Pepine, Carl J.

Abstract Background Adverse pregnancy outcomes (APO) are associated with increased maternal risk of cardiovascular disease (CVD) and mortality. Ischemia with no obstructive coronary artery disease (INOCA) is predominant in women, however the association of APO history with INOCA is poorly understood. Purpose To compare clinical characteristics, symptoms, cardiac structure and function and coronary microvascular dysfunction in women suspected to have INOCA with or without a history of APO. Methods Women’s Ischemia Syndrome Evaluation (WISE) CVD (NCT00832702) and WISE pre-HFpEF (NCT02582021) prospective cohorts of women with suspected INOCA were merged and utilized to determine among women with at least 1 prior pregnancy whether a history of APO was associated with ischemic symptoms, and to characterize CMRI measured left ventricle (LV) structure and function, myocardial deformation (systolic and diastolic strain) and coronary microvascular dysfunction on invasive coronary functional testing (CFT). Self-reported APO was defined as hypertensive disorder of pregnancy (HDP), gestational diabetes, preterm birth (<37-week gestation), low birth weight (<5lbs). Results In a cohort of 469 women with suspected INOCA, (mean average age 55 [SD 10.2] years) and at least 1 prior pregnancy, 138 (29%) had history of at least 1 APO. Among women with history of APO, 78 reported HDP, 50 gestational diabetes, 27 pre-term birth, 8 low birth weight. Women with a history of APO were younger, had higher rates of hypertension and diabetes, higher BMI and lower SAQ and DASI scores compared to those with no history of APO (Table). LV ejection fraction (EF) was lower and early diastolic strain rate/LVEDP was higher in women with APO history compared to those without APO history. Conclusion(s) In cohort of women with INOCA, history of APO was highly prevalent. Despite younger age, women with history of APO had higher rates of CVD risk factors, worse ischemic symptoms and functional capacity, lower EF, and higher filling pressures. Our findings suggest a potential for APO history to better identify women with worse prognosis that warrants further investigation and aggressive management.

Abstract MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I 2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I 2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease and vasodilators are the mainstay for its therapy. However, they offer restricted advancement opportunities for the control and treatment of PAH. Thus, the PAH field needs a paradigm-shifting strategy for its successful management and control. Objective: To test the hypothesis that gut microbial dysbiosis and its increased permeability are associated with PAH. Methods: Healthy control subjects and patients with PAH were recruited from two hospitals in the Americas to ascertain the wider applicability of our hypothesis. Fecal samples of PAH patients (n=19) and control, reference subjects (n=16) were obtained at the Hospital de Clinicas de Porto Alegre, Brazil, for microbiota analysis. Plasma/serum samples were collected from PAH patients (n=22) and control, reference subjects (n=19) at the Mayo Clinic, Jacksonville, Florida, USA, for analysis of gut leakiness and inflammatory biomarkers. Results: In PAH patients, a significant decrease in abundance, diversity and evenness of gut microbial population was observed as measured by 16S ribosomal DNA analyses of fecal samples. Analysis of fecal bacteria populations also demonstrated significant increases in gram-positive, facultative-anaerobic genera, such as Actinomyces, Bifidobacterium Slackia, and Streptococcus in PAH patients. Further, plasma zonulin and iFABP, the biomarkers for gut leakiness increased by 40.3% (p=0.0018) and 81% (p=0.0012), respectively in PAH patients. High plasma LPS, HMGB1, and TIMP1 levels are involved in increased gut inflammation and gut mucosal injury. We also observed LPS, HMGB1, and TIMP1 levels were increased by 363% (p=0.0096), 20.5% (p=0.0027), and 213% (p<0.0001), respectively in PAH patients. Conclusions: PAH patients demonstrate profound gut microbial dysbiosis and increased permeability and inflammation. Further characterization of PAH specific microbial species holds novel management potential with the use of pre- and probiotics, designer antibiotics, appropriate fecal/bacterial transplantation, on top of background proven therapies.

We sought to update norms for peak systolic blood pressure (SBP) on the graded exercise test and examine its prognostic value in patients without baseline cardiovascular disease. Mayo graded exercise test data (1993–2010) were reviewed for nonimaging tests using Bruce protocol, selecting Minnesota residents 30 to 79 years without baseline cardiovascular disease. We formed a pure cohort of patients without factors significantly affecting peak SBP to determine peak SBP percentile norms by age and sex. Then we divided the full cohort of patients into 5 groups based on peak SBP percentiles: low (<10th), borderline low (10th–25th), referent (25th–75th), borderline high (75th–90th), and high (>90th). The relationship between peak SBP and mortality was tested using Cox regression adjusting for age, sex, and comorbidities affecting peak SBP or mortality. We identified 20 760 eligible patients with 7313 females (35%) and mean age 51.5±10.7 years. Our pure cohort included 7810 patients. Over 12.5±5.0 years follow-up, there were 1582 deaths, including 541 cardiovascular deaths. In the fully adjusted model, low-peak SBP was associated with increased total mortality (heart rate, 1.41 [1.19–1.66], P <0.0001) and cardiovascular mortality (heart rate, 1.54 [1.16–2.03], P =0.001), while borderline low-peak SBP was associated with increased cardiovascular mortality only (heart rate, 1.36 [1.02–1.81], P =0.027). High peak SBP was associated with increased total mortality only in the age-sex adjusted model (heart rate, 1.18 [1.02–1.36], P =0.026), not after full adjustment. We conclude that low exercise peak SBP is an independent predictor of higher total and cardiovascular mortality.

Objectives: Pulmonary arterial hypertension (PAH) is a deadly disease without any effective cure. Identification of the PAH-associated gut microbiome may shift conceptual paradigms of the disease that could lead to new therapeutic advancement. We tested the hypothesis that PAH patients have distinct gut microbiome composition contributing to PAH that predicts the disease. Methods: A total of 71 participants were recruited. Fecal microbiomes of 18 type 1 PAH patients (mean pulmonary arterial pressure [mPAP] 57.4±16.7 mmHg) and 13 reference subjects were compared by shotgun metagenomics methods. Plasma from 22 PAH patients (mPAP 48.3± 18.4 mmHg) and 18 reference subjects was used in untargeted metabolomic analysis. Results: Significant taxonomic and functional changes in the microbiome of the PAH cohort were observed. PAH patients had increased gut barrier dysfunction and inflammation as evidenced by plasma markers and metagenomics. A random forest model predicted PAH from gut microbiome composition with 82.6% accuracy. Changes in the gut microbiome were associated with purine metabolism, arginine biosynthesis, trimethylamine production and tryptophan biosynthesis, all previously associated with PAH. Area under the curve of the multi-variate receiver operating characteristics (ROC) plot for metabolites of these pathways had a predictive accuracy of 0.965. Conclusions: The gut microbiome/metabolites of PAH patients predict disease in random forest models and ROC analyses. The unique PAH gut microbiome influences carnitine, arginine and purine metabolisms contributing to pathophysiology. These highlight previously unknown roles of gut bacteria and their metabolites in PAH that could lead to new therapeutic or management paradigms.

Background There exists a wide interindividual variability in blood pressure ( BP ) response to β 1 ‐blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome‐wide meta‐analysis of genetic variants influencing β 1 ‐blocker BP response. Methods and Results Genome‐wide association analysis for systolic BP and diastolic BP response to β 1 ‐blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta‐analysis and single nucleotide polymorphisms (SNPs) with P <10 −4 were tested for replication in 2 independent randomized clinical trials of β 1 ‐blocker–treated patients of European ancestry (n=1552). Regions harboring the replicated SNP s were validated in a β 1 ‐blocker–treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST 1 was associated with systolic BP response to β 1 ‐blockers in the discovery meta‐analysis ( P =9.33×10 −5 , β=−3.21 mm Hg) and replicated at Bonferroni significance ( P =1.85×10 −4 , β=−4.86 mm Hg) in the replication meta‐analysis with combined meta‐analysis approaching genome‐wide significance ( P =2.18×10 −7 ). This SNP in BST 1 is in linkage disequilibrium with several SNP s with putative regulatory functions in nearby genes, including CD 38 , FBXL 5 , and FGFBP 1 , all of which have been implicated in BP regulation. SNP s in this genetic region were also associated with BP response in the black cohort. Conclusions Data from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST 1 containing locus on chromosome 4 is associated with β 1 ‐blocker BP response. Given the previous associations of this region with BP , this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.

Abstractβ‐Blockers’ heart rate (HR)‐lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β‐blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β‐blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single‐nucleotide polymorphisms (SNPs) previously associated with the HR response to β‐blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β‐blocker used in the PEAR (n = 757), PEAR‐2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR‐2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β‐blockers in whites (rs1042714 C‐allele carriers, meta‐analysis β = –0.95 beats per minute [bpm], meta‐analysis P = 3×10–4; rs1042713 A‐allele carriers, meta‐analysis β = –1.15 bpm, meta‐analysis P = 2×10–3). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β‐blockade in hypertensive patient cohorts.

Objectives: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease without effective cure. The objective of this study is to test the hypothesis that PAH patients have a distinct gut microbiome composition acting as a driving force for the increased PAH metabolic biomarkers, acyl carnitines and urate. Methods: Fecal samples from 18 type 1 PAH patients (mean pulmonary arterial pressure [mPAP] 57.4±16.7 mmHg) and 13 reference subjects in Brazil were collected for comparison of microbiome using shotgun metagenomics. Plasma samples from 33 type I PAH patients (mPAP 51.7± 13.5 mmHg) and 19 reference subjects in the USA were used for untargeted metabolomic analysis. Results: More than 80 bacterial taxa were differentially enriched in the microbiomes of the PAH cohort. Random forest machine-learning algorithm predicted PAH patients with 82.4% accuracy from their gut microbiome composition. The most increased taxa in the PAH microbiome were trimethylamine (TMA) producing bacteria like Collinsella (P=0.0037). The PAH metabolome also showed increases of gut microbiome-derived short chain acyl carnitines like isubutyrylcarnitine (P=0.010) and valerylcarnitine (P=0.030), which are the precursors of TMA. In addition, increased urate (P=0.0004) and allantoin (P=0.027) in PAH plasma correlated with significantly increased enzymes producing urate in the PAH microbiome (purine metabolism (P=0.017) and xanthine oxidase (P<0.05)). Conclusion: These findings suggest that the random forest modeling of the gut microbiome composition can be used for prediction of PAH and that the unique gut microbiome of PAH influences acyl carnitines and urate metabolism to contribute to pathophysiology.