Cardiac amyloidosis remains a rare disease caused by the extracellular deposition of abnormal proteins-amyloids in the myocardium. These protein structures in the myocardium are associated with high morbidity and mortality, with prognosis hinging on early detection and treatment. Three main types of cardiac amyloidosis have been identified: light chain (AL), familial or senile (ATTR), and secondary amyloidosis which is associated with chronic inflammation. Cardiac amyloidosis classically presents as diastolic heart failure with symptoms of volume overload low voltage on electrocardiogram ( ECG) and echocardiographic features of diastolic dysfunction and paradoxical left ventricular hypertrophy (paradoxical with respect to low voltage on ECG). Early suspicion should trigger additional laboratory and imaging workup to facilitate early detection. Early detection remains critical to prognosis. Herein, we present two patients admitted to a safety-net hospital within one month of each other with distinct presentations yet important, overlapping characteristics that led to the diagnosis of AL amyloidosis in both patients.

Cellular metabolism influences immune cell function, with mitochondrial fatty acid β-oxidation and oxidative phosphorylation required for multiple immune cell phenotypes. Carnitine palmitoyltransferase 1a (Cpt1a) is considered the rate-limiting enzyme for mitochondrial metabolism of long-chain fatty acids, and Cpt1a deficiency is associated with infant mortality and infection risk. This study was undertaken to test the hypothesis that impairment in Cpt1a-dependent fatty acid oxidation results in increased susceptibility to infection. Screening the Cpt1a gene for common variants predicted to affect protein function revealed allele rs2229738_T, which was associated with pneumonia risk in a targeted human phenome association study. Pharmacologic inhibition of Cpt1a increases mortality and impairs control of the infection in a murine model of bacterial pneumonia. Susceptibility to pneumonia is associated with blunted neutrophilic responses in mice and humans that result from impaired neutrophil trafficking to the site of infection. Chemotaxis responsible for neutrophil trafficking requires Cpt1a-dependent mitochondrial fatty acid oxidation for amplification of chemoattractant signals. These findings identify Cpt1a as a potential host determinant of infection susceptibility and demonstrate a requirement for mitochondrial fatty acid oxidation in neutrophil biology.

Introduction: The physiologic role of calcium for cardiomyocyte contractility is well established. Post cardiac surgery, maintaining normocalcemia is associated with improved right ventricular (RV) function as compared to hypocalcemia. Hypothesis: We hypothesize that lower serum ionized calcium (iCa) is associated with RV dysfunction in non-surgical subjects. Methods: From a de-identified electronic health record, we extracted demographic, laboratory, echocardiographic, and first right heart catheterization (RHC) data to perform a cross-sectional analysis. iCa, obtained within 2 days of RHC, was tested for association with hemodynamics and pulmonary artery pulsatility index (PAPI; pulmonary artery pulse pressure / right atrial pressure) as a measure of RV function. We tested the association of iCa with reader-assessed RV dysfunction by echocardiography. RV dysfunction was coded as 0=none, 1=mild, 2=moderate, and 3=severe. All analyses were performed using ordinal regression adjusted for age, sex, and self-declared race. Results: From the 1,658 participants identified: median age 61 years, 42% female, 76% white, 18% black, 82% with mean pulmonary artery pressure ≥20mmHg, and 28% with pulmonary vascular resistance ≥3 Wood units. We observed a positive association between iCa and PAPI (Figure 1A, P<0.0001, n=1,658). Higher iCa was positively associated with systemic pressures and negatively associated with pulmonary pressures (P<0.01). By echocardiography, lower iCa was associated with higher prevalence of RV dysfunction (Figure 1B, P<0.0001, n=1,355). Conclusion: In a clinical population referred for RHC, we concluded that higher iCa was associated with better RV function assessed by invasive hemodynamics and echocardiography. Further studies are needed to assess whether there is an etiologic relationship between iCa and RV function.

Objective Red cell distribution width (RDW) is an enigmatic biomarker associated with the presence and severity of multiple cardiovascular diseases (CVDs). It is unclear whether elevated RDW contributes to, results from, or is pleiotropically related to CVDs. We used contemporary genetic techniques to probe for evidence of aetiological associations between RDW, CVDs, and CVD risk factors. Methods Using an electronic health record (EHR)-based cohort, we built and deployed a genetic risk score (GRS) for RDW to test for shared genetic architecture between RDW and the cardiovascular phenome. We also created GRSs for common CVDs (coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, venous thromboembolism) and CVD risk factors (body mass index (BMI), low-density lipoprotein, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, serum triglycerides, estimated glomerular filtration rate, diabetes mellitus) to test each for association with RDW. Significant GRS associations were further interrogated by two-sample Mendelian randomisation (MR). In a separate EHR-based cohort, RDW values from 1-year pre-gastric bypass surgery and 1–2 years post-gastric bypass surgery were compared. Results In a cohort of 17 937 subjects, there were no significant associations between the RDW GRS and CVDs. Of the CVDs and CVD risk factors, only genetically predicted BMI was associated with RDW. In subsequent analyses, BMI was associated with RDW by multiple MR methods. In subjects undergoing bariatric surgery, RDW decreased postsurgery and followed a linear relationship with BMI change. Conclusions RDW is unlikely to be aetiologically upstream or downstream of CVDs or CVD risk factors except for BMI. Genetic and clinical association analyses support an aetiological relationship between BMI and RDW.

BACKGROUND:There is an unclear relationship of obesity to the pathogenesis and severity of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH).RESEARCH QUESTION:Is BMI casually associated with pulmonary artery pressure (PAP) and/or markers of pulmonary vascular remodeling?STUDY DESIGN AND METHODS:The study design was a two-sample inverse-variance weighted Mendelian randomization. We constructed two BMI genetic risk scores from genome-wide association study summary data and deployed them in nonoverlapping cohorts of subjects referred for right heart catheterization (RHC) or echocardiography. A BMI highly polygenic risk score (hpGRS) optimally powered to detect shared genetic architecture of obesity with other traits was tested for association with RHC parameters including markers of pulmonary vascular remodeling. A BMI strict genetic risk score (sGRS) composed of high-confidence genetic variants was used for Mendelian randomization analyses to assess if higher BMI causes higher PAP.RESULTS:Among all subjects, both directly measured BMI and hpGRS were positively associated with pulmonary arterial pressures but not markers of pulmonary vascular remodeling. Categorical analyses revealed BMI and hpGRS were associated with PVH but not PAH. Mendelian randomization of the sGRS supported that higher BMI is causal of higher systolic pulmonary artery pressure (sPAP). Sensitivity analyses showed sPAP-BMI sGRS relationship was preserved when either individuals with PAH or PVH were excluded. In the echocardiographic cohort, BMI and hpGRS were positively associated with estimated PAP and markers of left heart remodeling.INTERPRETATION:BMI is a modifier of pulmonary hypertension severity in both PAH and PVH but is only involved in the pathogenesis of PVH.

Acute heart failure and acute coronary syndrome (ACS) compel early coronary angiography (SCA); however, both conditions can be precipitated by hyperthyroidism, and in the setting of hyperthyroid state, iodinated contrast can precipitate life-threatening thyroid storm. No short-term strategy to

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH. A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively. We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80–2.01) in a multicentre case–control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (OR causal 1.07, 95% CI 0.92–1.24) or the secondary (OR causal 1.09, 95% CI 0.77–1.54) MR analysis. The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH.

Introduction: Red cell distribution width (RDW) and iron deficiency are strongly associated with PAH diagnosis and prognosis, but the longitudinal relationship of clinical hematologic variables and...

Acidic milieu is a hallmark of glycolytic metabolism which occurs in cancerous cells. The effect of the acidic environment on cancer progression can be categorized into effects on tumor cell survival, tumor metastasis, inflammatory response, and blood vessels. Yet the underlying signaling and cell biological underpinnings of these phenomena are not well understood. Here, we describe, ogremorphen, a first in class inhibitor of proton-sensing GPCR GPR68. Discovered from a chemical genetic zebrafish screen, ogremorphen perturbed neural crest migration. Furthermore, ogremorphen was shown to inhibit migration in a number of human melanoma lines, which derive from the neural crest. Phenome-wide association study identified a natural variant that is aberrantly active and is associated with metastasis of common cancers. Our study suggests that GPR68 activity is associated with an increased ability for cancer cell migration and contributes to metastasis.

Rationale: Red cell distribution width (RDW) is a prognostic factor in many diseases; however, its clinical utility remains limited because the relative value of RDW as a biomarker across disease states has not been established. Objectives: To establish an unbiased RDW disease hierarchy to guide the clinical use of RDW and to assess its relationship to cardiovascular hemodynamic and structural parameters. Methods: We performed phenome-wide association studies for RDW in discovery and replication cohorts derived from a deidentified electronic health record in nonanemic individuals. RDW values obtained within 30 days of echocardiogram or right heart catheterization were tested for association with structural and hemodynamic variables. Results: RDW was associated with 263 phenotypes in both men and women in the discovery cohort (n = 121,530), 48 of which replicated in an independent cohort (n = 2,039). The strongest associations were observed with pulmonary arterial hypertension (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.9-2.3), chronic pulmonary heart disease (OR, 2.0; 95% CI, 1.9-2.2), and congestive heart failure (OR, 1.9; 95% CI, 1.8-2.0); P < 1 X 10(-74) for all. By echocardiography, RDW was higher in the setting of right ventricular dysfunction than left ventricular dysfunction (P < 0.001). Measured invasively, mean pulmonary arterial pressure was associated with RDW (21 vs. 33 mm Hg at 25th vs. 75th percentile RDW; P < 1 X 10(-7)) and remained strongly significant even when controlling for mean pulmonary capillary wedge pressure (21 vs. 29 mm Hg at 25th vs. 75th percentile RDW; P < 1 X 10(-7)). Conclusions: Among 1,364 coded medical conditions, increased RDW was strongly associated with pulmonary hypertension and heart failure. Hemodynamic and echocardiographic phenotyping confirmed these associations and underscored that the most clinically relevant phenotype associated with RDW was pulmonary hypertension. These hypothesis-generating findings highlight the potential shared pathophysiology of pulmonary hypertension and elevated RDW. Elevated RDW in the absence of anemia should alert clinicians to the potential for underlying cardiopulmonary disease.

Introduction: Heart failure with reduced ejection fraction (HFrEF) is commonly attributed to hypertension, with transition from concentric left ventricular (LV) hypertrophy to maladaptive LV hypert...

ImportanceCurrent guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk.ObjectivesTo determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) function and increased risk of mortality.Design, Setting, and ParticipantsIn this cohort study, electronic health record data of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 and had recorded estimates of RVSP values were studied. Data were analyzed from February 2017 to May 2019.ExposuresMild ePH was defined as an RVSP value of 33 to 39 mm Hg. Right ventricular function was assessed using tricuspid annular plane systolic excursion (TAPSE), and RV-pulmonary arterial coupling was measured using the ratio of TAPSE to RVSP.Main Outcomes and MeasuresAssociations of mild ePH with mortality adjusted for relevant covariates were examined using Cox proportional hazard models with restricted cubic splines.ResultsOf the 47 784 included patients, 26 758 of 47 771 (56.0%) were female and 6040 of 44 763 (13.5%) were black, and the mean (SD) age was 59 (18) years. Patients with mild ePH had worse RV function compared with those with no ePH (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P < .001) and nearly double the prevalence of RV dysfunction (32.6% [92 of 282] vs 16.7% [170 of 1015]; P < .001). Compared with patients with RVSP less than 33 mm Hg, those with mild ePH also had reduced RV-pulmonary arterial coupling (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P < .001). An increase in adjusted mortality began at an RVSP value of 27 mm Hg (hazard ratio, 1.32; 95% CI, 1.02-1.70). Female sex was associated with increased mortality risk at any given RVSP value.Conclusions and RelevanceMild ePH was associated with RV dysfunction and worse RV-pulmonary arterial coupling in a clinical population seeking care. Future studies are needed to identify patients with mild ePH who are susceptible to adverse outcomes.

Parenteral prostacyclin therapy is the most efficacious pharmacologic treatment for pulmonary arterial hypertension (PAH), but clinical response is variable. We sought to identify clinical, hemodynamic, and genetic associations with response to prostacyclin therapy. We performed a retrospective analysis of patients within a de-identified electronic health record and associated DNA biobank. Patients with PAH and a right heart catheterization (RHC) in the six months before initiation of a parenteral prostacyclin were included. Responders were defined a priori by attainment of World Health Organization (WHO) functional class (FC) 2 or better at the time of repeat RHC within two years. We performed exploratory analyses to identify genomic associations with prostacyclin response. Of 129 patients identified, 54 met our criteria for "responders". These patients were younger, more likely to be male, and were less likely to have connective tissue disease-related PAH. At follow-up, responders had improved hemodynamics, 6-min walk distance, and long-term survival. Baseline PA oxygen saturation (hazard ratio [HR] 0.568 [0.34-0.95]) and follow-up FC (HR=2.57 [1.22-5.43]) were associated with survival. Prostacyclin responders were enriched in alleles related to cell development and circulatory system development and pathways related to aldosterone metabolism, cAMP signaling, and vascular smooth muscle contraction (P<0.001). Age at treatment initiation, WHO FC at short-term follow-up, and PA O-2% are associated with survival in patients with PAH exposed to parenteral prostacyclins. Exploratory genetic analysis yielded associations in biologically relevant pathways in the pathogenesis of PAH.

Introduction: One third of adults in the US have NAFLD, a disease characterized by accumulation of triglycerides (TG) in the liver. NAFLD is an independent risk factor for coronary artery disease. ...