Transverse aortic constriction (TAC) is a well-established model of pressure overload-induced cardiac hypertrophy and failure in mice. The degree of constriction "tightness" dictates the TAC severity ...and is determined by the gauge (G) of needle used. Though many reports use the TAC model, few studies have directly compared the range of resulting phenotypes. In this study adult male mice were randomized to receive TAC surgery with varying degrees of tightness: mild (25G), moderate (26G) or severe (27G) for 4 weeks, alongside sham-operated controls. Weekly echocardiography and terminal haemodynamic measurements determined cardiac remodelling and function. All TAC models induced significant, severity-dependent left ventricular hypertrophy and diastolic dysfunction compared to sham mice. Mice subjected to 26G TAC additionally exhibited mild systolic dysfunction and cardiac fibrosis, whereas mice in the 27G TAC group had more severe systolic and diastolic dysfunction, severe cardiac fibrosis, and were more likely to display features of heart failure, such as elevated plasma BNP. We also observed renal atrophy in 27G TAC mice, in the absence of renal structural, functional or gene expression changes. 25G, 26G and 27G TAC produced different responses in terms of cardiac structure and function. These distinct phenotypes may be useful in different preclinical settings.
Nutrition transition towards a Western diet is happening in parallel with the rapidly increasing rates of cardiovascular disease and its risk factors in Kuwait. The cardiometabolic deaths ...attributable to poor diet have not been quantified among Kuwaiti adults.
Using a Comparative Risk Assessment model that incorporated dietary intake data from Kuwait's first national nutrition survey, number of cardiometabolic deaths from the World Health Organization, and estimated associations of diet with cardiometabolic deaths from the Global Burden of Disease project, we estimated the number and proportion of cardiometabolic deaths attributable to suboptimal intake of 10 dietary factors among Kuwaiti adults ages 25+ years, and by population subgroups.
An estimated 1,308 (95% uncertainty interval UI = 1,228-1,485) cardiometabolic deaths were attributed to suboptimal diet, accounting for 64.7% (95% UI = 60.7%-73.4%) of all cardiometabolic deaths in Kuwait in 2009. The low intake of nuts/seeds was associated with the highest estimated number and proportion of cardiometabolic deaths (n = 380, 18.8%), followed by high intake of sodium (n = 256, 12.6%), low intake of fruits (n = 250, 12.4%), low intake of vegetables (n = 236, 11.7%), low intake of whole grains (n = 201, 9.9%), and high intake of sugar-sweetened beverages (n = 201, 9.9%). The estimated proportions of cardiometabolic deaths attributable to suboptimal diet were higher in men (67.7%) than women (57.8%) and in younger adults aged 25-34 years (84.5%) than older adults aged ≥55 years (55.6%).
Suboptimal dietary intake was associated with a very substantial proportion of cardiometabolic deaths among Kuwaiti adults in 2009, with young adults and men experiencing the largest proportion of diet-associated cardiometabolic deaths in Kuwait.
Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, ...myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine.
Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In ...2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.
Acute declines in kidney function occur in approximately 20%-30% of patients with acute decompensated heart failure, but its significance is unclear, and the importance of its context is not known. ...This study aimed to determine the prognostic value of a decline in kidney function in the context of decongestion among patients admitted with acute decompensated heart failure.
Using data from patients enrolled in the Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome Study (CARRESS) and Diuretic Optimization Strategies Evaluation (DOSE) trials, we used multivariable Cox regression models to evaluate the association between decline in estimated glomerular filtration rate (eGFR) and change in N-terminal pro-b-type natriuretic peptide (NT-proBNP) with a composite outcome of death and rehospitalization, as well as testing for an interaction between the two.
Among 435 patients, in-hospital decline in eGFR was not significantly associated with death and rehospitalization (hazard ratio HR = 0.89 per 30% decline, 95% confidence interval CI 0.74, 1.07), whereas decline in NT-proBNP was associated with lower risk (HR = 0.69 per halving, 95% CI 0.58, 0.83). There was a significant interaction (P = 0.002 unadjusted; P = 0.03 adjusted) between decline in eGFR and change in NT-proBNP where a decline in eGFR was associated with better outcomes when NT-proBNP declined (HR = 0.78 per 30% decline in eGFR, 95% CI 0.61, 0.99), but not when NT-proBNP increased (HR = 0.99, 95% CI 0.76, 1.30).
Decline in kidney function during therapy for acute decompensated heart failure is associated with improved outcomes as long as NT-proBNP levels are decreasing as well, suggesting that incorporation of congestion biomarkers may aid clinical interpretation of eGFR declines.
Hypertrophic cardiomyopathy (HCM) is considered a primary disorder of the sarcomere resulting in unexplained left ventricular hypertrophy but the paradoxical association of nonmyocyte phenotypes such ...as fibrosis, mitral valve anomalies and microvascular occlusion is unexplained. To understand the interplay between cardiomyocyte and nonmyocyte cell types in human HCM, single nuclei RNA-sequencing was performed on myectomy specimens from HCM patients with left ventricular outflow tract obstruction and control samples from donor hearts free of cardiovascular disease. Clustering analysis based on gene expression patterns identified a total of 34 distinct cell populations, which were classified into 10 different cell types based on marker gene expression. Differential gene expression analysis comparing HCM to Normal datasets revealed differences in sarcomere and extracellular matrix gene expression. Analysis of expressed ligand-receptor pairs across multiple cell types indicated profound alteration in HCM intercellular communication, particularly between cardiomyocytes and fibroblasts, fibroblasts and lymphocytes and involving integrin β1 and its multiple extracellular matrix (ECM) cognate ligands. These findings provide a paradigm for how sarcomere dysfunction is associated with reduced cardiomyocyte secretion of ECM ligands, altered fibroblast ligand-receptor interactions with other cell types and increased fibroblast to lymphocyte signaling, which can further alter the ECM composition and promote nonmyocyte phenotypes.
Genome-wide association studies (GWAS) have identified consistent associations with obesity. However, the mechanisms remain unclear.
The objective was to determine the association between obesity ...susceptibility loci and dietary intake.
The association of GWAS-identified obesity risk alleles (FTO, MC4R, SH2B1, BDNF, INSIG2, TNNI3K, NISCH-STAB1, MTIF3, MAP2K5, QPCTL/GIPR, and PPARG) with dietary intake, measured through food-frequency questionnaires, was investigated in 2075 participants from the Look AHEAD (Action for Health in Diabetes) clinical trial. We adjusted for age, sex, population stratification, and study site.
Obesity risk alleles at FTO rs1421085 significantly predicted more eating episodes per day (P = 0.001)-an effect that persisted after adjustment for body weight (P = 0.004). Risk variants within BDNF were significantly associated with more servings from the dairy product and the meat, eggs, nuts, and beans food groups (P ≤ 0.004). The risk allele at SH2B1 rs4788099 was significantly associated with more servings of dairy products (P = 0.001), whereas the risk allele at TNNI3K rs1514176 was significantly associated with a lower percentage of energy from protein (P = 0.002).
These findings suggest that obesity risk loci may affect the pattern and content of food consumption among overweight or obese individuals with type 2 diabetes. The Look AHEAD Genetic Ancillary Study was registered at clinicaltrials.gov as NCT01270763 and the Look AHEAD study as NCT00017953.
Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide ...polymorphisms (SNPs) in the μ-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults.
To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS.
Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero .
Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications.
Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant.
Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.
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