The Efficacy of Cardiac Myosin Inhibitors Versus Placebo in Patients With Symptomatic Hypertrophic Cardiomyopathy: A Meta-Analysis and Systematic Review.

We aimed to assess the overall clinical impact of cardiac myosin inhibitors in hypertrophic cardiomyopathy (HCM). We performed a meta-analysis of published trials assessing the effect of cardiac myosin inhibitors (mavacamten and aficamten) on resting and Valsalva left ventricular outflow tract (LVOT) gradients and functional capacity in symptomatic HCM. The co-primary outcomes were mean percent change (mean difference [MD]) from baseline in LVOT gradient at rest and Valsalva LVOT gradient and the proportion of patients achieving New York Heart Association class improvement ≥1. The secondary outcomes included the mean percent change from baseline N-terminal pro-B-type natriuretic peptide, troponin I, and left ventricular ejection fraction (LVEF). A total of 4 studies (all randomized controlled trials, including 3 mavacamten-focused and 1 aficamten-focused trials) involving 463 patients were included in the meta-analysis. Compared with placebo, the cardiac myosin inhibitor group demonstrated statistically significant differences in the baseline percent change in mean LVOT gradient at rest (MD -62.48, confidence interval [CI] -65.44 to -59.51, p <0.00001) and Valsalva LVOT gradient (MD -54.21, CI -66.05 to -42.36, p <0.00001) and the proportion of patients achieving New York Heart Association class improvement ≥1 (odds ratio 3.43, CI 1.90 to 6.20, p <0.0001). Regarding the secondary outcomes, the intervention group demonstrated statistically significant reductions in mean percent change from baseline in N-terminal pro-B-type natriuretic peptide (MD -69.41, CI -87.06 to -51.75, p <0.00001), troponin I (MD, -44.19, CI -50.59 to -37.78, p <0.00001), and LVEF (MD -6.31, CI -10.35, -2.27, p = 0.002). In conclusion, cardiac myosin inhibitors may confer clinical and symptomatic benefits in symptomatic HCM at the possible expense of LVEF. Further trials with large sample sizes are needed to confirm our findings.

Recurrent Leflunomide-Induced Drug Reaction With Eosinophilia and Systemic Symptom (DRESS) Syndrome Despite Prolonged Steroid Taper: A Case Report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction characterized primarily by nonspecific systemic symptoms such as fever, a classical rash, and eosinophilia. While this is an adverse reaction more often related to medications such as anticonvulsants, many drugs have been reported to be implicated in this event. We report a case of a 35-year-old male who developed DRESS syndrome within one month of beginning leflunomide therapy. Despite treatment with a prolonged steroid taper, he developed a flare-up with transaminitis less than two months after his initial hospitalization. Our patient was managed with steroid pulse therapy and cyclosporine, which resulted in an improvement of symptoms and transaminitis. To our knowledge, only nine previous cases of leflunomide-induced DRESS syndrome have been previously reported.

A Case Report and 31-Case Study: Does Takotsubo Cardiomyopathy in Myasthenia Gravis Patients Have a High Mortality Rate?

Myasthenia gravis is an autoimmune disorder in which antibodies are formed against post-synaptic nicotinic acetylcholine receptors that lead to impeded muscle contraction and commonly affects the oculomotor muscles. Takotsubo cardiomyopathy (TTC) is a dilated cardiomyopathy that can mimic a myocardial infarction and causes reversible systolic dysfunction. This is a case of a 66-year-old Caucasian male with a known history of ocular myasthenia gravis that presented to the emergency room with worsening dyspnea secondary to a myasthenic crisis. One day, following admission, his shortness of breath failed to improve and was found to meet the diagnostic criteria for takotsubo cardiomyopathy. A brief review of 31 previous cases summarizes the current case reports, patterns, and mortality associated with the myasthenic crisis associated with TTC.

Excess Growth Hormone Alters the Male Mouse Gut Microbiome in an Age-dependent Manner.

The gut microbiome has an important role in host development, metabolism, growth, and aging. Recent research points toward potential crosstalk between the gut microbiota and the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Our laboratory previously showed that GH excess and deficiency are associated with an altered gut microbial composition in adult mice. Yet, no study to date has examined the influence of GH on the gut microbiome over time. Our study thus tracked the effect of excess GH action on the longitudinal changes in the gut microbial profile (ie, abundance, diversity/maturity, predictive metabolic function, and short-chain fatty acid [SCFA] levels) of bovine GH (bGH) transgenic mice at age 3, 6, and 12 months compared to littermate controls in the context of metabolism, intestinal phenotype, and premature aging. The bGH mice displayed age-dependent changes in microbial abundance, richness, and evenness. Microbial maturity was significantly explained by genotype and age. Moreover, several bacteria (ie, Lactobacillus, Lachnospiraceae, Bifidobacterium, and Faecalibaculum), predictive metabolic pathways (such as SCFA, vitamin B12, folate, menaquinol, peptidoglycan, and heme B biosynthesis), and SCFA levels (acetate, butyrate, lactate, and propionate) were consistently altered across all 3 time points, differentiating the longitudinal bGH microbiome from controls. Of note, the bGH mice also had significantly impaired intestinal fat absorption with increased fecal output. Collectively, these findings suggest that excess GH alters the gut microbiome in an age-dependent manner with distinct longitudinal microbial and predicted metabolic pathway signatures.

Growth hormone alters gross anatomy and morphology of the small and large intestines in age- and sex-dependent manners.

PURPOSE: Growth hormone (GH) has an important role in intestinal barrier function, and abnormalities in GH action have been associated with intestinal complications. Yet, the impact of altered GH on intestinal gross anatomy and morphology remains unclear. METHODS: This study investigated the influence of GH signaling on gross anatomy, morphology, and fibrosis by characterizing the small and large intestines in male and female bovine growth hormone transgenic (bGH) mice and GH receptor gene-disrupted (GHR-/-) mice at multiple timepoints. RESULTS: The length, weight, and circumference of the small and large intestines were increased in bGH mice and decreased in GHR-/- mice across all ages. Colon circumference was significantly increased in bGH mice in a sex-dependent manner while significantly decreased in male GHR-/- mice. Villus height, crypt depth, and muscle thickness of the small intestine were generally increased in bGH mice and decreased in GHR-/- mice compared to controls with age- and sex-dependent exceptions. Colonic crypt depth and muscle thickness in bGH and GHR-/- mice were significantly altered in an age- and sex-dependent manner. Fibrosis was increased in the small intestine of bGH males at 4 months of age, but no significant differences were seen between genotypes at other timepoints. CONCLUSION: This study observed notable opposing findings in the intestinal phenotype between mouse lines with GH action positively associated with intestinal gross anatomy (i.e. length, weight, and circumference). Moreover, GH action appears to alter morphology of the small and large intestines in an age- and sex-dependent manner.

Impact of Nutritional Epigenetics in Essential Hypertension: Targeting microRNAs in the Gut-Liver Axis.

PURPOSE OF REVIEW: To review the current knowledge on interactions between dietary factors and microRNAs (miRNAs) in essential hypertension (EH) pathogenesis. RECENT FINDINGS: There exists an integration of maintenance signals generated by genetic, epigenetic, immune, and environmental (e.g., dietary) factors that work to sustain balance in the gut-liver axis. It is well established that an imbalance in this complex, intertwined system substantially increases the risk for EH. As such, pertinent research has been taken to decipher how each signal operates in isolation and together in EH progression. Recent literature indicates that both macro- and micronutrients interrupt regulatory miRNA expressions and thus, alter multiple cellular processes that contribute to EH and its comorbidities. We highlight how carbohydrates, lipids, proteins, salt, and potassium modify miRNA signatures during EH. The disruption in miRNA expression can negatively impact communication systems such as over activating the renin-angiotensin-aldosterone system, modulating the vascular smooth muscle cell phenotype, and promoting angiogenesis to favor EH. We also delineate the prognostic value of miRNAs in EH and discuss the pros and cons of surgical vs dietary prophylactic approaches in EH prevention. We propose that dietary-dependent perturbation of the miRNA profile is one mechanism within the gut-liver axis that dictates EH development.

Growth Hormone Deficiency and Excess Alter the Gut Microbiome in Adult Male Mice.

The gut microbiome has been implicated in host metabolism, endocrinology, and pathophysiology. Furthermore, several studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. Yet, no study to date has examined the specific role of GH on the gut microbiome. Our study thus characterized the adult gut microbial profile and intestinal phenotype in GH gene-disrupted (GH-/-) mice (a model of GH deficiency) and bovine GH transgenic (bGH) mice (a model of chronic, excess GH action) at 6 months of age. Both the GH-/- and bGH mice had altered microbial signatures, in opposing directions at the phylum and genus levels. For example, GH-/- mice had significantly reduced abundance in the Proteobacteria, Campylobacterota, and Actinobacteria phyla, whereas bGH mice exhibited a trending increase in those phyla compared with respective controls. Analysis of maturity of the microbial community demonstrated that lack of GH results in a significantly more immature microbiome while excess GH increases microbial maturity. Several common bacterial genera were shared, although in opposing directions, between the 2 mouse lines (e.g., decreased in GH-/- mice and increased in bGH mice), suggesting an association with GH. Similarly, metabolic pathways like acetate, butyrate, heme B, and folate biosynthesis were predicted to be impacted by GH. This study is the first to characterize the gut microbiome in mouse lines with altered GH action and indicates that GH may play a role in the growth of certain microbiota thus impacting microbial maturation and metabolic function.

Heterogeneity spacers in 16S rDNA primers improve analysis of mouse gut microbiomes via greater nucleotide diversity.

Illumina-based amplicon sequencing suffers from the deleterious effects of highly homogenous nucleotide composition, limiting the number of high-quality reads generated per run. We attempted to alleviate this limitation by comparing the results obtained from 16S ribosomal DNA (16S rDNA) sequencing of mouse gut microbiomes using Illumina V3-V4 primers (Run 1) and custom primers that incorporate a heterogeneity spacer (0-7 nucleotides) upstream of the 16S priming region (Run 2). Overall, Run 2 had higher quality sequences, a more diverse microbial profile, and higher precision within, and variation between, experimental groups than Run 1. Our primer design offers a simple way to increase the quality of 16S rDNA sequencing and increases the number of useable reads generated per Illumina run.