Jacob Joseph

• Doctor of Medicine
• Medical Doctor at Brigham and Women's Hospital

Introduction Understanding predictors of adverse outcomes in patients with peripartum cardiomyopathy (PPCM) is essential for risk stratification and prognosis. The aim of this study is to examine the relationship between heart rate (HR) at diagnosis and adverse outcomes in PPCM. Methods We conducted a multi-center cohort study to identify patients...

Objective Event capture in clinical trials is resource-intensive, and electronic medical records (EMRs) offer a potential solution. This study develops algorithms for EMR-based death and hospitalization capture and compares them with traditional event capture methods. Materials and Methods We compared the effectiveness of EMR-based event capture a...

To understand the genetic basis of heart failure (HF) in the Japanese population, we performed genome-wide association studies (GWASs) comprising 16,251 all-cause HF cases, 4,254 HF with reduced ejection fraction cases, 7,154 HF with preserved ejection fraction cases, and 11,122 non-ischemic HF cases among 213,828 individuals and identified five no...

Introduction: Substantial evidence indicates that racial and ethnic diversity among the physician workforce bridges cultural gaps and improves patient care. Trends in racial diversity across the full training pipeline from undergraduate to practicing cardiologist are not yet well-characterized. Aims: We analyze racial disparities at each stage of t...

Background: Heart failure (HF), a progressive condition with a complex etiopathology causes significant morbidity, mortality, and reduced quality of life. HF affects 64 million people worldwide and imposes a global healthcare burden exceeding $346 billion annually. Currently, HF is classified into two major clinical subtypes based on cardiac contra...

Introduction: Transthyretin (TTR) dissolution into monomer form and subsequent misfolding causes amyloidosis through deposition of beta-pleated sheets in end organs. Genetic sequence variations can decrease the stability of TTR leading to earlier disease manifestation, a condition known as hereditary TTR amyloidosis (hATTR). The most common variant...

Background: Social determinants, such as educational attainment level (EAL), are indicators of socioeconomic status and have been shown to be inversely related with adverse health outcomes. However, the association between EAL and risk of cardio-pulmonary events in heart failure (HF) and myocardial infarction (MI) survivors has not been extensively...

Background: Heart failure (HF) is a life-threatening aging-related syndrome with growing impact on the global population. It is estimated that >8 million adults in the US will be living with HF by 2030. HF with preserved EF (HFpEF), defined by an ejection fraction ≥50%, frequently has delayed diagnosis and limited treatment options. HFpEF progressi...

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressu...

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the...

Background Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome increasing in prevalence and affecting millions worldwide but with limited evidence‐based therapies. Results from explanatory clinical trials suggest that spironolactone may help to improve outcomes in patients with HFpEF. We sought to investigate the effectiven...

Background Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF. Methods and Results...

Importance High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown....

Background Statins are highly effective for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and mortality. Data on the benefit of statins in adults with heart failure with preserved ejection fraction (HFpEF) and without ASCVD are limited. Objectives The purpose of this study was to determine whether statins are associated with...

Background Adult congenital heart disease (ACHD) patients have significant morbidity and rise in cardiac admissions. Their outcome with high-dose influenza vaccination is unknown in comparison to those without ACHD. Objectives The purpose of this study was to compare all-cause mortality or cardiopulmonary hospitalizations in self-identified ACHD v...

We used expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to conduct genome-wide Mendelian randomization (MR) using 27,799 cases of heart failure (HF) with reduced ejection fraction (HFrEF), 27,579 cases of HF with preserved ejection fraction (HFpEF), and 367,267 control individuals from the Million Veteran Prog...

Background: Heart failure (HF) is a life-threatening syndrome with growing impact on the global population. It is estimated that >8 million people in the US will be living with HF by 2030. Aging is a major risk factor for HF. Age-at-onset (AAO) is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide associat...

Introduction: Little is known about the relation of total alcohol intake and beverage types on risk of heart failure (HF). This study aims to examine the relation between amount of alcohol consumed and type of alcohol with risk for HF including subtypes [heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction] in a large cohort o...

Background: Heart failure (HF) incidence has increased over past decades and is associated with poor quality of life, increased comorbidities, and high treatment costs. Prevention for HF warrant a major public health priority. Aim: To quantify the association of Life’s Essential 8 (LE8) score with HF. Methods: LE8 score (0-800) was developed based...

Introduction: Heart failure (HF) continues to be the leading cause of hospitalization in older men in the United States. While previous studies have reported beneficial effects of leisure time physical activity (LTPA) on cardiovascular disease, it is unclear whether LTPA is associated with incidence of HF with reduced or preserved ejection fraction...

Background: Heart failure (HF) is a complex trait influenced by environmental and genetic factors. Genome-wide association studies (GWAS) have found common genetic variants associated with HF risk, but the extent that common and rare variants explain risk and implicate similar genes and pathways in HF remains less understood. Methods: For common va...

Introduction: Understanding predictors of adverse outcomes in patients with peripartum cardiomyopathy (PPCM) is essential to inform clinical practice and improve outcomes. Aim: The aim of this study is to examine the relationship between heart rate (HR) at diagnosis and adverse outcomes in PPCM. Methods: We conducted a multi-center cohort study to...

Introduction: Heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction differ in pathophysiology and treatment response. Determining shared and unique protein biomarkers for these phenotypes can aid in understanding their biological mechanisms. Methods: We studied 4485 participants in the community-based Atherosclerosis Risk in Co...

Background: Influenza vaccines are recommended for patients with CVD due to their protective effects and favorable safety profile. Patients with recent MI/HF hospitalization are at high risk of multiple events, but it is not known which flu vaccine type can mitigate recurrent events. Research Questions: What are predictors of recurrent cardiopulmon...

Importance Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to...

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, linking rare genetic variants to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfu...

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian random...

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derive...

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardio...

Background: Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for cardiovascular diseases, including HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability a...

Introduction: Heart failure (HF) is a disease with high morbidity and mortality, and affects an estimated total of 6.2 million HF patients in the US. Obesity is an established risk factor for HF, and fluctuation in body mass index (BMI) has shown a negative effect in health. Hypothesis: We assessed the hypothesis that BMI variability is associated...

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unkn...

Introduction: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. We assessed the association between vaccine-related AR and m...

Aims: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. This post hoc analysis explored the association between vaccine-rel...

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. Methods: In a...

Background: Hospice and palliative care were originally implemented for patients dying of cancer, both of which continue to be underused in patients with heart failure (HF). The objective of this study was to understand the unique challenges faced by patients dying of HF compared with cancer. Methods: We assessed differences in demographics, hea...

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk F...

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in SARS-CoV-2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Ve...

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with...

Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 20...

We conducted a large-scale meta-analysis of heart failure (HF) genome-wide association studies (GWAS) consisting of over 90,000 HF cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for HF. Using the GWAS results and blood protein quantitative loci (pQTLs), we performed Mendelian randomizati...

Background: Coronary revascularization is recommended to treat ischemic cardiomyopathy. However, the relations of revascularization-associated ejection fraction (EF) change to subsequent outcomes have not been elucidated. Methods: In 10 071 veterans (mean age 67 years; 1% women; 15% non-White) who underwent a first percutaneous coronary interven...

Introduction Pragmatic clinical trials (PCTs) employ innovative approaches to improve clinical trial efficiency and reduce trial-related costs. Leveraging electronic medical records (EMR) has the potential to lower trial burden and cost related to patient follow-up and data acquisition. Hypothesis Centralized (EMR-based) and traditional (trial-bas...

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants...

Genetic predisposition to venous thrombosis may impact COVID-19 infection and its sequelae. Participants in the ongoing prospective cohort study, Million Veteran Program (MVP), who were tested for COVID-19, with European ancestry, were evaluated for associations with polygenic venous thromboembolic risk, Factor V Leiden mutation (FVL) (rs6025) and...

Importance: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. Objective: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We test...

Background: Pharmacologic clinical trials for heart failure (HF) with preserved ejection fraction (HFpEF) have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction (HFrEF). Whether differences in the genetic underpinnings of these HF subtypes may provide insights into the disparate outcomes of these clinic...

Along with its heavy toll of morbidity and mortality, the coronavirus disease 2019 (COVID-19) pandemic exposed several limitations of the current global research response. The slow and inefficient process of carrying out traditional randomized clinical trials led regulatory authorities to hastily approve treatments and tests without sufficient evid...

Introduction: Observational studies have implicated atrial fibrillation (AF) as a risk factor for a number of cardiovascular diseases (CVD). Whether AF is causally related to these CVD is unknown. Methods: We included participants with both electronic health record-derived phenotypes and imputed genotype data in this study. A genetic instrument for...

Introduction: Heart failure (HF) increases morbidity, mortality, and costs, with complex pathogenic mechanisms. Interleukin-6 (IL-6) is a key cytokine and immune regulator with broad impact on inflammation – a critical component of HF pathophysiology. Circulating levels of IL-6 receptor (IL-6R) determines the activity of the IL-6 signaling pathway....

Introduction: Rare, Mendelian drivers of dilated cardiomyopathy (DCM) are well-established, but the contribution of common genetic variation to DCM risk has emerged more recently. As common variant discovery has largely relied on genome wide association studies (GWAS) of prospectively recruited DCM cases, we sought to conduct a GWAS of retrospectiv...

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran...

Selenium (Se) is a trace nutrient that promotes human health through its incorporation into selenoproteins in the form of the redox-active amino acid selenocysteine (Sec). There are 25 selenoproteins in humans, and many of them play essential roles in the protection against oxidative stress. Selenoproteins, such as glutathione peroxidase and thiore...

Aims This study aims to develop the first race-specific and sex-specific risk prediction models for heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods and results We created a cohort of 1.8 million individuals who had an outpatient clinic visit between 2002 and 2007 within the Veterans Affairs (VA) Healthcare Syste...

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in...

The link between viral respiratory infection and non-pulmonary organ-specific injury, including cardiac injury, has become increasingly appreciated during the current coronavirus disease 2019 (COVID-19) pandemic. Even prior to the pandemic, however, the association between acute infection with influenza and elevated cardiovascular risk was evident....

Introduction: Worsening renal function (WRF) predicts poor prognosis in patients with left ventricular systolic dysfunction. The effect of WRF in heart failure with preserved ejection fraction (HFpEF) is unclear. Objective: The objective of this study was to determine whether WRF during index hospitalization for HFpEF is associated with increase...

Redox balance and methylation are crucial to homeostasis and are linked by the methionine-homocysteine cycle. We examined whether differences in methylation potential, measured as plasma levels of S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), occur at baseline and during anti-oxidant therapy with the xanthine oxidase inhibitor allo...

Sodium is an essential mineral and nutrient used in dietary practices across the world and is important to maintain proper blood volume and blood pressure. A high sodium diet is associated with increased expression of β—myosin heavy chain, decreased expression of α/β—myosin heavy chain, increased myocyte enhancer factor 2/nuclear factor of activate...

Importance Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. Objective To evaluate whether high-dose trivalent influenza vaccin...

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs o...

Introduction Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. The V122I variant, a common pathogenic TTR mutation found primarily in individuals of West African descent, is frequently associated with cardiomyopathy. Other hATTR amyloidosis manifestatio...

Introduction Heart failure (HF) is a common concomitant diagnosis in the intensive care unit (ICU) population. Whether mortality is impacted by secondary diagnosis of HF is less well studied. We sought to assess the impact of secondary diagnosis of heart failure on 90-day mortality. Hypothesis A secondary diagnosis of HF is associated with increas...

Abstract Background In a real-world setting, the effect of pulse rate measured at the time of diagnosis and serially during follow-up and management, on outcomes in heart failure with reduced ejection fraction (HFrEF), has not been well-studied. Furthermore, how beta-blockade use in a real-world situation modifies this relation between pulse rate a...

Background Early electronic identification of patients at the highest risk for heart failure (HF) readmission presents a challenge. Data needed to identify HF patients are in a variety of areas in the electronic medical record (EMR) and in different formats. Objective The purpose of this paper is to describe the development and data validation of a...

Among older adults, heart failure (HF) is the leading cause of hospitalization in the US and is associated with high costs and mortality1. Vitamin D and marine omega-3 (n-3) fatty acids have each been associated with reduced risks of HF in observational studies, but randomized trial evidence is limited. The current ancillary study sought to investi...

Objective: The purpose of our study is to examine whether serial measurements of serum sodium values after diagnosis identify a higher-risk subset of patients with heart failure with preserved ejection fraction. Methods: We identified 50,932 subjects with HFpEF with 759,577 recorded sNa measurements (mean age 72 ± 11 years) using a validated alg...

Aims: To evaluate population-based electronic health record (EHR) definitions of atrial fibrillation (AF) and valvular heart disease (VHD) subtypes, time trends in prevalence and prognosis. Methods and results: A total of 76 019 individuals with AF were identified in England in 1998-2010 in the CALIBER resource, linking primary and secondary car...

Background: Myocardial fibrosis is a major pathophysiologic substrate of heart failure with preserved ejection fraction. Vasopressin is an important therapeutic target in heart failure with preserved ejection fraction since it can modulate fluid balance, and based on a few studies, myocardial matrix deposition. Hence we examined the role of vasopr...

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on t...

Background Heart failure (HF) with preserved ejection fraction (HFpEF) comprises nearly half of prevalent HF, yet is challenging to curate in a large database of electronic medical records (EMR) since it requires both accurate HF diagnosis and left ventricular ejection fraction (EF) values to be consistently ≥50%. Methods We used the national Veter...

Background: The purpose of this study was to evaluate the relationship between serum sodium at the time of diagnosis and long term clinical outcomes in a large national cohort of patients with heart failure with preserved ejection fraction. Methods and results: We studied 25 440 patients with heart failure with preserved ejection fraction treate...

Background: Telehealth is a promising intervention to reduce readmissions and healthcare-associated costs in patients with heart failure. Methods: We performed a retrospective analysis of the impact of telehealth on 197 heart failure patients who had successfully completed one year of home telehealth monitoring following a heart failure admissio...

Background: Influenza leads to significant cardiopulmonary morbidity and mortality-particularly in patients with cardiovascular disease-that may be prevented with a standard influenza vaccine. However, patients with cardiovascular conditions have a reduced immune response to influenza vaccine, potentially resulting in reduced effectiveness for pre...

Introduction: Heart failure with preserved ejection fraction (HFpEF) affects about 5% of people 65 or older, with a higher prevalence in women. Previous studies suggest that women with HFpEF may live longer than men. Further understanding of mortality outcomes by gender could be useful in implementing gender-specific treatment strategies to improve...

Background/aims: Celastrol pretreatment has been shown to protect against myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism is poorly understood. This study aimed to investigate the cardioprotective effects of celastrol pretreatment on I/R injury and to further explore whether its mechanism of action was associated with th...

Background: Anemia is increasingly being identified as a poor prognostic factor in patients with heart failure with reduced ejection fraction. However, few studies, and with small sample sizes, have examined the role of anemia in patients with heart failure with preserved ejection fraction (HFpEF). Thus, the purpose of our study is to examine wheth...

Galectin-3 is an emerging biomarker of myocardial fibrosis, inflammation, and immune response. We sought to examine the relation of plasma galectin-3 with cardiovascular (CVD) mortality, all-cause mortality, and incident heart failure (HF). We performed a literature search for all relevant publications using Ovid MEDLINE, Google Scholar, and other...

Background and purpose: Thoracic (chemo)radiation therapy is increasingly administered with tyrosine kinase inhibitors (TKI). While TKI have adverse effects on the heart, it is unknown whether combination with other cancer therapies causes enhanced toxicity. We used an animal model to investigate whether radiation and sunitinib interact in their e...