Publications by authors named "Sanjiv J Shah"

398 Publications

Clinical Characteristics and Outcomes of Adults With a History of Heart Failure Hospitalized for COVID-19.

Circ Heart Fail 2021 Sep 14:CIRCHEARTFAILURE121008354. Epub 2021 Sep 14.

Department of Medicine, Weill Cornell Medicine, New York, NY. (P.G., E.R., M.M., J.K., R.B.D., P.M.O., J.W.W., M.M.S.).

Background: It is important to understand the risk for in-hospital mortality of adults hospitalized with acute coronavirus disease 2019 (COVID-19) infection with a history of heart failure (HF).

Methods: We examined patients hospitalized with COVID-19 infection from January 1, 2020 to July 22, 2020, from 88 centers across the US participating in the American Heart Association's COVID-19 Cardiovascular Disease registry. The primary exposure was history of HF and the primary outcome was in-hospital mortality. To examine the association between history of HF and in-hospital mortality, we conducted multivariable modified Poisson regression models that included sociodemographics and comorbid conditions. We also examined HF subtypes based on left ventricular ejection fraction in the prior year, when available.

Results: Among 8920 patients hospitalized with COVID-19, mean age was 61.4±17.5 years and 55.5% were men. History of HF was present in 979 (11%) patients. In-hospital mortality occurred in 31.6% of patients with history of HF, and 16.9% in patients without a history of HF. In a fully adjusted model, history of HF was associated with increased risk for in-hospital mortality (relative risk: 1.16 [95% CI, 1.03-1.30]). Among 335 patients with left ventricular ejection fraction, heart failure with reduced ejection fraction was significantly associated with in-hospital mortality in a fully adjusted model (heart failure with reduced ejection fraction relative risk: 1.40 [95% CI, 1.10-1.79]; heart failure with mid-range ejection fraction relative risk: 1.06 [95% CI, 0.65-1.73]; heart failure with preserved ejection fraction relative risk, 1.06 [95% CI, 0.84-1.33]).

Conclusions: Risk for in-hospital mortality was substantial among adults with history of HF, in large part due to age and comorbid conditions. History of heart failure with reduced ejection fraction may confer especially elevated risk. This population thus merits prioritization for the COVID-19 vaccine.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.121.008354DOI Listing
September 2021

Spironolactone in Patients With an Echocardiographic HFpEF Phenotype Suggestive of Cardiac Amyloidosis: Results From TOPCAT.

JACC Heart Fail 2021 Sep 1. Epub 2021 Sep 1.

Department of Cardiovascular Medicine, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA; University of Missouri-Kansas City, Kansas City, Missouri, USA.

Objectives: This study investigated an enriched cohort of patients with heart failure and preserved ejection fraction (HFpEF) in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with an echocardiographic phenotype of cardiac amyloidosis.

Background: There is a high prevalence of increased interventricular septal (IVS) thickness and decreased mitral annular systolic (s') velocity in cardiac amyloidosis. In addition, clinical trials of neurohormonal blockade are missing in this population.

Methods: TOPCAT randomized patients with HFpEF to spironolactone or placebo therapy with a primary endpoint of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Patients with IVS and s' velocity measurements were included, and adjusted Cox models assessed the effect of echocardiographic variables and spironolactone on the primary endpoint.

Results: Among 590 patients, mean s' velocity was 6.4 ± 2.1 cm/s and IVS thickness was 1.2 ± 0.2 cm. The enriched cohort with characteristics of cardiac amyloidosis (s' velocity ≤6 cm/s and IVS thickness ≥1.2 cm) included 135 patients (23% of the cohort). After a median follow-up of 2.6 years (1.5 years-3.9 years), these patients had the worst prognosis (adjusted HR: 2.10; 95% CI: 1.26 to 3.50; P = 0.004). Both s' velocity and IVS thickness were individually associated with the primary endpoint, and abnormalities in these parameters were additive as lower s' velocity was particularly prognostic in those with greater IVS thickness (interaction: P = 0.013). Spironolactone was associated with improved outcomes in the overall cohort (P = 0.024), and patients in the enriched cohort had a benefit similar to that in other groups (interaction: P = 0.382).

Conclusions: An enriched subset of patients with structural and functional echocardiographic features of cardiac amyloidosis had the worst prognosis in the TOPCAT study, but they benefitted similarly from spironolactone therapy. Future studies of mineralocorticoid receptor antagonists in patients with cardiac amyloidosis are warranted.
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http://dx.doi.org/10.1016/j.jchf.2021.06.007DOI Listing
September 2021

Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Sep;78(11):1166-1187

Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.
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http://dx.doi.org/10.1016/j.jacc.2021.07.014DOI Listing
September 2021

Insulin Resistance Is Associated with Right Ventricular Dysfunction.

Ann Am Thorac Soc 2021 Sep 9. Epub 2021 Sep 9.

Northwestern University, Medicine/Cardiology, Chicago, Illinois, United States;

Rationale: The effect of insulin resistance on left ventricular function is well documented, however less is known regarding its effect on the right ventricle (RV).

Objectives: To evaluate the association between insulin resistance and RV function by echocardiography in a cohort of adults without baseline cardiovascular disease.

Methods: We performed a retrospective cohort study in the Multi-Ethnic Study of Atherosclerosis (MESA). Linear regression was used to examine the association between overall insulin resistance measured by the mean triglyceride to HDL cholesterol ratio (TG:HDL), and change in TG:HDL over time for each participant with echocardiographic RV function. Logistic regression was used to calculate the odds ratios of RV systolic and diastolic dysfunction.

Results: Among 3,032 participants, higher mean TG:HDL was associated with lower (worse) absolute RV longitudinal strain (β -0.38; 95%CI -0.64, -0.13; p<0.01), tricuspid annular plane systolic excursion (TAPSE; β -0.05; 95%CI -0.07, -0.04; p<0.001) and higher odds of abnormal RV strain (OR 1.26; 95%CI 1.08, 1.47; p<0.01) and abnormal TAPSE (OR 1.31; 95%CI 1.14, 1.51; p<0.001). TG:HDL was also associated with lower tricuspid E/A ratio (β -0.03; 95%CI -0.04, -0.01; p<0.01), higher E/e' ratio (β 0.15; 95%CI 0.07, 0.23; p<0.001), and higher odds of graded RV diastolic dysfunction (OR 1.19; 95%CI 1.03, 1.39; p<0.05). These associations remained following multivariable adjustment.

Conclusions: Insulin resistance was associated with decreased RV systolic and diastolic function after adjusting for alternative causes of RV dysfunction, suggesting that insulin resistant individuals are at risk for early RV dysfunction, even in the absence of cardiovascular disease.
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http://dx.doi.org/10.1513/AnnalsATS.202107-766OCDOI Listing
September 2021

A composite metric for predicting benefit from spironolactone in heart failure with preserved ejection fraction.

ESC Heart Fail 2021 Aug 8. Epub 2021 Aug 8.

Section of Cardiology, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA.

Aims: The TOPCAT trial showed no benefit for spironolactone in heart failure patients with preserved ejection fraction (HFpEF). Post-hoc, spironolactone helped participants from the Americas, but not Eastern Europe. Determining which patients with HFpEF could respond like TOPCAT's responders should help guide their care. We aimed to develop a TOPCAT Trial Score (TS) as a composite metric to identify such patients.

Methods And Results: From the TOPCAT individual-level data, we calculated a TS of age, body mass index, systolic blood pressure, heart rate, creatinine, potassium, glucose, left ventricular ejection fraction, and left atrial volume for each participant as a weighted distance in multidimensional space from the theoretical perfectly average Americas participant. Logistic regression was used to measure TS and spironolactone as predictors of TOPCAT's primary outcome. The relationship between TS and the H FPEF score was also determined in TOPCAT and a registry cohort of real-world patients in the U.S. with HFpEF. A bimodal distribution of TS separated American (n = 1766) and Eastern European (n = 1,677) participants. Those with lower TS showed no significant response to spironolactone. Spironolactone's benefit rose with rising TS [β  = -0.28 (P < 0.01)]. Significantly more American participants had benefit from spironolactone based on higher TS (> 1.14), in addition to higher likelihood of HFpEF based on higher H FPEF scores (≥3). The cohort of real-world patients with HFpEF had even higher TS than American TOPCAT participants.

Conclusions: Patients with HFpEF can be quantified by the TS to capture the likelihood of benefit from spironolactone.
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http://dx.doi.org/10.1002/ehf2.13523DOI Listing
August 2021

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

J Am Heart Assoc 2021 Aug 7;10(16):e020499. Epub 2021 Aug 7.

Division of Cardiology University of California San Francisco CA.

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV. Methods and Results The study population consisted of participants enrolled in the multisite cross-sectional study called CHART-HIV (Characterizing Heart Function on Anti-Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut-related circulating metabolites; diastolic dysfunction was determined by study-specific criteria. Multivariable linear regression models were performed to examine the relationship of gut-related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV-related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART-HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis (=0.35; <0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis. Conclusions In this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV-associated cardiovascular disease warrants further investigation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT02860156.
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http://dx.doi.org/10.1161/JAHA.120.020499DOI Listing
August 2021

Associations of body size and composition with subclinical cardiac dysfunction in older individuals: the cardiovascular health study.

Int J Obes (Lond) 2021 Aug 4. Epub 2021 Aug 4.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: Focused studies in younger to middle-aged populations have demonstrated a relationship between obesity and adverse cardiac mechanics. We examined whether measures of overall and central adiposity are associated with cardiac mechanics, assessed by speckle-tracking echocardiography, in an older population without prevalent coronary heart disease or heart failure.

Methods: Body composition was measured by anthropometry, bioelectrical impedance, and dual-energy x-ray absorptiometry among participants in the Cardiovascular Health Study, a population-based cohort of adults aged 65 years or older. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of body composition measures and cardiac mechanics.

Results: Mean age for the 3525 included participants was 72.6 years, 39% were male, and 10% were black. Mean body-mass index (BMI) was 26.3 ± 4.4 kg/m, waist circumference (WC) was 93.2 ± 12.9 cm, and waist-to-hip ratio was 0.92 ± 0.09. In fully adjusted analyses, all adiposity measures were associated with worse LV longitudinal strain, LV early diastolic strain rate, and left atrial reservoir strain; however, associations were strongest for WC and BMI (p < 0.001). When both BMI and WC were included in the same model, only WC remained associated with each cardiac strain measure.

Conclusion: In this cross-sectional study of older adults, central obesity was most robustly associated with impaired left ventricular systolic and diastolic strain as well as left atrial strain. The adverse effects of central obesity appear to extend even into older age.
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http://dx.doi.org/10.1038/s41366-021-00926-yDOI Listing
August 2021

Efficacy and safety of diuretics in heart failure with preserved ejection fraction: a scoping review.

Heart 2021 Aug 2. Epub 2021 Aug 2.

Department of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Objective: Diuretics reduce congestion in patients with heart failure with preserved ejection fraction (HFpEF). However, comparison of clinical effects across diuretic classes or combinations of diuretics in patients with HFpEF are not well described. Therefore, we sought to conduct a scoping review to map trial data of diuretic efficacy and safety in patients with HFpEF.

Review Methods And Results: We searched multiple bibliometric databases for published literature and ClinicalTrials.gov, and hand searched unpublished studies comparing different classes of diuretics to usual care or placebo in patients with HFpEF. We included randomised controlled trials or quasi-experimental studies. Two authors independently screened and extracted key data using a structured form. We identified 13 published studies on diuretics in HFpEF, with 1 evaluating thiazide use, 7 on mineralocorticoid receptor antagonists (MRAs) and 5 on sodium-glucose co-transporter 2 inhibitors (SGLT2i). There remain 17 ongoing trials evaluating loop diuretics (n=1), MRAs (n=5), SGLT2i (n=10) and a polydiuretic (n=1), including 2 well-powered trials of SGLT2i that will be completed in 2021.

Conclusions: The limited number of published trials evaluating different classes of diuretics in patients with HFpEF have been generally small and short term. Ongoing and emerging trials of single or combination diuretics with greater power will be useful to better define their safety and efficacy. SCOPING REVIEW REGISTRATION: doi:10.18131/g3-dejv-tm77.
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http://dx.doi.org/10.1136/heartjnl-2021-319643DOI Listing
August 2021

Prognostic Value of Minimal Left Atrial Volume in Heart Failure With Preserved Ejection Fraction.

J Am Heart Assoc 2021 Aug 30;10(15):e019545. Epub 2021 Jul 30.

Cardiovascular Division Brigham and Women's Hospital and Harvard Medical School Boston MA.

Background Maximal left atrial (LA) volume is reported by most echocardiography laboratories and is associated with clinical outcomes in patients with heart failure (HF). Recent studies suggest that minimal LA volume may better reflect left ventricular filling pressure and may be more prognostic than maximal LA volume. This study assessed the prognostic value of indexed minimal LA volume (LAVImin) in patients with HF with preserved ejection fraction. Methods and Results We assessed the relationship of LAVImin with a primary composite end point of cardiovascular death, aborted cardiac death, or HF hospitalization in 347 patients with HF with preserved ejection fraction enrolled from the Americas region in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We compared LAVImin with indexed maximal LA volume with respect to their prognostic values. In addition, we assessed if LA functional parameters provide additional prognostic information over LAVImin. During a median follow-up of 2.5 years, 107 patients (31%) experienced a primary composite end point. LAVImin was associated with increased risk of a primary composite outcome (hazard ratio [HR], 1.35; 95% CI, 1.12-1.61) and HF hospitalization alone (HR, 1.42; 95% CI, 1.17-1.71) after adjusting for clinical confounders and ejection fraction. In contrast, indexed maximal LA volume was not related to the primary composite outcome, but related to HF alone (HR, 1.25; 95% CI, 1.02-1.54). In comparison with indexed maximal LA volume, LAVImin was significantly more prognostic for primary composite outcome ( for comparison=0.032). Both LA emptying fraction and LA strain were prognostic of primary outcome independent of LAVImin (all <0.05). Conclusions In patients with HF with preserved ejection fraction, LAVImin was more predictive of cardiovascular outcome than indexed maximal LA volume, suggesting this measure may be more physiologically relevant and might better identify patients at high risk for cardiovascular events. LA functional parameters provide prognostic information independent of LAVImin. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00094302.
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http://dx.doi.org/10.1161/JAHA.120.019545DOI Listing
August 2021

Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.

Heart 2021 Jul 13. Epub 2021 Jul 13.

Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Objectives: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults.

Methods: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years.

Results: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations.

Conclusion: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.
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http://dx.doi.org/10.1136/heartjnl-2021-319296DOI Listing
July 2021

Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis.

JCI Insight 2021 Jul 8;6(13). Epub 2021 Jul 8.

Department of Medicine.

BackgroundImmunomodulatory therapy may help prevent heart failure (HF). Data on immune cells and myocardial remodeling in older adults with cardiovascular risk factors are limited.MethodsIn the Multi-Ethnic Study of Atherosclerosis cohort, 869 adults had 19 peripheral immune cell subsets measured and underwent cardiac MRI during the baseline exam, of which 321 had assessment of left ventricular global circumferential strain (LV-GCS). We used linear regression with adjustment for demographics, cardiovascular risk factors, and cytomegalovirus serostatus to evaluate the cross-sectional association of immune cell subsets with left ventricular mass index (LVMI) and LV-GCS.ResultsThe average age of the cohort was 61.6 ± 10.0 years and 53% were women. Higher proportions of γ/δ T cells were associated with lower absolute (worse) LV-GCS (-0.105% [95% CI -0.164%, -0.046%] per 1 SD higher proportion of γ/δ T cells, P = 0.0006). This association remained significant after Bonferroni's correction. Higher proportions of classical monocytes were associated with worse absolute LV-GCS (-0.04% [95% CI -0.07%, 0.00%] per 1 SD higher proportion of classical monocytes, P = 0.04). This did not meet significance after Bonferroni's correction. There were no other significant associations with LV-GCS or LVMI.ConclusionPathways associated with γ/δ T cells may be potential targets for immunomodulatory therapy targeted at HF prevention in populations at risk.FundingContracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and grant R01 HL98077 from the National Heart, Lung, and Blood Institute/NIH and grants KL2TR001424, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences/NIH.
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http://dx.doi.org/10.1172/jci.insight.149193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410049PMC
July 2021

Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction.

Eur J Heart Fail 2021 Sep 26;23(9):1541-1551. Epub 2021 Jul 26.

Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité University Medicine, Berlin, Germany.

Aims: We sought to describe the baseline characteristics of PARALLAX [a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure (HF) with mildly reduced and preserved ejection fraction (HFpEF)]; compare PARALLAX to recent HFpEF trials; and examine the clinical characteristics associated with quality of life (QOL) and 6-min walk test distance (6MWD).

Methods And Results: A total of 2566 patients with HF and left ventricular ejection fraction (LVEF) >40% were randomized, of whom 96% had an LVEF ≥45%. Multivariable linear regression was used to determine characteristics associated with Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and 6MWD. Mean age was 73 ± 8 years, 51% were female, and comorbidities were common. Of the QOL measures tested in PARALLAX, the Short Form Health Survey-36 physical functioning score was most closely correlated with 6MWD (R = 0.41, P < 0.001), and outperformed the KCCQ physical limitation score (R = 0.33) and KCCQ-CSS (R = 0.31) on multivariable analyses. Female sex, higher body mass index, history of coronary artery disease, lower LVEF, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with worse (lower) KCCQ-CSS; older age, female sex, higher body mass index, diabetes, coronary artery disease, chronic obstructive pulmonary disease, prior HF hospitalization, lower LVEF, and higher NT-proBNP were associated with shorter 6MWD (P < 0.05 for all associations).

Conclusions: PARALLAX is the largest HFpEF study to date to examine 6MWD together with QOL. The KCCQ-CSS and 6MWD were modestly correlated, and several factors were associated with worse values of both. These results provide insight into the association between QOL and exercise capacity in HFpEF.
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http://dx.doi.org/10.1002/ejhf.2277DOI Listing
September 2021

Changes in Stressed Blood Volume with Levosimendan in Pulmonary Hypertension from Heart Failure with Preserved Ejection Fraction: Insights Regarding Mechanism of Action From the HELP Trial.

J Card Fail 2021 Sep 16;27(9):1023-1026. Epub 2021 Jun 16.

Division of Cardiology, Columbia University Medical Center, New York, New York; Cardiovascular Research Foundation, New York, New York.

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http://dx.doi.org/10.1016/j.cardfail.2021.05.022DOI Listing
September 2021

The splanchnic reservoir: an oasis for blood volume in heart failure with preserved ejection fraction?

Eur J Heart Fail 2021 07 16;23(7):1144-1146. Epub 2021 Jul 16.

Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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http://dx.doi.org/10.1002/ejhf.2268DOI Listing
July 2021

Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial.

Eur J Heart Fail 2021 07 9;23(7):1217-1225. Epub 2021 Jun 9.

University of Glasgow, Glasgow, UK.

Aims: Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering agents, have been shown to reduce heart failure hospitalizations in patients with type 2 diabetes without established heart failure, and in patients with heart failure with and without diabetes. Their role in patients with heart failure with preserved and mildly reduced ejection fraction remains unknown.

Methods: Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) is an international, multicentre, parallel group, event-driven, randomized, double-blind trial in patients with chronic heart failure and left ventricular ejection fraction (LVEF) >40%, comparing the effect of dapagliflozin 10 mg once daily, vs. placebo, in addition to standard of care. Patients with or without diabetes, with signs and symptoms of heart failure, a LVEF >40%, elevation in natriuretic peptides and evidence of structural heart disease are eligible. The primary endpoint is time-to-first cardiovascular death or worsening heart failure event (heart failure hospitalization or urgent heart failure visit), and will be assessed in dual primary analyses - the full population and in those with LVEF <60%. The study is event-driven and will target 1117 primary events. A total of 6263 patients have been randomized.

Conclusions: DELIVER will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with heart failure and preserved and mildly reduced ejection fraction.
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http://dx.doi.org/10.1002/ejhf.2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361994PMC
July 2021

Distribution and Correlates of Incident Heart Failure Risk in South Asian Americans: The MASALA Study.

J Card Fail 2021 May 25. Epub 2021 May 25.

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

Background: South Asian Americans experience disproportionately high burden of cardiovascular diseases. Estimating predicted heart failure (HF) risk distribution may facilitate targeted prevention. We estimated the distribution of 10-year predicted risk of incident HF in South Asian Americans and evaluated the associations with social determinants of health and clinical risk factors.

Methods And Results: In the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study, we calculated 10-year predicted HF risk using the Pooled Cohort Equations to Prevent Heart Failure multivariable model. Distributions of low (<1%), intermediate (1%-5%), and high (≥5%) HF risk, identified overall and by demographic and clinical characteristics, were compared. We evaluated age- and sex-adjusted associations of demographic characteristics and coronary artery calcium with predicted HF risk category using ordinal logistic regression. In 1159 participants (48% women), with a mean age of 57 ± 9 years, 40% had a low, 37% had an intermediate, and 24% had a high HF risk. Significant differences in HF risk distribution existed across demographic (income, education, birthplace) and clinical (diabetes, hypertension, body mass index, coronary artery calcium) groups (P < .01). Significant associations with high predicted HF risk were observed for a family of income 75,000/year or more (adjusted odds ratio 0.5 [95% confidence interval (CI) 0.4-0.7]), college education (0.6 [95% CI 0.4-0.9]), birthplace in another South Asian country (1.9 [95% CI 1.2-3.2], vs. born in India), and prevalent coronary artery calcium (2.6 [95% CI 1.9-3.6]).

Conclusions: Almost two-thirds of South Asian Americans in the MASALA cohort are at intermediate or high predicted 10-year HF risk, with varying risk across demographic and clinical characteristics.
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http://dx.doi.org/10.1016/j.cardfail.2021.05.013DOI Listing
May 2021

Association Between Myocardial Strain and Frailty in CHS.

Circ Cardiovasc Imaging 2021 05 17;14(5):e012116. Epub 2021 May 17.

Department of Epidemiology and Population Health, Stanford University, CA (A.X.T., M.C.O.).

Background: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve.

Methods: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having ≥3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography.

Results: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95% CI, 1.07-1.61] per 1-SD lower strain; =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95% CI, 1.08-1.61] per 1-SD lower strain; =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95% CI, 0.96-1.89] =0.086) and 1.58 ([95% CI, 1.11-2.27] =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95% CI, 1.81-2.66]; <0.0001).

Conclusions: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323789PMC
May 2021

Associations of Cardiac Mechanics With Exercise Capacity: The Multi-Ethnic Study of Atherosclerosis.

J Am Coll Cardiol 2021 Jul 13;78(3):245-257. Epub 2021 May 13.

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

Background: Lower exercise capacity, as measured by 6-minute walk distance (6MWD), is associated with incident heart failure (HF). Among those without HF, the associations of measures of cardiac function with 6MWD are unclear, and may provide insight regarding the risk of incident HF.

Objectives: The purpose of this study was to understand the relationships between cardiac function and exercise capacity.

Methods: This study evaluated the associations of cardiac mechanics with 6MWD in the sixth examination of the Multi-Ethnic Study of Atherosclerosis. Echocardiography (2-dimensional, Doppler, and speckle-tracking) was performed at rest and after passive leg raise to evaluate functional reserve after intravascular volume challenge.

Results: Of 2,096 participants without HF (mean age 73 years, 48% men, 58% non-White), individuals with lower (worse) left atrial (LA) reservoir strain were older and had higher blood pressure. Lower resting LA reservoir strain (β coefficient per SD decrease: -5.0; 95% confidence interval [CI]: -8.8 to -1.3 m; p = 0.009), inability to augment LA reservoir strain after passive leg raise (β coefficient per SD decrease: -5.8; 95% CI: -9.1 to -2.5 m; p < 0.001), and lower right atrial reservoir strain (β coefficient per SD decrease: -4.4; 95% CI: -7.8 to -1.1 m; p = 0.01) were associated with shorter 6MWD. Worse left ventricular (LV) diastolic function was also associated with lower 6MWD. There were no independent associations of measures of LV systolic function (global longitudinal strain, circumferential strain, ejection fraction) with 6MWD.

Conclusions: Among individuals without HF, worse biatrial function, lack of LA functional reserve, and worse LV diastolic function were associated with reduced submaximal exercise capacity. Therapies aimed to improve these functional domains may increase exercise capacity and prevent HF.
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http://dx.doi.org/10.1016/j.jacc.2021.04.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299435PMC
July 2021

A machine learning model for identifying patients at risk for wild-type transthyretin amyloid cardiomyopathy.

Nat Commun 2021 05 11;12(1):2725. Epub 2021 May 11.

Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Transthyretin amyloid cardiomyopathy, an often unrecognized cause of heart failure, is now treatable with a transthyretin stabilizer. It is therefore important to identify at-risk patients who can undergo targeted testing for earlier diagnosis and treatment, prior to the development of irreversible heart failure. Here we show that a random forest machine learning model can identify potential wild-type transthyretin amyloid cardiomyopathy using medical claims data. We derive a machine learning model in 1071 cases and 1071 non-amyloid heart failure controls and validate the model in three nationally representative cohorts (9412 cases, 9412 matched controls), and a large, single-center electronic health record-based cohort (261 cases, 39393 controls). We show that the machine learning model performs well in identifying patients with cardiac amyloidosis in the derivation cohort and all four validation cohorts, thereby providing a systematic framework to increase the suspicion of transthyretin cardiac amyloidosis in patients with heart failure.
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http://dx.doi.org/10.1038/s41467-021-22876-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113237PMC
May 2021

Artificial intelligence-enabled fully automated detection of cardiac amyloidosis using electrocardiograms and echocardiograms.

Nat Commun 2021 05 11;12(1):2726. Epub 2021 May 11.

One Brave Idea and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Patients with rare conditions such as cardiac amyloidosis (CA) are difficult to identify, given the similarity of disease manifestations to more prevalent disorders. The deployment of approved therapies for CA has been limited by delayed diagnosis of this disease. Artificial intelligence (AI) could enable detection of rare diseases. Here we present a pipeline for CA detection using AI models with electrocardiograms (ECG) or echocardiograms as inputs. These models, trained and validated on 3 and 5 academic medical centers (AMC) respectively, detect CA with C-statistics of 0.85-0.91 for ECG and 0.89-1.00 for echocardiography. Simulating deployment on 2 AMCs indicated a positive predictive value (PPV) for the ECG model of 3-4% at 52-71% recall. Pre-screening with ECG enhance the echocardiography model performance at 67% recall from PPV of 33% to PPV of 74-77%. In conclusion, we developed an automated strategy to augment CA detection, which should be generalizable to other rare cardiac diseases.
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http://dx.doi.org/10.1038/s41467-021-22877-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113484PMC
May 2021

Visceral adiposity, muscle composition, and exercise tolerance in heart failure with preserved ejection fraction.

ESC Heart Fail 2021 Aug 3;8(4):2535-2545. Epub 2021 May 3.

School of Medicine, Johns Hopkins University, 600 N. Wolfe St., Baltimore, MD, 21287, USA.

Aims: Visceral adipose tissue (AT) promotes inflammation and may be associated with disease progression in heart failure with preserved ejection fraction (HFpEF). We characterized regional AT distribution in HFpEF patients and controls and analysed associations with co-morbidities and exercise tolerance.

Methods And Results: Magnetic resonance imaging was performed to quantify epicardial, liver, abdominal, and thigh skeletal muscle AT. We assessed New York Heart Association (NYHA) class, 6 min walk distance, and global well-being score. Multivariable linear regression models adjusting for body surface area were used. We studied 55 HFpEF patients (41 women, mean age 67 ± 11 years) and 33 controls (21 women, mean age 57 ± 10 years). Epicardial AT (median [interquartile range] 4.6 [2.0] vs. 3.2 [1.4] mm, P < 0.001), thigh intermuscular fat (11.0 [11.5] vs. 5.0 [2.7] cm , P < 0.001) and liver fat fraction (6.4% [6.1] vs. 4.1% [5.5], P = 0.001) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal and thigh subcutaneous AT than men. Greater thigh intermuscular fat was associated with higher blood pressure (β [SE] 0.73 [0.17], P < 0.001) and diabetes (odds ratio [95% confidence interval] 1.2 [1.0-1.5], P = 0.03). Greater thigh intramuscular fat was associated with both worse NYHA class (β [SE] 2.7 [1.0], P = 0.01) and shorter 6 min walk distance (β [SE] -4.1 [1.9], P = 0.03), and greater epicardial AT (β [SE] -0.2 [0.1], P < 0.001) and liver fat fraction (β [SE] -0.4 [0.2], P = 0.04) were associated with lower global well-being score.

Conclusions: Heart failure with preserved ejection fraction patients have increased epicardial, liver, and skeletal muscle fat compared with controls out of proportion to their increased body size, and adiposity was associated with worse NYHA class and exercise tolerance in HFpEF. These results provide the basis for further investigation into the effect of interventions to reduce regional AT distribution in relation to HFpEF symptoms and pathophysiology.
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http://dx.doi.org/10.1002/ehf2.13382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318398PMC
August 2021

Splanchnic nerve modulation in heart failure: mechanistic overview, initial clinical experience, and safety considerations.

Eur J Heart Fail 2021 07 9;23(7):1076-1084. Epub 2021 May 9.

Duke University Hospital, Durham, NC, USA.

Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long-term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.
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http://dx.doi.org/10.1002/ejhf.2196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298285PMC
July 2021

Left Atrial Myopathy in Atrial Fibrillation and Heart Failure: Clinical Implications, Mechanisms, and Therapeutic Targets.

Curr Heart Fail Rep 2021 06 17;18(3):85-98. Epub 2021 Apr 17.

Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Purpose Of Review: This review discusses the mechanisms, clinical implications, and treatments of left atrial (LA) myopathy in comorbid atrial fibrillation (AF) and heart failure (HF) across the spectrum of ejection fraction.

Recent Findings: AF and HF are highly comorbid conditions. Left atrial (LA) myopathy, characterized by impairments in LA structure, function, or electrical conduction, plays a fundamental role in the development of both AF and HF with preserved ejection fraction (AF-HFpEF) along with AF and HF with reduced ejection fraction (AF-HFrEF). While the nature of LA myopathy in AF-HFpEF is unique from that of AF-HFrEF, LA myopathy also leads to progression of both of these conditions. There may be a vulnerable cohort of AF-HF patients who have a disproportionate degree of LA myopathy compared with left ventricular (LV) dysfunction. Further investigations are required to identify therapies to improve LA function in this cohort.
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http://dx.doi.org/10.1007/s11897-021-00510-5DOI Listing
June 2021
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