Vasan S. Ramachandran's research while affiliated with Berlin Institute of Health at Charité (BIH) and other places
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Publications (167)
Introduction
The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations.
Methods and analysis
A total...
Background: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection...
Rationale & Objective
Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established.
Study Design
Prospective observational cohort....
Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights in downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which links to several cancer and non-cancer outcomes, including coronary artery disease. Among 12,911 ancestra...
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed b...
Background and Objectives
Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer’s disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN wi...
We studied the association between inflammatory biomarkers and magnetic resonance imaging (MRI) visible perivascular spaces (PVS) in Framingham Heart Study participants free of stroke and dementia. PVS in the basal ganglia (BG) and centrum semiovale (CSO) were rated with validated methods and categorized based on counts. A mixed score of high PVS b...
Background: Low-normal serum potassium (K) and low dietary K intake are more prevalent in Black than White individuals and are potentially modifiable risk factors for cardiovascular disease (CVD), hypertension, and diabetes, conditions that disproportionately affect Black adults. Arterial stiffness predicts the development of CVD. We sought to dete...
Introduction: Many studies have reported that obesity-related metabolic abnormalities (such as diabetes and hypertension) lead to myocardial dysfunction and adverse cardiac remodeling. However, it is challenging to disentangle the effects of obesity from those of its associated metabolic comorbidities. Comparing metabolically healthy adults across...
Background: The RURAL cohort study is a uniquely designed study using a Mobile Examination Unit (MEU) to study heart and lung disorders in rural counties in the southeastern US. Complete blood counts (CBC) are included in the participant baseline examination. We wanted to use an instrument in the MEU for onsite blood counts and chose the Pixcell He...
Introduction: Spherical remodeling of atria and ventricles is associated with cardiovascular disease (CVD) and mortality. We hypothesized that volumetric left atrial (LA) and left ventricular (LV) sphericity index (SI) are associated with adverse measures of LV structure and function in older adults free of CVD.
Methods: Framingham Heart Study 2nd...
Rationale: The impact of the COVID-19 pandemic on tobacco use patterns remains incompletely understood. We aimed to examine changes in cigarette smoking patterns over the first 2 years of the COVID-19 pandemic (2020-22) in a large, multiethnic, US community-based sample.
Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) ascer...
Few studies have demonstrated reproducible gene–diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient–glycemia relationship...
Physical function predicts health-related quality of life. The biological mechanisms underlying declines in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes of physical functions measured by gait speed and grip strength in community-dwelling adults. We applied aptamer-based pla...
Importance
Ascending thoracic aortic disease is an important cause of sudden death in the US, yet most aortic aneurysms are identified incidentally.
Objective
To develop and validate a clinical score to estimate ascending aortic diameter.
Design, Setting, and Participants
Using an ongoing magnetic resonance imaging substudy of the UK Biobank coho...
Background: Use of artificial intelligence-guided echocardiography (AI echo) may increase access to imaging, but there is little experience of its application in rural and low resource settings. The Risk Underlying Rural Areas Longitudinal (RURAL) cohort is the first NHLBI population-based cohort study to employ AI echo.
Hypothesis: AI echo is feas...
Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japane...
Introduction: Resting heart rate (HR) is an established predictor of cardiorespiratory fitness. Commercial smartwatches permit remote HR monitoring in real world settings over long periods of time, but the relations of smartwatch measured HR and cardiorespiratory fitness in the general public remain uncharacterized. Objective We aimed to examine th...
Introduction: Platelets are key mediators in atherosclerotic cardiovascular disease (CVD). Low cardiorespiratory fitness (CRF) is a major risk factor for atherosclerosis. However, little is known about the effects of CRF on platelet function.
Methods: Platelet assays and cardiopulmonary exercise testing were conducted in the Framingham Heart Study...
Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a phenomenon where hematopoietic stem cells acquire leukemogenic mutations without blood cancer. CHIP is a causal risk factor for coronary artery disease (CAD), yet underlying mechanisms remain unclear. The plasma proteome may provide novel mechanistic insights into the links b...
Introduction: The blood pressure (BP) response during acute exercise (acute exercise blood pressure (AEBP)) is related to future risk of hypertension (HTN) and cardiovascular disease (CVD). Biochemical characterization of AEBP could identify novel biomarkers of CVD risk and inform understanding of its biology.
Methods: We applied an aptamer-based p...
Smoking cessation reduces CVD risk, but whether significant reduction ( > 50%) in cigarettes per day (CPD) decreases CVD risk is unclear. Some prior studies have reported no benefit but are limited by incomplete capture of smoking exposure due to few smoking assessments or short follow-up. We used Framingham Heart Study data to quantify CVD risk be...
Introduction: Modest experimental and human evidence implicate a role for physical activity or sedentary lifestyle in the perturbation of the gut microbiome, yet large human studies are lacking.
Methods: This study included 1846 US Hispanic/Latino adults without diabetes aged 23-82 years (mean age 48 years, 49% women) with gut microbiome data by sh...
Introduction: Short-term blood pressure variability (BPV) is associated with arterial stiffness in patients with hypertension. Few studies examined associations between arterial stiffness and digital home BPV over an intermediate time span.
Objective: We investigated if antecedent arterial stiffness was associated with home BPV among participants i...
Background and Objectives
Diet may be a key contributor to brain health in midlife. In particular, Omega-3 fatty acids have been related to better neurological outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) Omega-3 fatty acid concentrations with MRI...
Background
Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses.
Meth...
Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known meta...
Persons with type 2 diabetes (T2D) remain at increased risk of heart failure (HF) despite control of known cardiovascular risk factors. The aim of this study was to identify genes and molecular pathways specifically linking T2D to HF. To this end, we conducted a trans-ancestral genome-wide association study (GWAS) using data from ACCORD, ORIGIN, an...
DNA methylation commonly occurs at cytosine-phosphate-guanine sites (CpGs) that can serve as biomarkers for many diseases. We analyzed whole genome sequencing data to identify DNA methylation quantitative trait loci (mQTLs) in 4,126 Framingham Heart Study participants. Our mQTL mapping identified 94,362,817 cis-mQTLvariant-CpG pairs (for 210,156 un...
Background: Data is sparse regarding the utility of social media in engaging southern, rural communities in health awareness education and research. Community Advisory Board (CAB) members of the Mississippi (MS) Core of the Risk Underling Rural Areas Longitudinal (RURAL) Study suggested the use of a Facebook social media platform to promote the RUR...
Background: Rural communities have historically been difficult to study compared to their urban counterparts and are underrepresented in research. There are several potential barriers to reaching rural populations; however, there remains a knowledge gap regarding participation in health research by rural people. To drive meaningful, lasting change...
Objective: We evaluated whether intra-individual changes in blood metabolites in response to an oral glucose challenge were associated with incident CVD and mortality.
Methods: An oral glucose tolerance test (OGTT; 75g glucose) was administered to a subsample of non-diabetic Framingham Heart Study participants (n=361). Metabolite profiling was perf...
Introduction: The RURAL cohort study addresses critical knowledge gaps regarding heart and lung disorders in rural Southeastern USA. Using CDC mortality data, RURAL selected ten counties from four states (Alabama, Mississippi, Louisiana, and Kentucky) that are ecologically paired for their five-year low and high CVD mortality rates. RURAL will recr...
Background: The current surge in COVID-19 infections in the rural south is primarily due to the large number of unvaccinated individuals. Increasing the number of individuals getting vaccinated in rural areas remains a challenge due to multiple factors including education, vaccine literacy and hesitancy, and access to vaccination sites.
Objective:...
Background: Identifying circulating proteins associated with healthy dietary patterns may offer novel insights into the key biological processes underlying diet-related chronic disease. As a first step toward achieving this goal, we examined the relations between a proteomic score of healthy dietary patterns and the risk of cardiovascular disease (...
Background: The rural population in the Southeastern United States has been historically understudied despite an elevated risk of cardiovascular disease. Mobile technology can help elucidate the epidemiology of cardiovascular disease in rural areas when deployed in a culturally appropriate manner.
Objectives: To describe the design of a mobile heal...
We examined the association between resting heart rate and life span using linear regression in the Paris Prospective Study I, the Whitehall I Study, and the Framingham Heart Study. We used Cox proportional hazards regression to relate change in heart rate over years to mortality risk. We confirmed the inverse relation between resting heart rate an...
Background
Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux...
Habitual, heavy alcohol consumption increases the risk of detrimental outcomes such alcoholic dilated cardiomyopathy; however, alcohol’s complex effects on cardiac structure and function are incompletely understood. We previously identified 144 differentially methylated CpGs associated with alcohol consumption and sought to create an epigenetic ris...
Introduction: Mortality rates in heart failure (HF) are greatest early after onset and decline rapidly with time (with the survival of the less sick patients). However, it is not known if the presence of atrial fibrillation (AF), a well-known risk factor for mortality in this population, alters such course.
Methods: From the Danish nationwide admin...
Introduction: Risk of hypertension is explained by both behavioral and genetic factors that may act on transcriptomic mechanisms to affect blood pressure variability.
Methods: Whole genome sequencing and RNA sequencing data were obtained on 1,671 Framingham Heart Study (FHS) participants (mean age 54±13 years). Allelic expression of heterozygous SN...
Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haploty...
Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP ha...
We developed novel closed-form estimators of genetic and environmental correlation coefficients. We applied them to estimate over 4,000 genetic and environmental correlations between multiple phenotypes in a diverse sample from the Trans-Omics in Precision Medicine (TOPMed) program. We found substantial differences in heritabilities, genetic, and e...
Aim
Peptide markers of inflammation have been associated with the development of type 2 diabetes. The role of upstream, lipid-derived mediators of inflammation such as eicosanoids, remains less clear. The aim was to examine whether eicosanoids are associated with incident type 2 diabetes.
Methods
In the FINRISK 2002 study, a population-based sample...
Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for plate...
In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term ‘variance stratification’. Unaccounted for, variance stratification can lead to both decrea...
Objective: CHIP is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in elevated atherosclerotic heart disease (CHD) and all-cause mortality, but its association with incident T2D is unknown. We hypothesize CHIP is adversely associated with glycemic traits...
Rationale & objective:
Plasma kidney injury molecule-1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown.
Study design:
Prospective, observational cohort study.
Setting & participants:
524 individuals undergoing clinically indicat...
Introduction: Atrial fibrillation (AF) is the most common arrhythmia and a leading cause of stroke. Blood pressure (BP) responses to submaximal exercise are associated with incident cardiovascular disease and mortality. The association of BP responses to submaximal exercise with incident AF in the community is unknown.
Hypothesis: We hypothesized t...
Introduction: Although type 2 diabetes (T2DM) is one of the strongest risk factors for heart failure (HF), there is limited data on contemporary lifetime risk estimates in this segment. Incident HF appears to be decreasing in the general population, but little is known how the risk has changed over time in patients with T2DM. The increasing prevale...
Introduction: Orthostatic hypotension (OH) and hypertension (OHT) are associated with cardiovascular disease and mortality. The relation of OH and OHT with heart failure (HF) in the community is not well explored, particularly among the elderly and those with hypertension. Moreover, there remains a paucity of longitudinal data on the development of...
Introduction: The Framingham Risk Score (FRS) has been widely used to predict cardiovascular disease (CVD) risk. However, a comparison of the incremental prognostic utility of different subclinical disease (SubDz) measures is not clear.
Methods: We evaluated participants aged 40-79 years (mean age 55 years, 56% women) from the Framingham Offspring...
A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00832-z.
Background. Sex- and race-specific pooled cohort equations (PCE) are recommended for estimating the 10-year risk of cardiovascular disease (CVD), with an absolute risk >7.5% indicating a clinical decision threshold.
Methods. We generated in silico 30,565 risk profiles in men and 29,515 in women by combining numerical (age, total and high-density li...
Objective
To assess age differences in risk factors for incident heart failure in the general population.
Design
Pooled population based cohort study.
Setting
Framingham Heart Study, Prevention of Renal and Vascular End-stage Disease Study, and Multi-Ethnic Study of Atherosclerosis.
Participants
24 675 participants without a history of heart fai...
Background
Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.
Methods
We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtr...
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10⁻⁸), of which 32 were in new BP-associated loci...
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci...
Background: The current clinical practice of defining obesity based on body mass index (BMI) does not capture differences in fat distribution between men and women. Visceral adipose tissue (VAT) as measured by computed tomography (CT), is an advanced measure of obesity that closely correlates with cardiometabolic risk independent of BMI. However, i...
Introduction: Greater parity has been associated with increased risk of cardiovascular disease, though effects on cardiac remodeling and heart failure risk remain unclear.
Hypothesis: We hypothesized that multiple prior live births are associated with (1) structural and functional cardiac remodeling and (2) risk of future heart failure.
Methods: We...
Recent results from 5 decades of Framingham Heart Study (FHS) data suggest former heavy smokers (≥20 pack-years) have higher ASCVD risk than never smokers up to 16 years after quitting. However, the ASCVD Risk Estimator Plus, which is based on the 2013 Pooled Cohort Equations (PCE) does not account for pack-years smoked and considers former smokers...
Introduction: Obesity and cardiometabolic dysfunction may be shared risk factors for development of cancer. We sought to examine the association of obesity and abdominal adiposity with incident cancer.
Methods: We studied participants of the Framingham Heart Study and Prevention of Renal and Vascular End-Stage Disease study. We examined the associa...
Background: Increased left ventricular (LV) mass is associated with future adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect black individuals. To understand the mechanisms that drive disease, particularly in black individuals, we undertook a proteomic screen in a black cohort and co...
Rural-urban differences in morbidity and mortality across the United States have been well documented and termed the “rural mortality penalty”. However, research studies frequently treat rural areas as homogeneous and often do not account for geospatial variability in rural health risks by both county, state, region, race, and sex within the United...
Importance:
Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.
Objective:
To assess performance of the PCE across clini...
Background
Measures of vascular dysfunction are related to adverse cardiovascular disease (CVD) outcomes in non‐Hispanic, White populations; however, data from Black individuals are limited. We aimed to investigate the associations between novel hemodynamic measures and prevalent CVD in a sample of Black individuals.
Methods and Results
Among olde...
Background:
After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR de...
Background:
Liver fibrosis, is independently associated with incident heart failure (HF). Investigating the association between liver fibrosis and type of HF, specifically HF with reduced ejection fraction (EF; HFrEF) or HF with preserved ejection fraction (HFpEF), may provide mechanistic insight into this association. We sought to determine the a...
Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing d...
Medical studies for chronic disease are often interested in the relation between longitudinal risk factor profiles and individuals' later life disease outcomes. These profiles may typically be subject to intermediate structural changes due to treatment or environmental influences. Analysis of such studies may be handled by the joint model framework...
Introduction and Hypothesis: Intrinsic frequencies (IFs) derived from arterial waveforms, representing the dominant instantaneous frequency during systole and diastole, are associated with cardiovascular performance, aging, and prevalent cardiovascular disease (CVD). However, prognostic value of these novel measures in a community-based sample is u...
Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence and coronary heart disease prevalence. Somatic...
Objectives:
A Mediterranean style diet may impact cardiometabolic health by modifying concentrations of circulating lipid species. Distinct circulating ceramide species are positively associated with cardiometabolic risk; whereas, ratios of very-long to long-chain ceramides demonstrate an inverse association. We evaluated the relation between cons...
Objectives:
To assess prospective association between circulating biomarkers of individual trans fatty acids (TFAs) and incident type 2 diabetes (T2D) in diverse populations.
Methods:
A harmonized analysis of individual level data was conducted for TFA biomarkers and incident T2D by pooling ten prospective cohort or nested-case-control studies f...
Introduction: Diet quality may alter cardiometabolic risk by the modification of circulating lipid species. Ceramides are a class of sphingolipid implicated in cardiometabolic risk. We hypothesized that a higher diet quality may be associated with lower plasma concentrations of three ceramide species.
Methods: Diet quality was reflective of adheren...
