Novel Risk Factor For Development Research Articles

Donor-Specific Antibody Testing is an Effective Surveillance Strategy for High-Risk Antibody Mediated Rejection in Heart Transplant Patients in the Contemporary Era.

Pathologic antibody mediated rejection (pAMR) evaluation and donor specific antibody (DSA) testing are recommended in the first year after heart transplantation (HTx) in adult patients. Whether DSA testing adds prognostic information to contemporary pAMR surveillance has not been fully studied. This was a single center study of consecutive endomyocardial biopsies (EMB) performed between November 2010 and February 2023 in adult HTx patients. The primary objective was to evaluate whether DSA testing contributes additional information to pAMR surveillance to better predict overall survival. Secondary endpoints included cardiac allograft dysfunction and loss. A total of 6,033 EMBs from 544 HTx patients were reviewed for the study. The pAMR+/DSA+ group had significantly lower overall survival versus the pAMR-/DSA- group (hazard ratio [HR] = 2.63; 95% confidence interval [CI], 1.35-5.11; pc = 0.013). In the pAMR+/DSA+ group, patients with cardiac allograft dysfunction, compared to those without allograft dysfunction, had significantly lower overall and cardiac survival (pc < 0.001 for both). In contrast, pAMR+/DSA+ and pAMR-/DSA- patients without cardiac allograft dysfunction showed no difference in overall and cardiac survival. Primary graft dysfunction (PGD) was a novel risk factor for development of de novo DSAs (dnDSA) three weeks post-HTx (p = 0.007). DSA testing as the primary surveillance method can identify high-risk pAMR+/DSA+ patients. Surveillance pAMR testing in the contemporary era may need to be reevaluated. Earlier DSA testing at 10-14 days post-HTx should be considered in PGD patients.

Dysbiosis—An Etiological Factor for Cardiovascular Diseases and the Therapeutic Benefits of Gut Microflora

The human gut is colonized by a variety of microorganisms especially bacteria. There are multiple evidences that gut microflora dysbiosis is a novel risk factor for development of various intestine-related diseases such as irritable bowel syndrome and inflammatory bowel disease as well as nonintestinal diseases including obesity, type II diabetes, and cardiovascular diseases. A mutual relationship among the host’s immune system and the metabolites produced by the gut microflora, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, is present. Alterations in the host-microbial interaction lead to impaired homeostasis and thus contribute towards the activation of several pathways that causes progression of cardiovascular diseases. This review summarizes the role of gut microflora dysbiosis in the development and progression of atherosclerosis, coronary artery disease, and hypertension. Dysbiosis has been implicated in the pathogenesis of atherosclerosis by TLR activation, intracellular Ca2+ release, FXR-induced signalling, and decreased removal of cholesterol from peripheral macrophages, while in hypertension the mechanism involved is prolonged haemodynamic effects of angiotensin-II and oxLDL-induced hypertension. In fact, CVDs are the leading cause of mortality across the globe; thus, targeting the gut microflora in the treatment of these diseases along with the conventional therapy can markedly reduce the cardiovascular disease burden. The gut microbiota-targeted treatment including prebiotics, probiotics, and postbiotics can be therapeutically beneficial. In future, the heart-gut axis can be presented as a novel and clinically relevant area for research.

Whole Genome Sequencing Uncovers a Rare Germline Variant in ATM Associated with Familial Myeloproliferative Neoplasms

Introduction: Myeloproliferative neoplasms (MPN) are sporadic diseases characterized by a somatic driver mutation in the JAK2, CALR or MPL gene. Although it is generally considered a sporadic disease, approximately 10% of MPN cases display familial clustering, and there is a 5 to 7-fold increased risk of developing an MPN among first degree relatives of MPN patients. In contrast to other myeloid malignancies, investigation of large pedigrees with familial clustering of MPN has failed to identify high-risk predisposition genes relevant to the general MPN population. Genome wide association studies (GWAS) have identified common, low penetrance risk alleles for MPN predisposition in multiple genes including JAK2, TERT, TET2, ATM and SH2B3. In order to identify novel germline predisposition variants in MPN, an unbiased whole genome sequencing (WGS) approach was utilized to examine genomic structure and germline variations in a cohort of individuals with familial MPN.Methods: The study cohort was comprised of 67 individuals with familial MPN enrolled in a prospective research registry at Johns Hopkins Hospital. Familial MPN was defined as a diagnosis of MPN in an individual with a family history of MPN or related myeloid malignancy (myelodysplastic syndrome and chronic myelomonocytic leukemia) in a first or second degree relative. Neutrophil genomic DNA was subjected to WGS using Illumina HiSeq platform and sequenced to 60x depth. We performed germline variant calling using HaplotypeCaller and following the GATK best practices. The variants detected were further enriched for germline by allele frequency 40-60% or >90% and presence in the gnomAD database. Non-synonymous coding variants that occurred in the study cohort at a statistically higher frequency that in the general population (gnomAD) were selected for further analysis. Prediction of variant deleteriousness was assessed by 4 algorithms (Provean, SIFT, Polyphen-2, CADD).Results: Filtering of 32,788 non-synonymous, likely germline variants produced 148 that occurred at a higher frequency in our cohort than in the general population (p < 0.01, Fisher's exact test). Of these, 29 were predicted to be pathogenic in 3 out of 4 algorithms. Five unrelated individuals were found to harbor a heterozygous p.Leu2307Phe variant in the ATM gene (chr11:108326169 C>T). The clinical characteristics of these individuals are presented in Table 1. The structure prediction of ATM indicates that Ser2306 is a potential phosphorylation site of protein kinase A, suggesting that the methionine-aromatic bond between M2026 and the mutated F2307 may block the phosphorylation of S2306 (Figure 1).Conclusions: We identified a rare ATM germline variant (chr11:108326169 C>T; p.Leu2307Phe) present in 5 individuals with familial MPN. ATM is involved in DNA damage repair and important in the maintenance of genomic integrity. Heterozygous germline variants in ATM are known to predispose to multiple cancer types, including breast, prostate, pancreatic and melanoma. Further, common polymorphisms in ATM have been found to be associated with the MPN phenotype via GWAS. Our data suggests that this variant may impact ATM activation and its function in DNA damage repair, and functional studies are in progress. These data implicate a rare germline ATM variant as a novel risk factor for development of MPN. [Display omitted] DisclosuresHourigan: Sellas: Research Funding.

Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23

Both genetic predisposition and environmental factors appear to play a role in inflammatory bowel disease (IBD) development. Genetic studies in humans have linked the interleukin (IL)-23 signaling pathway with IBD, but the environmental factors contributing to disease have remained elusive. Here, we show that the azo dyes Red 40 and Yellow 6, the most abundant food colorants in the world, can trigger an IBD-like colitis in mice conditionally expressing IL-23, or in two additional animal models in which IL-23 expression was augmented. Increased IL-23 expression led to generation of activated CD4+ Tcells that expressed interferon-γ and transferred disease to mice exposed to Red 40. Colitis induction was dependent on the commensal microbiota promoting the azo reduction of Red 40 and generation of a metabolite, 1-amino-2-naphthol-6-sulfonate sodium salt. Together these findings suggest that specific food colorants represent novel risk factors for development of colitis in mice with increased IL-23 signaling.

Clinical Implications

HomeHypertensionVol. 75, No. 4Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published11 Mar 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.14732Hypertension. 2020;75:893is related toRisk of Developing Hypokalemia in Patients With Hypertension Treated With Combination Antihypertensive TherapyPrevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension UnitBlood Pressure Variability and the Risk of DementiaBlood Pressure Variability and Dementia (page 982)Download figureDownload PowerPointDementia is a major health concern and the prevalence rises with the aging of the population. Recently, raised blood pressure variability (BPV) has emerged as a novel risk factor for development and progression of cognitive decline. However, evidence for the association of BPV and incidence of dementia is limited. In this nationwide retrospective cohort study, we therefore aimed to investigate the association between visit-to-visit BPV and the incidence of dementia in 7 844 814 participants without a history of any dementia who underwent ≥3 health examinations from 2005 to 2012 in the Korean National Health Insurance System cohort. Dementia was directly associated with higher BPV, both systolic and diastolic. In particular, having both higher systolic and diastolic BPV had additive effects on the risk of all-cause dementia, Alzheimer dementia, and vascular dementia. These associations were consistent across variability indices and independent of various factors, including use of antihypertensive drugs, blood pressure control status, or absolute blood pressure change during follow-up. These observations suggest the possibility of a causal relationship between BPV and development of dementia. They highlight that antihypertensive treatment which attenuates long-term BPV may offer benefits in reducing dementia risk in high-risk groups such as older people. Further research is warranted to examine whether reducing variability of blood pressure parameters decreases adverse outcomes.Hypokalemia: Combination Antihypertensive Therapy (page 966)Download figureDownload PowerPointManagement of arterial hypertension implies both lifestyle changes and medical treatment. In most cases, nonpharmacological strategies are not sufficient to achieve optimal blood pressure control and ≈70% of patients with high blood pressure achieve the therapeutic goal of <140/90 mm Hg with combination therapy only. Hypokalemia and hyperkalemia are common side effects of the drugs used to treat hypertension. Awareness of the risk factors associated with potassium disturbances is important to identify patients at risk. We found that the combination of thiazides with calcium channel blockers, renin-angiotensin system inhibitors, or β-blockers was strongly associated with increased hypokalemia risk within 90 days of treatment initiation, despite potassium supplementation in many patients. We recommend close monitoring of potassium status in patients prescribed thiazide diuretics. Maybe use of thiazide-like diuretics instead of thiazides can reduce the risk of low potassium concentrations, as they have a lower natriuretic effect.Hypokalemia and Primary Aldosteronism in Patients with Hypertension (page 1025)Download figureDownload PowerPointPrimary aldosteronism (PA) used to be considered a rare disorder associated with severe hypertension and spontaneous hypokalemia. The widespread screening of patients with hypertension using the aldosterone-to-renin-ratio increased the detection of milder forms and, as a consequence, normokalemic hypertension was uncovered as the most common phenotype of PA, with hypokalemia detected in around a third of cases. The Endocrine Society guideline recommends screening for PA in patients with moderate and severe hypertension, drug-resistant hypertension, and in cases of adrenal incidentaloma. The prevalence of PA is well defined in these patient cohorts. The guideline also highly recommends screening hypertensive patients with spontaneous or diuretic-induced hypokalemia. Surprisingly, the prevalence of PA in patients with hypokalemic hypertension is unknown; the guideline recommendation is based on expert opinion and pathophysiological considerations. In our retrospective observational study, we present the first report of the prevalence of PA in patients with hypokalemia referred to a tertiary hypertension unit. The prevalence of PA gradually increased with decreasing serum potassium concentrations reaching 9 of every 10 patients with spontaneous hypokalemia and serum potassium <2.5 mmol/L. Patients with hypertension and hypokalemia displayed a worse cardiovascular risk profile than patients with normokalemia, independent of PA diagnosis. With our findings, we confirm that hypokalemia strongly suggests PA and support the guideline recommendation to screen hypokalemic patients with hypertension, although normokalemia does not exclude the diagnosis. Previous Back to top Next FiguresReferencesRelatedDetailsCited By (2020) Worldwide Increase in Diagnosis of Hypertension in Children, AAP Grand Rounds, 10.1542/gr.43-5-59, 43:5, (59-59), Online publication date: 1-May-2020. Related articlesRisk of Developing Hypokalemia in Patients With Hypertension Treated With Combination Antihypertensive TherapyMaria Lukács Krogager, et al. Hypertension. 2020;75:966-972Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension UnitJacopo Burrello, et al. Hypertension. 2020;75:1025-1033Blood Pressure Variability and the Risk of DementiaJung Eun Yoo, et al. Hypertension. 2020;75:982-990 April 2020Vol 75, Issue 4 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.14732PMID: 32160097 Originally publishedMarch 11, 2020 PDF download Advertisement

Aortic Valve Thickening as a Novel Risk Factor for Development of Aortic Incompetence after Left Ventricular Assist Device Implantation

Introduction The development of aortic incompetence (AI) after left ventricular assist device (LVAD) implantation occurs in 25-30% of all LVAD patients and contributes to increased morbidity. While the underlying pathophysiology is still unclear, previous pathology studies have shown that LVAD patients have accelerated aortic valve cusp remodeling when compared to other heart failure patients; this has been postulated to be the mechanism for AI in the LVAD population. A number of studies have attempted to identify populations that are at risk of developing AI, but none have assessed the effect of preoperative aortic valve sclerosis as a risk factor. We sought to assess the impact of preoperative aortic valve sclerosis on the development of AI in patients requiring LVAD support. Methods We retrospectively reviewed medical charts of patients implanted with Heartmate II (Abbott) and Heartware HVAD (Medtronic) LVADs at a large academic medical center between January 2011 and September 2018. We reviewed transthoracic echocardiography preoperatively and at 1, 3, 6, 9, and 12-months post LVAD implantation. Preoperative aortic valve thickening was predefined as mild or worse sclerosis on transthoracic echocardiogram. Patients with more than mild AI preoperatively or concomitant aortic valve replacement (AVR) were excluded from the analysis. Results A total of 660 echocardiography studies in 176 patients on LVAD support (mean age 55.1±14.0 years old, 84% male, 36.9% HVAD, 63.1% Heartmate2) were identified and analyzed. 25.5% were identified as bridge to transplant, 55.7% as destination therapy, 15.3% as bridge to decision and 3.4% as bridge to recovery. 21.6% were INTERMACS profile 1 and 71.0% were INTERMACS 2 and 3. 49.4% of the patients (n=87) had at least mild AI over the follow up period. The main risk factors identified for the development of AI post-operatively were aortic valve thickening on preoperative echocardiography (61.9% vs 42.4%, p = 0.014) and older age (58.9 ± 13.1 vs 51.4 ± 13.1, p = 0.003). On a multivariate analysis, patients with preoperative aortic valve thickening had a 2.1 times increased risk of developing mild or worse AI post LVAD implant (odds ratio of 2.1, p = 0.027). Conclusions Occurrence of aortic insufficiency is very frequent in patients on prolonged LVAD support. Our study is the first to show that preoperative aortic valve thickening is a significant risk factor for postoperative AI and should be included as a risk factor in decision making prior to LVAD implantation.

Gestational Diabetes Is Characterized by Reduced Mitochondrial Protein Expression and Altered Calcium Signaling Proteins in Skeletal Muscle

The rising prevalence of gestational diabetes mellitus (GDM) affects up to 18% of pregnant women with immediate and long-term metabolic consequences for both mother and infant. Abnormal glucose uptake and lipid oxidation are hallmark features of GDM prompting us to use an exploratory proteomics approach to investigate the cellular mechanisms underlying differences in skeletal muscle metabolism between obese pregnant women with GDM (OGDM) and obese pregnant women with normal glucose tolerance (ONGT). Functional validation was performed in a second cohort of obese OGDM and ONGT pregnant women. Quantitative proteomic analysis in rectus abdominus skeletal muscle tissue collected at delivery revealed reduced protein content of mitochondrial complex I (C-I) subunits (NDUFS3, NDUFV2) and altered content of proteins involved in calcium homeostasis/signaling (calcineurin A, α1-syntrophin, annexin A4) in OGDM (n = 6) vs. ONGT (n = 6). Follow-up analyses showed reduced enzymatic activity of mitochondrial complexes C-I, C-III, and C-IV (−60–75%) in the OGDM (n = 8) compared with ONGT (n = 10) subjects, though no differences were observed for mitochondrial complex protein content. Upstream regulators of mitochondrial biogenesis and oxidative phosphorylation were not different between groups. However, AMPK phosphorylation was dramatically reduced by 75% in the OGDM women. These data suggest that GDM is associated with reduced skeletal muscle oxidative phosphorylation and disordered calcium homeostasis. These relationships deserve further attention as they may represent novel risk factors for development of GDM and may have implications on the effectiveness of physical activity interventions on both treatment strategies for GDM and for prevention of type 2 diabetes postpartum.

Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.

Signaling by hormones and neurotransmitters that activate G protein-coupled receptors (GPCRs) maintains blood pressure within the normal range despite large changes in cardiac output that can occur within seconds. This implies that blood pressure regulation requires precise kinetic control of GPCR signaling. To test this hypothesis, we analyzed mice deficient in RGS2, a GTPase-activating protein that greatly accelerates the deactivation rate of heterotrimeric G proteins in vitro. Both rgs2+/- and rgs2-/- mice exhibited a strong hypertensive phenotype, renovascular abnormalities, persistent constriction of the resistance vasculature, and prolonged response of the vasculature to vasoconstrictors in vivo. Analysis of P2Y receptor-mediated Ca2+ signaling in vascular smooth muscle cells in vitro indicated that loss of RGS2 increased agonist potency and efficacy and slowed the kinetics of signal termination. These results establish that abnormally prolonged signaling by G protein-coupled vasoconstrictor receptors can contribute to the onset of hypertension, and they suggest that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans.