Publications by authors named "Senthil Selvaraj"

72 Publications

Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs.

Mol Genet Genomic Med 2021 Jun 17:e1709. Epub 2021 Jun 17.

College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.

Background: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations.

Methods: Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives.

Results: In HCM, the analysis of 25 HCM-associated genes showed that 20% of HCM cases had putative pathogenic variants for cardiomyopathy, mainly in sarcomere genes. Additional 49% of HCM cases had variants of uncertain significance, while 31% of HCM cases had likely benign variant(s) or had no variants identified within the analyzed HCM genes. In DCM, 56 putative DCM genes were analyzed. Eight percent of DCM cases had putative pathogenic variants for DCM, in the TTN gene while 70% of cases had variants of uncertain significance, in the analyzed DCM genes, that will need further pathogenicity assessment. Moreover, 22% of DCM cases remain unexplained, by having likely benign variant(s) or having no variants detected in any of the analyzed DCM genes.

Conclusion: We identified or replicated at least four recurrent variants among cardiomyopathy patients, which could be founder disease mutations in the Arabic population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) of unknown significance in the FKTN gene which seems to cause DCM in homozygosity, and HCM in heterozygosity. In vivo and/or in vitro functional validation need to be pursued in order to assess the pathogenicity of the identified variants.
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http://dx.doi.org/10.1002/mgg3.1709DOI Listing
June 2021

Effects of Sacubitril/Valsartan on Serum Lipids in Heart Failure with Preserved Ejection Fraction.

J Am Heart Assoc 2021 May 16:e022069. Epub 2021 May 16.

Division of Cardiology Department of Medicine Brigham and Women's Hospital Boston MA.

Background Dyslipidemia is common in heart failure with preserved ejection fraction (HFpEF). Sacubitril/valsartan improves insulin sensitivity and augments natriuretic peptide (NP) signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4,744 participants from PARAGON-HF with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate (cGMP)/creatinine [a biomarker of NP activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (-6.6%, -3.5%), increased high-density lipoprotein cholesterol (HDL-c) +2.6% (+1.7%, +3.4%), and increased low-density lipoprotein cholesterol (LDL-c) +1.7% (+0.4%, +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (p-interaction<0.001), and at 16-weeks by -13.0% (-18.1%, -7.6%), or -29.9 (-44.3, -15.5) mg/dL, in this group. Adjusting for the change in urinary cGMP/creatinine significantly attenuated treatment effects on triglycerides and HDL-c, but not LDL-c, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was substantially stronger in those with elevated baseline triglycerides. Modest increases in HDL-c and LDL-c cholesterol were also observed with therapy. The underlying mechanism(s) of changes in HDL-c and triglycerides are related to sacubitril/valsartan's effects on NP activity.
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http://dx.doi.org/10.1161/JAHA.121.022069DOI Listing
May 2021

Incremental prognostic value of visually estimated coronary artery calcium in patients undergoing positron emission tomography imaging.

Open Heart 2021 May;8(1)

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Objective: Visually estimated coronary artery calcium (VECAC) from chest CT or attenuation correction (AC)/CT obtained during positron emission tomography (PET)-myocardial perfusion imaging (MPI) is feasible. Our aim was to determine the prognostic value of VECAC beyond conventional risk factors and PET imaging parameters, including coronary flow reserve (CFR).

Methods: We analysed 608 patients without known coronary artery disease who underwent PET-MPI between 2012 and 2016 and had AC/CT and/or chest CT images. We used Cox regression to estimate the association of VECAC categories (≤10, 11-400, >400 Agatston units (AU)) with the primary outcome of all-cause death, acute coronary syndrome or stroke (mean follow-up 4.3±1.8 years). C-statistics assessed the relationship between PET parameters and VECAC with the primary outcome.

Results: Mean age was 58±11 years, 65% were women and 67% were black. VECAC ≤10, 11-400 and >400 AU was observed in 68%, 12% and 20% of subjects, respectively. Compared with VECAC ≤10, VECAC categories 11-400 (HR 2.25, 95% CI 1.24 to 4.08) and >400 AU (HR 3.05, 95% CI 1.87 to 4.98) were associated with the primary outcome after adjusting for traditional risk factors, MPI findings and CFR. Adding VECAC to a model that included PET-MPI, CFR and clinical risk factors improved the prognostic value for the primary outcomes (c-statistic 0.71 to 0.75 with VECAC, p=0.01).

Conclusions: VECAC is a potent predictor of events beyond traditional risk factors and PET imaging markers, including CFR. These data further support the importance for routine VECAC implementation.
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http://dx.doi.org/10.1136/openhrt-2021-001648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108688PMC
May 2021

Atrial Fibrillation and Ischemic Stroke with the Amyloidogenic V122I Transthyretin Variant among Black Americans.

J Am Coll Cardiol 2021 Apr 19. Epub 2021 Apr 19.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2021.04.042DOI Listing
April 2021

Deconstructing the mouse olfactory percept through an ethological atlas.

Curr Biol 2021 Apr 29. Epub 2021 Apr 29.

Sidra Medicine, PO Box 26999, Doha, Qatar; Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar. Electronic address:

Odor perception in non-humans is poorly understood. Here, we generated the most comprehensive mouse olfactory ethological atlas to date, consisting of behavioral responses to a diverse panel of 73 odorants, including 12 at multiple concentrations. These data revealed that mouse behavior is incredibly diverse and changes in response to odorant identity and concentration. Using only behavioral responses observed in other mice, we could predict which of two odorants was presented to a held-out mouse 82% of the time. Considering all 73 possible odorants, we could uniquely identify the target odorant from behavior on the first try 20% of the time and 46% within five attempts. Although mouse behavior is difficult to predict from human perception, they share three fundamental properties: first, odor valence parameters explained the highest variance of olfactory perception. Second, physicochemical properties of odorants can be used to predict the olfactory percept. Third, odorant concentration quantitatively and qualitatively impacts olfactory perception. These results increase our understanding of mouse olfactory behavior and how it compares to human odor perception and provide a template for future comparative studies of olfactory percepts among species.
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http://dx.doi.org/10.1016/j.cub.2021.04.020DOI Listing
April 2021

Management of hypertension in heart failure with preserved ejection fraction: is there a blood pressure goal?

Curr Opin Cardiol 2021 Jul;36(4):413-419

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Purpose Of Review: Hypertension remains a leading risk factor for heart failure with preserved ejection fraction (HFpEF), and elevated blood pressure (BP) portends an adverse prognosis in patients with established HFpEF. We summarize current evidence for mechanisms linking hypertension to HFpEF and management of hypertension in HFpEF.

Recent Findings: Data suggest a complex, multifactorial pathophysiology driving the association between hypertension and HFpEF, including left ventricular hypertrophy, diastolic dysfunction, atrial dysfunction, coronary microvascular disease, endothelial dysfunction, myocardial injury and fibrosis. Although intensive BP control may attenuate these processes, this hypothesis has not been tested on clinical outcomes in a dedicated randomized controlled trial (RCT) in HFpEF. Antihypertensive therapies variably improve key surrogate markers in HFpEF, though BP reduction generally does not account for these benefits. Accordingly, BP targets are extrapolated from observational studies and RCTs testing heart failure therapies that affect BP in addition to dedicated RCT data in patients at elevated risk (without heart failure).

Summary: Clinicians should recognize the risk of disease progression and poor outcomes associated with uncontrolled hypertension in HFpEF. Intensive BP control, preferably by therapies known to improve outcomes in heart failure, may slow key pathways in disease progression. Future RCTs testing intensified BP control strategies in HFpEF are warranted.
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http://dx.doi.org/10.1097/HCO.0000000000000852DOI Listing
July 2021

Cardiopulmonary transit time: Reinforcing the case for positron emission tomography after heart transplantation.

J Nucl Cardiol 2021 Feb 1. Epub 2021 Feb 1.

Division of Cardiovascular Medicine, Department of Medicine, Univeresity of Pennsylvania Perelman School of Medicine, 11-103, Smilow Center for Translational Research, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.

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http://dx.doi.org/10.1007/s12350-020-02514-5DOI Listing
February 2021

Performance Comparison of Advanced Ceramic Cladding Approaches via Solid-State and Traditional Welding Processes: A Review.

Materials (Basel) 2020 Dec 19;13(24). Epub 2020 Dec 19.

Department of Mechanical and Electromechanical Engineering, National ILan University, Yilan City 26047, Yilan County, Taiwan.

Ceramic coating has applications in enhancing the material's properties and can significantly improve the material's usability in varied temperatures and adverse operating conditions and widen its applicability scope. It can add to the various properties such as wear resistance, high-temperature degradation, thermal conductivity, material toughness, tensile strength, corrosion resistance, friction reduction, electric insulation, and the lifespan of the material. Various techniques have been suggested and implemented to achieve ceramic coating on a metal surface, each having their respective advantages and disadvantages. Hence, they can be distinguished for their applicability in different places. The bonding mechanism of metal particle systems has been researched to date, but there are still certain uncertainties regarding the ceramic particle system because of the dissimilarities in properties. The paper aims to profoundly investigate the various coating technologies available through welding processes and do a comparative study through numerical analysis and experimental results on the properties of coatings obtained from two broad categories of welding-solid-state and traditional/fusion processes. It was found that the solid-state processes in which the temperature remained well below the fusion temperatures overcame the mismatch in property and produced reliable coatings with enhanced mechanical properties.
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http://dx.doi.org/10.3390/ma13245805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766675PMC
December 2020

Potential Cardiovascular Applications of Total-body PET Imaging.

PET Clin 2021 Jan;16(1):129-136

Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Cardiothoracic Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Cardiovascular conditions can exist as part of a systemic disorder (eg, sarcoidosis, amyloidosis, or vasculitis) or have systemic consequences as a result of the cardiovascular insult (eg, myocardial infarction). In other circumstances, multisystem evaluation of metabolism and blood flow might be key for evaluation of multisystemic syndromes or conditions. Long axial field-of-view PET/computed tomography systems hold the promise of transforming the investigation of such systemic disorders. This article aims at reviewing some of the potential cardiovascular applications of this novel instrumentation device.
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http://dx.doi.org/10.1016/j.cpet.2020.09.004DOI Listing
January 2021

Diagnostic accuracy of SPECT and PET myocardial perfusion imaging in patients with left bundle branch block or ventricular-paced rhythm.

J Nucl Cardiol 2020 Oct 20. Epub 2020 Oct 20.

Division of Cardiology, Department of Medicine, Hospital of the University of Pennsylvania, 3400 Civic Center Blvd, 11-154 South Pavilion, Philadelphia, PA, 19104, USA.

Background: The difference in diagnostic accuracy of coronary artery disease (CAD) between vasodilator SPECT and PET myocardial perfusion imaging (MPI) in patients with left bundle branch block (LBBB) or ventricular-paced rhythm (VPR) is unknown.

Methods: We identified patients with LBBB or VPR who underwent either vasodilator SPECT or PET MPI and subsequent coronary angiography. LBBB/VPR-related septal and anteroseptal defects were defined as perfusion defects involving those regions in the absence of obstructive CAD in the left anterior descending artery or left main coronary artery.

Results: Of the 55 patients who underwent coronary angiography, 38 (69%) underwent SPECT and 17 patients (31%) underwent PET. PET compared to SPECT demonstrated higher sensitivity (88% vs 60%), specificity (56% vs 14%), positive predictive value (64% vs 20%), negative predictive value (83% vs 50%), and overall superior diagnostic accuracy (AUC .72 (95% CI .50-.93) vs .37 (95% CI .20-.54), P = .01) to detect obstructive CAD. LBBB/VPR-related septal and anteroseptal defects were more common with SPECT compared to PET (septal: 72% vs 17%, P = .001; anteroseptal: 47% vs 8%, P = .02).

Conclusions: PET has higher diagnostic accuracy when compared to SPECT for the detection of obstructive CAD in patients with LBBB or VPR.
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http://dx.doi.org/10.1007/s12350-020-02398-5DOI Listing
October 2020

Exogenous ketones in the healthy heart: the plot thickens.

Cardiovasc Res 2021 Mar;117(4):995-996

Division of Cardiovascular Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1093/cvr/cvaa283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983004PMC
March 2021

Body Composition, Natriuretic Peptides, and Adverse Outcomes in Heart Failure With Preserved and Reduced Ejection Fraction.

JACC Cardiovasc Imaging 2021 01 16;14(1):203-215. Epub 2020 Sep 16.

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA. Electronic address:

Objectives: The purpose of this study was to determine the relationship between body composition, N-terminal B-type natriuretic peptide (NT-proBNP) levels, and heart failure (HF) phenotypes and outcomes.

Background: Abnormalities in body composition can influence metabolic dysfunction and HF severity; however, data assessing fat distribution and skeletal muscle (SM) size in HF with reduced (HFrEF) and preserved EF (HFpEF) are limited. Further, whether NPs relate more closely to axial muscle mass than measures of adiposity is not well studied.

Methods: We studied 572 adults without HF (n = 367), with HFrEF (n = 113), or with HFpEF (n = 92). Cardiac magnetic resonance was used to assess subcutaneous and visceral abdominal fat, paracardial fat, and axial SM size. We measured NT-proBNP in 334 participants. We used Cox regression to analyze the relationship between body composition and mortality.

Results: Compared with controls, pericardial and subcutaneous fat thickness were significantly increased in HFpEF, whereas patients with HFrEF had reduced axial SM size after adjusting for age, sex, race, and body height (p < 0.05 for comparisons). Lower axial SM size, but not fat, was significantly predictive of death in unadjusted (standardized hazard ratio: 0.63; p < 0.0001) and multivariable-adjusted analyses (standardized hazard ratio = 0.72; p = 0.0007). NT-proBNP levels more closely related to lower axial SM rather than fat distribution or body mass index (BMI) in network analysis, and when simultaneously assessed, only SM (p = 0.0002) but not BMI (p = 0.18) was associated with NT-proBNP. However, both NT-proBNP and axial SM mass were independently predictive of death (p < 0.05).

Conclusions: HFpEF and HFrEF have distinct abnormalities in body composition. Reduced axial SM, but not fat, independently predicts mortality. Greater axial SM more closely associates with lower NT-proBNP rather than adiposity. Lower NT-proBNP levels in HFpEF compared with HFrEF relate more closely to muscle mass rather than obesity.
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http://dx.doi.org/10.1016/j.jcmg.2020.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796896PMC
January 2021

Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

Eur J Heart Fail 2020 11 30;22(11):2093-2101. Epub 2020 Sep 30.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Aims: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies.

Methods And Results: We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA.

Conclusions: Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.
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http://dx.doi.org/10.1002/ejhf.1984DOI Listing
November 2020

The Landscape of Cardiovascular Clinical Trials in the United States Initiated Before and During COVID-19.

J Am Heart Assoc 2020 09 27;9(18):e018274. Epub 2020 Jul 27.

Brigham and Women's Hospital Heart & Vascular Center Harvard Medical School Boston MA.

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http://dx.doi.org/10.1161/JAHA.120.018274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726978PMC
September 2020

Application of Diagnostic Algorithms for Heart Failure With Preserved Ejection Fraction to the Community.

JACC Heart Fail 2020 08 10;8(8):640-653. Epub 2020 Jun 10.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Objectives: This study sought to describe characteristics and risk of adverse outcomes associated with the HFPEF and HFA-PEFF scores among participants in the community with unexplained dyspnea.

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) can be challenging. The HFPEF and HFA-PEFF scores have recently been developed to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea.

Methods: The study included 4,892 ARIC (Atherosclerosis Risk In Communities) study participants 67 to 90 years of age at visit 5 (2011 to 2013) without other common cardiopulmonary causes of dyspnea. Participants were categorized as asymptomatic (76.6%), having known HFpEF (10.3%), and having tertiles of each score among those with ≥moderate, self-reported dyspnea (13.1%). The primary outcome was heart failure (HF) hospitalization or death.

Results: Mean age was 75 ± 5 years, 58% were women, and 22% were black. After a mean follow-up of 5.3 ± 1.2 years, rates of HF hospitalization or death per 1,000 person-years for asymptomatic and known HFpEF were 20.7 (95% confidence interval [CI]: 18.9 to 22.7) and 71.6 (95% CI: 61.6 to 83.3), respectively. Among 641 participants with unexplained dyspnea, rates were 27.7 (95% CI: 18.2 to 42.1), 44.9 (95% CI: 34.9 to 57.7), and 47.3 (95% CI: 36.5 to 61.3) (tertiles of HFPEF score) and 31.8 (95% CI: 20.3 to 49.9), 32.4 (95% CI: 23.4 to 44.9), and 54.3 (95% CI: 43.8 to 67.3) (tertiles of HFA-PEFF score). Participants with unexplained dyspnea and scores above the diagnostic threshold suggested for each algorithm, HFPEF score ≥6 and HFA-PEFF score ≥5, had equivalent risk of HF hospitalization or death compared with known HFpEF. Among those with unexplained dyspnea, 28% had "discordant" findings (only high risk by 1 algorithm), while 4% were high risk by both.

Conclusions: Participants with unexplained dyspnea and higher HFPEF or HFA-PEFF scores face substantial risks of HF hospitalization or death. A significant fraction of patients are classified discordantly by using both algorithms.
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http://dx.doi.org/10.1016/j.jchf.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030634PMC
August 2020

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure.

Circulation 2020 06 1;141(22):1800-1812. Epub 2020 Jun 1.

Division of Cardiovascular Medicine, Department of Medicine (S.S., K.B.M.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304522PMC
June 2020

Systolic Blood Pressure in Heart Failure With Preserved Ejection Fraction Treated With Sacubitril/Valsartan.

J Am Coll Cardiol 2020 04 16;75(14):1644-1656. Epub 2020 Mar 16.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Background: Guidelines recommend targeting systolic blood pressure (SBP) <130 mm Hg in heart failure with preserved ejection fraction (HFpEF) with limited data.

Objectives: This study sought to determine the optimal achieved SBP and whether the treatment effects of sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from sacubitril/valsartan.

Methods: Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles (<120, 120 to 129, 130 to 139, ≥140 mm Hg) to the primary outcome (cardiovascular death and total heart failure hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 16-week visit, the study assessed the relationship between SBP change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The study analyzed whether the BP-lowering effects of sacubitril/valsartan accounted for its treatment effects.

Results: Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p < 0.001) but not KCCQ-OSS (p = 0.40). The association between sacubitril/valsartan and the primary outcome was not modified by baseline SBP (interaction p = 0.50) and was similar when adjusting for time-updated SBP, regardless of sex.

Conclusions: Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of sacubitril/valsartan, and the BP-lowering effects of sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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http://dx.doi.org/10.1016/j.jacc.2020.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109279PMC
April 2020

Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients With Heart Failure and Reduced Ejection Fraction: PARADIGM-HF.

Circulation 2019 10 12;140(17):1369-1379. Epub 2019 Sep 12.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., E.F.L, M.V., S.D.S.).

Background: The contemporary prognostic value of the physical examination- beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms-in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion.

Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up and whether improvement in congestion is related to changes in clinical outcomes and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores.

Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores (<0.05). After adjusting for baseline natriuretic peptides, time-updated Meta-Analysis Global Group in Chronic Heart Failure score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than did enalapril (=0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7-5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (<0.001).

Conclusions: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality.

Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039920DOI Listing
October 2019

Walking pace is inversely associated with risk of death and cardiovascular disease: The Physicians' Health Study.

Atherosclerosis 2019 10 16;289:51-56. Epub 2019 Aug 16.

Boston Veterans Affairs Healthcare System, 150 S Huntington Ave, Boston, MA, 02130, USA; Department of Medicine, Division of Aging, Brigham and Women's Hospital, Harvard Medical School, 1620 Tremont St, Boston, MA, 02120, USA.

Background: Walking pace is increasingly being used to assess functional status in ambulatory settings.

Methods: We conducted a prospective analysis within the Physicians' Health Study to examine whether walking pace is associated with mortality and incident cardiovascular disease (fatal or nonfatal myocardial infarction, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty). Participants included 21,919 male physicians with a mean age of 67.8 ± 9.0 years.

Results: After a median follow-up of 9.4 years (IQR: 7.9-10.3), 3906 deaths and 2487 incident CVD events occurred. In a multivariable Cox proportional hazards model adjusting for age, body mass index, smoking, exercise frequency, and prevalent hypertension, diabetes mellitus, heart failure, peripheral vascular disease, cancer, and total weekly walking time, hazard ratios for mortality were 0.72 (95% CI: 0.64-0.81) for walking pace of 2-2.9mph, 0.63 (95% CI: 0.55-0.73) for walking pace of 3-3.9mph and 0.63 (95% CI: 0.48-0.83) for walking pace of ≥4mph compared to the group that reported not walking regularly (p trend <0.0001). Similar findings were observed for incident CVD: HRs were 0.88 (95% CI: 0.75-1.03) for a walking pace of 2-2.9mph, 0.75 (95% CI: 0.63-0.89) for a walking pace of 3-3.9mph and 0.70 (0.53-0.94) for a walking pace of ≥4mph compared to the group that reported not walking regularly (p trend 0.0001). These associations persisted after excluding those who exercised regularly.

Conclusion: We found that walking pace is inversely associated with risk of mortality and CVD among US male physicians.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743067PMC
October 2019

Utility of the Cardiovascular Physical Examination and Impact of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2019 07 21;12(7):e006125. Epub 2019 Jun 21.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., E.F.L., M.V., S.Y.W., M.A.P., S.D.S.).

Background: The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known.

Methods And Results: We studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses. We evaluated whether spironolactone improved congestion at 4 months and whether improvement in congestion was related to quality of life as assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores and to outcomes. Among 1644 participants, 22%, 54%, 20%, and 4% had 0, 1, 2, and 3 signs of congestion, respectively, at baseline. After multivariable adjustment, each additional increase in sign of congestion was associated with a 30% to 60% increased risk of each outcome ( P<0.001). Spironolactone reduced the total number of signs of congestion by -0.10 ( P=0.005) signs, jugular venous distention (odds ratio, 0.60; P=0.01), and edema (odds ratio, 0.74; P=0.006) at 4 months compared with placebo. Each reduction in sign of congestion was independently associated with a 4.0 (95% CI, 2.4-5.6) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score. When assessed simultaneously, time-updated, but not baseline congestion, predicted outcomes.

Conclusions: In heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes. Spironolactone improved congestion compared with placebo. Reducing congestion was independently associated with improved quality of life and outcomes and is a modifiable risk factor.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686863PMC
July 2019

Axial Muscle Size as a Strong Predictor of Death in Subjects With and Without Heart Failure.

J Am Heart Assoc 2019 02;8(4):e010554

1 Hospital of the University of Pennsylvania Philadelphia PA.

Background The impact of skeletal muscle size, quantified using simple noninvasive images routinely obtained during cardiac magnetic resonance imaging studies on mortality in the heart failure ( HF ) population is currently unknown. Methods and Results We prospectively enrolled 567 subjects without HF (n=364), with HF with reduced ejection fraction (n=111), or with HF with preserved ejection fraction (n=92), who underwent a cardiac magnetic resonance imaging. Skeletal muscle cross-sectional area was assessed with manual tracing of major thoracic muscle groups on axial chest magnetic resonance images. Factor analysis was used to identify a latent factor underlying the shared variability in thoracic muscle cross-sectional area. Cox regression was used to assess the relationship between these measurements and all-cause mortality (median follow up, 36.4 months). A higher overall thoracic muscle area factor assessed with principal component analysis was independently associated with lower mortality (standardized hazard ratio, 0.51; P<0.0001). The thoracic muscle area factor was predictive of death in subjects with HF with preserved ejection fraction, HF with reduced ejection fraction, and those without HF . Among all muscle groups, the pectoralis major cross-sectional area was the most representative of overall muscle area and was also the most robust predictor of death. A higher pectoralis major cross-sectional area predicted a lower mortality (standardized hazard ratio, 0.49; P<0.0001), which persisted after adjustment for various confounders (standardized hazard ratio, 0.55; P=0.0017). Conclusions Axial muscle size, and in particular smaller size of the pectoralis major, is independently associated with higher risk of mortality in patients with and without HF . Further work should clarify the role of muscle wasting as a therapeutic target in patients with HF .
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http://dx.doi.org/10.1161/JAHA.118.010554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405649PMC
February 2019

HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study.

Hypertension 2019 01;73(1):68-74

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (S. Seidelmann, O.M.S., B.C., S.C., M.M.F.-S., A.M.S., S.D.S.).

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure ( P=0.004), diastolic blood pressure (0.012), and more frequently had hypertension ( P<0.001). Compared with WT/WT, H63D/WT and H63D/H63D participants had a 2% to 4% and 4% to 7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45 to 64 was 3.2% (95% CI, 1.3-5.1%) and 1.3% (95% CI, 0.0-2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome ( P>0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11730DOI Listing
January 2019

Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2018 11;11(11):e005288

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., E.F.L., M.A.P., S.D.S.).

Background: Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction.

Methods And Results: We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline. We examined the association of UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and its individual components, all-cause mortality, and several safety end points using multivariable-adjusted Cox regression. We evaluated whether spironolactone reduced albuminuria at the 1-year visit in a subpopulation (N=744). Thirty-five percent had microalbuminuria, 13% had macroalbuminuria, and 80% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Increasing UACR was associated with male sex, higher systolic blood pressure, diabetes mellitus, and renal dysfunction. Macroalbuminuria (hazard ratio, 1.67; 95% CI, 1.22-2.28) and microalbuminuria (hazard ratio, 1.47; 95% CI, 1.15-1.86) were independently associated with the TOPCAT primary end point (compared with normoalbuminuria). Adjusting for placebo response, spironolactone reduced albuminuria by 39% in all participants at the 1-year visit compared with baseline (geometric mean ratio, 0.61; 95% CI, 0.49-0.77) and by 76% (geometric mean ratio, 0.24; 95% CI, 0.10-0.56) among those with macroalbuminuria. Reducing UACR by 50% was independently associated with a reduction in heart failure hospitalization (hazard ratio, 0.90; P=0.017) and all-cause mortality (hazard ratio, 0.91; P=0.019). The change in UACR was significantly associated with change in systolic blood pressure ( P=0.001).

Conclusions: In TOPCAT, albuminuria was independently associated with worse cardiovascular outcomes. Spironolactone significantly reduced albuminuria compared with placebo. Reducing albuminuria was independently associated with improved outcomes.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594383PMC
November 2018

Lack of Association Between Anemia and Intrinsic Left Ventricular Diastolic Function or Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction.

Am J Cardiol 2018 10 19;122(8):1359-1365. Epub 2018 Jul 19.

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Anemia is associated with a poor prognosis in heart failure with preserved ejection fraction (HFpEF), but the reasons underlying this association are unclear. Previous studies have reported an association between anemia and diastolic dysfunction. However, these studies used volume- and flow-dependent indexes of diastolic dysfunction. We hypothesized that in HFpEF, anemia is more closely associated with volume status and not markers of intrinsic myocardial dysfunction. We prospectively studied 419 outpatients in a systematic HFpEF program, all of whom underwent hemoglobin measurement and comprehensive echocardiography. Longitudinal, radial, and circumferential strain were also measured in 311 patients. We defined anemia as hemoglobin <12g/dL in women and <13g/dL in men. Linear and Cox regression analyses were used to determine the association between anemia and echocardiographic/strain variables and adverse outcomes, respectively. Over half (224/419 [53%]) of the HFpEF patients had anemia. Anemia was associated with volume (preload)-dependent markers of diastolic dysfunction including echocardiographic E/A (p = 0.004) and E/e' ratio (p = 0.014) and elevated right heart pressures such as right atrial pressure (p = 0.002) and pulmonary artery systolic pressure (p<0.001). Anemia was not associated with markers of intrinsic myocardial dysfunction such as lateral e' (p = 0.16) and septal e' (p = 0.65) velocities or echocardiographic strain parameters (p > 0.05 for all comparisons). Anemia was associated with the combined outcome of cardiovascular hospitalization or death (hazard ratio = 1.50 [95% confidence interval 1.20, 1.88]; p < 0.001). In conclusion, anemia in HFpEF is associated with markers of volume status and not intrinsic markers of myocardial dysfunction.
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http://dx.doi.org/10.1016/j.amjcard.2018.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195843PMC
October 2018

MPP decreases store-operated calcium entry and TRPC1 expression in Mesenchymal Stem Cell derived dopaminergic neurons.

Sci Rep 2018 08 6;8(1):11715. Epub 2018 Aug 6.

Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.

Parkinson's disease is a neurodegenerative disorder involving the progressive loss of dopaminergic neurons (DNs), with currently available therapeutics, such as L-Dopa, only able to relieve some symptoms. Stem cell replacement is an attractive therapeutic option for PD patients, and DNs derived by differentiating patient specific stem cells under defined in-vitro conditions may present a viable opportunity to replace dying neurons. We adopted a previously published approach to differentiate Mesenchymal Stem Cells (MSCs) into DN using a 12-day protocol involving FGF-2, bFGF, SHH ligand and BDNF. While MSC-derived DNs have been characterized for neuronal markers and electrophysiological properties, we investigated store-operated calcium entry (SOCE) mechanisms of these DNs under normal conditions, and upon exposure to environmental neurotoxin, 1-methyl, 4-phenyl pyridinium ion (MPP). Overall, we show that MSC-derived DNs are functional with regard to SOCE mechanisms, and MPP exposure dysregulates calcium signaling, making them vulnerable to neurodegeneration. Since in-vitro differentiation of MSCs into DNs is an important vehicle for PD disease modeling and regenerative medicine, the results of this study may help with understanding of the pathological mechanisms underlying PD.
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http://dx.doi.org/10.1038/s41598-018-29528-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079049PMC
August 2018

Clinical correlates and heritability of cardiac mechanics: The HyperGEN study.

Int J Cardiol 2019 Jan 11;274:208-213. Epub 2018 Jul 11.

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States. Electronic address:

Background: Indices of cardiac mechanics are sensitive markers of subclinical myocardial dysfunction. Improved understanding of the clinical correlates and heritability of cardiac mechanics could result in novel insight into the acquired and genetic risk factors for myocardial dysfunction. Therefore, we sought to determine the clinical correlates and heritability of indices of cardiac mechanics in whites and African Americans (AAs).

Methods: We examined 2058 participants stratified by race (1104 whites, 954 AA) in the Hypertension Genetic Epidemiology Network (HyperGEN), a population- and family-based study, and performed digitization of analog echocardiograms with subsequent speckle-tracking analysis. We used linear mixed effects models to determine the clinical correlates of indices of cardiac mechanics (longitudinal, circumferential, radial strain; early diastolic strain rate; and early diastolic tissue velocities). Heritability estimates for cardiac mechanics were calculated using maximum-likelihood variance component analyses in Sequential Oligogenic Linkage Analysis Routine (SOLAR), with adjustment for clinical and echocardiographic covariates.

Results: Several clinical characteristics and conventional echocardiographic parameters were found to be associated with speckle-tracking traits of cardiac mechanics. Male sex, blood pressure, and fasting glucose were associated with worse longitudinal strain (LS) (P < 0.05 for all) after multivariable adjustment. After adjustment for covariates, LS, e' velocity, and early diastolic strain rate were found to be heritable; LS and e' velocity had higher heritability estimates in AAs compared to whites.

Conclusions: Indices of cardiac mechanics are heritable traits even after adjustment for clinical and conventional echocardiographic correlates. These findings provide the basis for future studies of genetic determinants of these traits that may elucidate race-based differences in heart failure development.
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http://dx.doi.org/10.1016/j.ijcard.2018.07.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242726PMC
January 2019

Lack of Association Between Heart Failure and Incident Cancer.

J Am Coll Cardiol 2018 04;71(14):1501-1510

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Several recent studies have suggested an increased cancer risk among patients with heart failure (HF). However, these studies are constrained by limited size and follow-up, lack of comprehensive data on other health attributes, and adjudicated cancer outcomes.

Objectives: This study sought to determine whether HF is associated with cancer incidence and cancer-specific mortality.

Methods: The study assembled a cohort from the Physicians' Health Studies I and II, 2 randomized controlled trials of aspirin and vitamin supplements conducted from 1982 to 1995 and from 1997 to 2011, respectively, that included annual health evaluations and determination of cancer and HF diagnoses. In the primary analysis, the study excluded participants with cancer or HF at baseline and performed multivariable-adjusted Cox models to determine the relationship between HF and cancer, modeling HF as a time-varying exposure. In a complementary analysis, the study used the landmark method and identified cancer-free participants at 70 years of age, distinguishing between those with and without HF, and likewise performed Cox regression. Sensitivity analyses were performed at 65, 75, and 80 years of age.

Results: Among 28,341 Physicians' Health Study participants, 1,420 developed HF. A total of 7,363 cancers developed during a median follow-up time of 19.9 years (25th to 75th percentile: 11.0 to 26.8 years). HF was not associated with cancer incidence in crude (hazard ratio: 0.92; 95% confidence interval: 0.80 to 1.08) or multivariable-adjusted analysis (hazard ratio: 1.05; 95% confidence interval: 0.86 to 1.29). No association was found between HF and site-specific cancer incidence or cancer-specific mortality after multivariable adjustment. Results were similar when using the landmark method at all landmark ages.

Conclusions: HF is not associated with an increased risk of cancer among male physicians.
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http://dx.doi.org/10.1016/j.jacc.2018.01.069DOI Listing
April 2018

Association of Electronic Health Record Use With Quality of Care and Outcomes in Heart Failure: An Analysis of Get With The Guidelines-Heart Failure.

J Am Heart Assoc 2018 03 30;7(7). Epub 2018 Mar 30.

Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, MA

Background: Adoption of electronic health record (EHR) systems has increased significantly across the nation. Whether EHR use has translated into improved quality of care and outcomes in heart failure (HF) is not well studied.

Methods And Results: We examined participants from the Get With The Guidelines-HF registry who were admitted with HF in 2008 (N=21 222), using various degrees of EHR implementation (no EHR, partial EHR, and full EHR). We performed multivariable logistic regression to determine the relation between EHR status and several in-hospital quality metrics and outcomes. In a substudy of Medicare participants (N=8421), we assessed the relation between EHR status and rates of 30-day mortality, readmission, and a composite outcome. In the cohort, the mean age was 71±15 years, 49% were women, and 64% were white. The mean ejection fraction was 39±17%. Participants were admitted to hospitals with no EHR (N=1484), partial EHR (N=13 473), and full EHR (N=6265). There was no association between EHR status and several quality metrics (aside from β blocker at discharge) or in-hospital outcomes on multivariable adjusted logistic regression (>0.05 for all comparisons). In the Medicare cohort, there was no association between EHR status and 30-day mortality, readmission, or the combined outcome.

Conclusions: In a large registry of hospitalized patients with HF, there was no association between degrees of EHR implementation and several quality metrics and 30-day postdischarge death or readmission. Our results suggest that EHR may not be sufficient to improve HF quality or related outcomes.
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http://dx.doi.org/10.1161/JAHA.117.008158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907596PMC
March 2018

Systolic blood pressure and cardiovascular outcomes in heart failure with preserved ejection fraction: an analysis of the TOPCAT trial.

Eur J Heart Fail 2018 03 16;20(3):483-490. Epub 2017 Nov 16.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Recent guidelines have advocated for stricter systolic blood pressure (SBP) control in heart failure with preserved ejection fraction (HFpEF), though data regarding the optimal SBP in HFpEF are sparse.

Methods And Results: We analysed participants from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study with available baseline and 8-week visit SBP data (n = 1645). We related baseline SBP to several efficacy and safety outcomes. To determine whether blood pressure lowering was responsible for the potential beneficial effects of spironolactone observed in the Americas, we assessed the randomized treatment adjusting for baseline and change in 8-week SBP. The average age was 71.7 ± 9.7 years, 50% were women, and 79% were White. Patients in the lowest baseline SBP quartile were less often female, more often White, had lower body mass index, lower baseline diastolic blood pressure and pulse pressure, and more often had atrial fibrillation. After multivariable adjustment, there was no relationship observed between baseline SBP quartiles and any outcome. Spironolactone reduced SBP by 4.4 ± 0.6 mmHg compared with placebo (and consistently across baseline SBP quartiles). There was minimal change in the treatment effect for all outcomes after adjusting for baseline SBP and 8-week change in SBP.

Conclusion: No relationship was observed between baseline SBP quartiles and outcomes in TOPCAT. The anti-hypertensive effects of spironolactone did not account for the potential benefit in cardiovascular outcomes in the Americas.
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http://dx.doi.org/10.1002/ejhf.1060DOI Listing
March 2018

Association of Estimated Sodium Intake With Adverse Cardiac Structure and Function: From the HyperGEN Study.

J Am Coll Cardiol 2017 Aug;70(6):715-724

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: The optimal level of sodium intake remains controversial.

Objectives: This study sought to determine whether examination of left ventricular longitudinal strain (LS), circumferential strain, and e' velocity can provide insight into thresholds for the detrimental effects of estimated sodium intake (ESI) on subclinical cardiovascular disease.

Methods: We performed speckle-tracking analysis on HyperGEN (Hypertension Genetic Epidemiology Network) study echocardiograms with available urinary sodium data (N = 2,996). We evaluated the associations among ESI and LS, circumferential strain, and e' velocity using multivariable-adjusted linear mixed-effects models (to account for relatedness among subjects) with linear splines (spline 1: ESI ≤3.7 g/day, spline 2: ESI >3.7 g/day based on visual inspection of fractional polynomial plots of the association between ESI and indices of strain and e' velocity). We performed mediation analysis to understand the indirect effects of systolic blood pressure and serum aldosterone on the relationship between ESI and strain and e' velocity.

Results: Mean age of participants was 49 ± 14 years, 57% were female, 50% were African American, and 54% had hypertension. The median ESI was 3.73 (interquartile range: 3.24, 4.25) g/day. ESI >3.7 g/day was associated with larger left atrial and left ventricular dimensions (p < 0.05). After adjusting for speckle-tracking analyst, image quality, study site, age, sex, smoking status, alcohol use, daily blocks walked, diuretic use, estimated glomerular filtration rate, left ventricular mass, ejection fraction, and wall motion score index, ESI >3.7 g/day was associated with both strain parameters and e' velocity (p < 0.05 for all comparisons), but ESI ≤3.7 g/day was not (p > 0.05 for all comparisons). There were significant interactions by potassium excretion for circumferential strain. Mediation analysis suggested that systolic blood pressure explained 14% and 20% of the indirect effects between ESI and LS and e' velocity, respectively, whereas serum aldosterone explained 19% of the indirect effects between ESI and LS.

Conclusions: ESI >3.7 g/day is associated with adverse cardiac remodeling and worse systolic strain and diastolic e' velocity.
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http://dx.doi.org/10.1016/j.jacc.2017.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571737PMC
August 2017