innocuous medications.

Background and purpose Galectin-3 is a biomarker of atherosclerotic and cardiovascular disease, and may be a useful marker for ischaemic stroke risk. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled and examined 30 239 US participants between 2003 and 2007 (41% black, 59% white and 55% in the southeastern stroke belt). Baseline galectin-3 was measured in 526 subjects with incident ischaemic stroke over 5.4 years and in a cohort random sample (CRS) of 947 participants. Cox proportional hazards models were used to calculate hazard ratios (HRs) of ischaemic stroke by quartiles of galectin-3. Results In the CRS, galectin-3 was significantly higher with older age, black race, female sex, body mass index, hypertension, diabetes mellitus and kidney disease, and also in those who developed incident stroke. Participants with galectin-3 levels in the fourth versus first quartile had a 2.3-fold increased stroke risk [95% confidence interval (CI) 1.6, 3.4] in an unadjusted model. An interaction with age was found (P = 0.06), and therefore age-stratified analyses were performed. Amongst those younger than age 64, baseline galectin-3 in the second–fourth quartiles was associated with increased stroke risk (HR 3.0, 95% CI 1.6, 5.5) compared to the first quartile in an age-, race- and sex-adjusted model. The HR was 2.0 (95% CI 1.0, 4.0) with multivariable adjustment. There was no association amongst older participants. Conclusions Galectin-3 was associated with incident ischaemic stroke in younger but not older individuals. Confirmation of this finding, and elucidation of its implications for stroke pathophysiology and prevention, is needed.

Aims The optimal revascularization strategy for left main coronary artery disease (LMD) remains controversial, especially with two recent randomized controlled trials showing conflicting results. We sought to address this controversy with our analysis. Methods and results Comprehensive literature search was performed. We compared percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for LMD revascularization using standard meta-analytic techniques. A 21% higher risk of long-term major adverse cardiac and cerebrovascular event [MACCE; composite of death, myocardial infarction (MI), stroke, and repeat revascularization] was observed in patients undergoing PCI in comparison with CABG [risk ratio (RR) 1.21, 95% confidence interval (CI) 1.05–1.40]. This risk was driven by higher rate of repeat revascularization in those undergoing PCI (RR 1.61, 95% CI 1.34–1.95). On the contrary, MACCE rates at 30 days were lower in PCI when compared with CABG (RR 0.55, 95% CI 0.39–0.76), which was driven by lower rates of stroke in the PCI arm (RR 0.41, 95% CI 0.17–0.98). At 1 year, lower stroke rates (RR 0.21, 95% CI 0.08–0.59) in the PCI arm were balanced by higher repeat revascularization rates in those undergoing PCI (RR 1.78, 95% CI 1.33–2.37), resulting in a clinical equipoise in MACCE rates between the two revascularization strategies. There was no difference in death or MI between PCI when compared with CABG at any time point. Conclusion Outcomes of CABG vs. PCI for LMD revascularization vary over time. Therefore, individualized decisions need to be made for LMD revascularization using the heart team approach.

The use of implantable cardioverter-defibrillators (ICDs) has been a major advancement in patients with ischemic cardiomyopathy with reduced ejection fraction 1100 patients with NICM on optimal medical therapy (OMT) and cardiac resynchronization therapy (CRT) to ICD versus no ICD for primary prevention of sudden cardiac death, revealed no difference in all-cause mortality between the 2 groups at 5-year follow-up.4 Although the primary results of DANISH were neutral, the ICD group showed reduction in incidence of sudden cardiac death by half, and there was an interaction …