Moderate Hypertrophy Research Articles

Abstract 4144529: Cardiac Allograft Hypertrophy (CAH) at 6 Months Post Transplant Is a Prognostic Marker of Long-Term Outcomes: Are We Missing a Simple Biomarker?

Introduction: Cardiac hypertrophy is a known adverse prognostic marker in various non-transplant pathologies. In heart transplant patients, due to many confounders, it has been controversial on the relevance and timing of cardiac hypertrophy as an adverse remodeling vs acute injury pattern in an immunologically hostile environment. Previous studies have shown prognostication of hypertrophy on echocardiogram at 1-year post-heart transplant. Research Questions: Does cardiac hypertrophy within a year after transplant have long-term prognostic implications? Methods: We collected relevant clinical variables for all heart transplants using EPIC EHR’s Clarity database. Hypertrophy was defined based on LV Mass Indexed to body surface area where LV Mass = 0.8 x (1.04 x (((LVIDD + IVSd + PWd) 3 - LVIDD 3 ))) + 0.6. Relative Wall Thickness was defined as RWT = 2 x PWd / LVIDD. We used a rule-based natural language processing program validated by correlation with manual readings by trained cardiologists (r=0.96, p=0.007) to abstract echo variables. Results: Inclusion criteria were heart transplants performed from 2015 to 2023 at our center, with an echocardiogram closest to 6 months (+/- 1 month). Ten percent (n=33) showed hypertrophy on echocardiograms at 6 months (Table 1). Of these, 20 (61%) had mild, 3 (9%) severe, and 10 (30%) moderate hypertrophy. Of 33 patients, 28 (85%) had concentric, and 5 (15%) had eccentric hypertrophy. Patients with hypertrophy at 6 months had significantly worse survival at 5 years (p=0.01) and 10 years (p=0.05) compared to patients without hypertrophy (Fig 1). Survival at 5 and 10 years was not statistically different for patients with hypertrophy at 3 months (5 yrs p=0.17, 10 yrs p=0.06), 12 months (5 yrs p=0.38, 10 yrs p=0.30), and 18 months (5 yrs p=0.15, 10 yrs p=0.08) compared to those without hypertrophy. Conclusion: Cardiac hypertrophy on echocardiogram at 6 months predicts adverse long-term survival, while other time points did not.

Abstract 4138690: A Case of Hypertrophic Cardimyopathy: Digenic Variants of Uncertain Significance Mutations in MHY7 and RYR2 Genes

Introduction: Hypertrophic Cardiomyopathy (HCM) is primarily a disease caused by mutations in single genes, but around 5% of HCM patients, exhibit 2 (digenic) or more (oligogenic) causal mutations in the same gene or in different genes. We present a case of familial HCM with variants of uncertain significance (VUS) mutations in the MYH7 and RYR2 genes, highlighting the complexity of genetic inheritance and its implications on disease severity. Case presentation: A 40-year-old male presented with a history of hypertension, HCM, and two prior myocardial infarctions. He had syncope, non-sustained ventricular tachycardia, and a family history of sudden cardiac death (SCD) in his maternal grandfather. A dual-chamber ICD was placed for primary prevention of SCD because of his high-risk profile. Echocardiography demonstrated normal LV size and function with moderate asymmetric septal hypertrophy. Cardiac MRI indicated diffuse asymmetric hypertrophy and a 10.9% LV myocardial scar burden. Left heart catheterization revealed normal coronary arteries with LVOT gradient up to 60 mmHg, consistent with HCM. Genetic testing revealed VUS in the MYH7 (c.1305G>A, p.Met435Ile) and RYR2 (c.10528C>A, p.Arg3510Ser) genes (Figure 1). Further family genetic testing confirmed these VUS mutations in multiple relatives (Figure 2). Discussion: The identification of VUS mutations in MYH7 and RYR2 genes in multiple family members highlights the complexity of genetic inheritance in HCM. These findings underscore the challenges in clinical interpretation and risk stratification, as the co-occurrence of mutations in different genes may have synergistic effects on disease severity and phenotype expression. Comprehensive genetic evaluation, including family studies, is crucial for understanding the clinical significance of these mutations and guiding personalized management strategies. Further research is needed to elucidate the impact of VUS mutations on the clinical outcomes of HCM patients.

INVESTIGATING ETIOPATHOGENETIC FACTORS OF LEFT VENTRICULAR REMODELING AS THE UNDERLYING MECHANISM OF ISCHEMIC MITRAL REGURGITATION

The purpose of this study is to determine the etiopathogenetic features of the development of ischemic mitral regurgitation in patients with coronary heart disease by investigating the mechanisms of left ventricular remodeling. Materials and Methods. The study included 140 patients (99 male, 41 female) with ischemic mitral regurgitation who underwent myocardial revascularization and mitral valve reconstruction (either repair or replacement). The average age of participants was 65.9 ± 4.0 years, and all had a history of coronary heart disease and ischemic mitral regurgitation. All patients in the sample underwent operations for myocardial revascularization and mitral valve reconstruction (replacement). The data analyzed were obtained from primary medical documentation, including medical histories, patient medical charts, findings of physical and clinical examinations, laboratory and instrumental evaluations, as well as echocardiography findings. The data obtain were processed statistically. Results. This article presents an analysis of the etiopathogenetic features associated with the development of ischemic mitral regurgitation under the clinical course of coronary heart disease. The study examined several etiopathogenetic factors, including the presence of arterial hypertension, left ventricular hypertrophy, and the type of left ventricle remodeling. It was found that 39.1% of patients in the experimental group and 40.8% in the control group had hypertension (p ≥ 0.05). The most prevalent condition was grade II arterial hypertension, which occurred in 52.3% of the experimental group and 60.6% of the control group (p ≥ 0.05). When analyzing the occurrence rate of left ventricular hypertrophy, mild hypertrophy was significantly more common in the experimental group (44.9%) compared to the control group (26.8%) (p = 0.03, χ² = 4.27). Moderate left ventricular hypertrophy was found to be significantly higher in the control group (45.1%) compared to the experimental group (27.5%) (p = 0.04, χ² = 3.92). Eccentric hypertrophy of the left ventricle was prevalent in both groups, with values of 79.7% in the experimental group and 80.3% in the control group. In contrast, the frequency of concentric hypertrophy was higher in the control group (8.4%) compared to the experimental group (2.9%) (p ≥ 0.05). Conclusions: The study has established that the incidence of ischemic heart disease and ischemic mitral regurgitation is significantly associated with sex, with men being affected more frequently than women. Analysis of arterial hypertension revealed that 39.1% of patients in the experimental group and 40.8% in the control group were affected, with grade II arterial hypertension being the most common. Moderate and severe left ventricular hypertrophy, as well as concentric remodeling of the left ventricle, were characteristic of patients who underwent mitral valve replacement. These findings underscore the importance of left ventricular remodeling in determining the appropriate surgical treatment for mitral valve conditions.

Myocardial infarction in a 17-year-old patient diagnosed with MPOD II syndrome.

Microcephalic osteodysplastic primordial dwarfism (MOPD) syndrome type 2, caused by a mutation in the PCNT gene (21q22.3), is a rare autosomal recessive disorder. Patients present with bone dysplasia, insulin resistance, kidney diseases, and cardiac malformations, making them prone to vascular diseases. Cardiomyopathy, hypertension, and coronary diseases are documented. The prognosis is associated with cerebrovascular complications. We report a case of a patient with MOPD type II who suffered a myocardial infarction in our institution. Informed consent for publishing was obtained. A 17-year-old female with MPOD II syndrome (20 kg and 86 cm) was referred for chest pain. Thoracic pains had been occurring for over a month, increasing in intensity, with an episode prompting emergency consultation. Initial tests revealed elevated troponin and an inflammatory response. Electrocardiogram (ECG) showed ST-segment depression and elevation. Echocardiography revealed hypokinetic inferior walls with moderate concentric hypertrophy. A coronary CT scan showed subendocardial hypodensity. Diagnostic coronary angiography revealed tri-branch lesions and almost complete stenoses or occlusions on the circumflex artery (Image). No indication for interventional treatment due to diffuse atheromatous lesions. Exclusive medical treatment was initiated. MPOD II syndrome is associated with cardiac malformations and neurovascular complications, including myocardial infarction. Regular ECG monitoring is advisable. Active surveillance for coronary diseases is necessary from adolescence. Recognising this complication allows for prompt intervention. This case highlights the need for specific monitoring and prompt management of chest pain in patients with MPOD II syndrome. Primary prevention could mitigate the occurrence of coronary events in this high-risk population.

Abstract Tu093: Adeno-associated virus-mediated gene delivery of PERM1 enhances cardiac contractility and mitochondrial biogenesis in mice.

Heart failure remains the leading cause of death in the U.S., and 50% of patients with heart failure still die within 5 years after diagnosis. Mitochondrial impairment and contractile dysfunction are the hallmarks of heart failure with reduced ejection fraction (HFrEF). Yet, there is currently no therapeutic strategy targeting both mitochondria and muscle contractility. PERM1 is a striated-muscle-specific regulator of mitochondrial bioenergetics and is predominantly expressed in the heart and skeletal muscle. Our recent studies demonstrated that PERM1 is downregulated in human and mouse HFrEF hearts and that loss of PERM1 in mice leads to reduced contractility and energy reserve in the heart. However, it is largely unknown whether PERM1 positively regulates both muscle contractility and energetics in the heart. Here, we performed the gene delivery of Perm1 to the heart in C57BL6 wild-type mice (8-12 weeks old) through retro-orbital injection of the adenovirus-associated virus (AAV)9 vector carrying Perm1 (AAV-PERM1). The protein expression levels of PERM1 in the heart was increased by 3 fold as compared with control (mice injected with AAV9-GFP vectors), while there was no change in PERM1 expression in skeletal muscle (n=4/group). Strikingly, AAV-PERM1 mice exhibited a significant increase in ejection fraction (EF) and fractional shortening (FS) (AAV-GFP vs. AAV-PERM1: 0.93 vs. 1.43 and 0.92 vs. 1.64 in DEF and DFS, respectively, both p<0.05 in t-test). In addition, we observed a subtle, yet significant increase in the ratio of the heart weight to tibial length in AAV-PERM1 mice (AAV-GFP vs. AAV-PERM1: 4.7 vs 5.97, p<0.05 in t-test), suggestive of moderate cardiac hypertrophy development. Furthermore, PERM1 overexpression in the heart increased the mitochondrial copy number by 38% as compared to control AAV-GFP mice (p<0.05 in t-test), concurrently with an upregulation of the mitochondrial bioenergetics master regulator PGC-1α (155% of control, p<0.05 in t-test). Overall, these results showed that AAV-mediated PERM1 overexpression simultaneously enhances muscle contractility and mitochondrial biogenesis in the heart. This study further suggests that the gene delivery of PERM1 could be a potential therapeutic approach to treat HFrEF patients.

Diagnostic Utility of Left Atrial Strain in Distinguishing Anderson-Fabry Disease From Mild to Moderate Left Ventricular Hypertrophy

Diagnostic Utility of Left Atrial Strain in Distinguishing Anderson-Fabry Disease From Mild to Moderate Left Ventricular Hypertrophy

The D-HCM score, a new diagnostic tool for distinguishing hypertrophic cardiomyopathy from hypertensive cardiopathy.

The diagnosis of hypertrophic cardiomyopathy (HCM) with moderate hypertrophy is challenging. Hypertensive heart disease (HHD) is the most common differential diagnosis that mimics the LVH of HCM. The aim of this study was to compare the QRS duration in HCM and HHD to create a novel diagnostic tool to identify primary HCM. We conducted an international retrospective multicentre study enrolling patients with true HCM and HHD. A total of 547 individuals with HCM and 139 with HHD were included. The median QRS duration was significantly shorter in HCM than in HHD (88ms [80-94] vs. 98ms [88-108]; P<0.01). Multivariable logistic regression identified for the novel diagnostic HCM (D-HCM) score: absence of antihypertensive drugs (+2); family history of unexplained sudden death (+2); QRS duration [<95ms]=+1; maximum wall thickness (mm) [≥17]=+1. A cumulative QRS-HCM score ≥2 supports the diagnostic certainty of true HCM with a sensitivity of 79%, specificity of 99%, negative predictive value (NPV) of 55%, and positive predictive value (PPV) of 99%. The QRS duration in patient with HCM is significantly shorter compared with patients with HHD-related LVH. QRS duration can be used as a diagnosis marker to distinguish between HCM and HHD. The D-HCM score is a novel, simple, and accurate diagnosis tool for HCM patients with mild to moderate phenotypes.

A Novel Rat Model of Mild Pulmonary Hypertension Associated with Pulmonary Venous Congestion Induced by Left Pulmonary Vein Banding.

Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most common form of PH. In PH-LHD, changes in the pulmonary vasculature are assumed to be mainly caused by pulmonary venous congestion. However, the underlying mechanisms of this form of PH are poorly understood. We aimed to establish a model of PH associated with pulmonary venous congestion. Wistar-Kyoto rats underwent partial occlusion of the left pulmonary vein to induce pulmonary venous congestion or sham surgery and were assessed at various time points post-surgery (3, 6, 9, 12 weeks). In vivo cardiopulmonary phenotyping was performed by using echocardiography along with heart catheterization. Histomorphometry methods were used to assess pulmonary vascular remodeling (e.g., wall thickness, degree of muscularization). Left pulmonary vein banding (PVB) resulted in mildly elevated right ventricular systolic pressure and moderate right ventricular hypertrophy. In PVB rats, small- and medium-sized pulmonary vessels in the left lung were characterized by increased wall thickness and muscularization. Taken together, our data demonstrate that left PVB-induced pulmonary venous congestion is associated with pulmonary vascular remodeling and mild PH.

Synergistically Acting on Myostatin and Agrin Pathways Increases Neuromuscular Junction Stability and Endurance in Old Mice.

Sarcopenia is the primary cause of impaired motor performance in the elderly. The current prevailing approach to counteract such condition is increasing the muscle mass through inhibition of the myostatin system: however, this strategy only moderately improves muscular strength, not being able to sustain the innervation of the hypertrophic muscle per se, leading to a progressive worsening of motor performances. Thus, we proposed the administration of ActR-Fc-nLG3, a protein that combines the soluble activin receptor, a strong myostatin inhibitor, with the C-terminal agrin nLG3 domain. This compound has the potential of reinforcing neuro-muscular stability to the hypertrophic muscle. We previously demonstrated an enhancement of motor endurance and ACh receptor aggregation in young mice after ActR-Fc-nLG3 administration. Now we extended these observations by demonstrating that also in aged (2 years-old) mice, long-term administration of ActR-Fc-nLG3 increases in a sustained way both motor endurance and muscle strength, compared with ActR-Fc, a myostatin inhibitor, alone. Histological data demonstrate that the administration of this biological improves neuromuscular stability and fiber innervation maintenance, preventing muscle fiber atrophy and inducing only moderate hypertrophy. Moreover, at the postsynaptic site we observe an increased folding in the soleplate, a likely anatomical substrate for improved neurotransmission efficiency in the NMJ, that may lead to enhanced motor endurance. We suggest that ActR-Fc-nLG3 may become a valid option for treating sarcopenia and possibly other disorders of striatal muscles.

A Noninvasive Circulating Signature of Combined Right Ventricular Pressure and Volume Overload in Tetralogy of Fallot/Pulmonary Atresia/Major Aortopulmonary Collateral Arteries.

Background: Despite surgical advances, children with tetralogy of Fallot/pulmonary atresia/major aortopulmonary collaterals (TOF/PA/MAPCAs) are subject to chronic right ventricular (RV) pressure and volume overload. Current diagnostic tools do not identify adverse myocardial remodeling and cannot predict progression to RV failure. We sought to identify a noninvasive, circulating signature of the systemic response to right heart stress to follow disease progression. Methods: Longitudinal data were collected from patients with TOF/PA/MAPCAs (N = 5) at the time of (1) early RV pressure overload and (2) late RV pressure and volume overload. Plasma protein and microRNA expression were evaluated using high-throughput data-independent mass spectroscopy and Agilent miR Microarray, respectively. Results: At the time of early RV pressure overload, median patient age was 0.34 years (0.02-9.37), with systemic RV pressures, moderate-severe hypertrophy, and preserved systolic function. Late RV pressure and volume overload occurred at a median age of 4.08 years (1.51-10.83), with moderate RV hypertrophy and dilation, and low normal RV function; 277 proteins were significantly dysregulated (log2FC ≥0.6/≤-0.6, FDR≤0.05), predicting downregulation in lipid transport (apolipoproteins), fibrinolytic system, and extracellular matrix structural proteins (talin 1, profilin 1); and upregulation in the respiratory burst. Increasing RV size and decreasing RV function correlated with decreasing structural protein expression. Similarly, miR expression predicted downregulation of extracellular matrix-receptor interactions and upregulation in collagen synthesis. Conclusion: To our knowledge, we show for the first time a noninvasive protein and miR signature reflecting the systemic response to adverse RV myocardial remodeling in TOF/PA/MAPCAs which could be used to follow disease progression.

Hypercontractile cardiac phenotype in mice overexpressing the regulatory subunit PR72 of protein phosphatase 2A.

The activity, localization, and substrate specificity of the protein phosphatase 2A (PP2A) heterotrimer are controlled by various regulatory B subunits. PR72 belongs to the B'' gene family and has been shown to be upregulated in human heart failure. However, little is known about the functions of PR72 in the myocardium. To address this issue, we generated a transgenic mouse model with heart-specific overexpression of PP2A-PR72. Biochemical and physiological methods were used to determine contractility, Ca2+ cycling parameters, and protein phosphorylation. A 2.5-fold increase in PR72 expression resulted in moderate cardiac hypertrophy. Maximal ventricular pressure was increased in catheterized transgenic mice (TG) compared to wild-type (WT) littermates. This was accompanied by an increased shortening of sarcomere length and faster relaxation at the single-cell level in TG. In parallel with these findings, the peak amplitude of Ca2+ transients was increased, and the decay in intracellular Ca2+ levels was shortened in TG compared to WT. The changes in Ca2+ cycling in TG were also evident from an increase in the full duration and width at half maximum of Ca2+ sparks. Consistent with the contractile data, phosphorylation of phospholamban at threonine-17 was higher in TG hearts. The lower expression of the Na+/Ca2+ exchanger may also contribute to the hypercontractile state in transgenic myocardium. Our results suggest that PP2A-PR72 plays an important role in regulating cardiac contractile function and Ca2+ cycling, indicating that the upregulation of PR72 in heart failure is an attempt to compensate functionally.

Evolving Concept of Aortic Valve Replacement in Asymptomatic Patients With Severe Aortic Stenosis

BackgroundSurgical treatment of asymptomatic severe aortic stenosis (AS) has been gaining attention ever since the results of the Early Surgery Versus Conventional Treatment in Very Severe Aortic Stenosis (RECOVERY) and Aortic Valve replacement versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR) trials showed survival benefits with early surgical aortic valve replacement (SAVR). This study analyzed the long-term clinical and echocardiographic outcomes of SAVR in asymptomatic severe AS. MethodsBetween 2002 and 2020, 272 patients with asymptomatic severe AS and a left ventricular ejection fraction ≥50% underwent SAVR with or without concomitant aortic surgery and met the study criteria. The median follow-up was 8.5 years (interquartile range, 6-12.8 years), for a total of 2584 patient-years. The time course of the left ventricular mass index (LVMI) and the average E/E′ (ratio of the Doppler-derived E wave to the tissue Doppler-derived E′ wave) were assessed using 594 postoperative echocardiograms. The association of preoperative LVMI and average E/E′ with survival was assessed using Cox proportional hazards. ResultsThere was no operative mortality. On longitudinal analyses, LVMI improved in patients who presented with moderate or severe preoperative left ventricular hypertrophy (LVH). However, after the early decline in average E/E′, there was a late increase to greater than upper limit normal, particularly in patients with a preoperative average E/E′≥14. Postoperative survival was 100%, 94%, 84%, and 76% at 1, 5, 10, and 15 years, respectively, comparable to age- and sex-matched expected survival on the basis of the US general population. On adjusted Cox survival analysis, only moderate to severe LVH was associated with a survival penalty (hazard ratio], 2.32; 95% CI, 1.02-5.27; P = .045). ConclusionsIn asymptomatic patients with AS, SAVR restores survival and improves LVH, but patients with diastolic dysfunction are left with persistent dysfunction. Presentation with moderate or severe LVH at the time of surgery translated to a survival penalty. This observational study supports early SAVR in this population before development of LVH, although further investigation is needed.

Non-clinical pharmacology and toxicology studies of LPM6690061, a novel 5-hydroxytryptamine (5-HT)2A receptor inverse agonist.

LPM6690061 is a novel compound with 5-HT2A receptor antagonist and inverse agonist activities. To support the clinical trial and marketing application of LPM6690061, a series of pharmacology and toxicology studies have been conducted. In vitro and in vivo pharmacology studies showed that LPM6690061 had high inverse agonism and antagonism activities against human 5-HT2A receptors, and demonstrated significant antipsychotic-like effects in two rat models: the DOI-induced head-twitch model and the MK-801-induced hyperactivity model, which was more effective than the control drug pimavanserin. LPM6690061 did not have detectable side effects on the neurobehavioral activities and respiratory function in rats, or on the ECG or blood pressure in dogs at the doses of 2 and 6mg/kg. The half maximal inhibitory concentration (IC50) of LPM6690061 for inhibiting hERG current was 1.02μM. Three in vivo toxicology studies were conducted. In the single dose toxicity study in rats and dogs, the maximum tolerated dose of LPM6690061 was 100mg/kg. In the 4-week repeat dose toxicity study in rats, the main detectable toxic reactions of LPM6690061 included moderate artery wall hypertrophy, minimal to mild mixed cell inflammation and increased macrophages in the lung, which generally recovered after a 4-week drug withdrawal period. In the 4-week repeat dose toxicity study in dogs, no detectable toxicity was observed. The doses of no-observed-adverse-effect-level (NOAEL) in rats and dogs were 10mg/kg and 20mg/kg, respectively. In conclusion, both in vitro and in vivo pharmacological and toxicological studies showed that LPM6690061 was a safe and efficacious 5-HT2A receptor antagonist/inverse agonist which supports the clinical development as a novel antipsychotic drug.

Adenoid lymphocyte heterogeneity in pediatric adenoid hypertrophy and obstructive sleep apnea.

Adenoid hypertrophy is the main cause of obstructive sleep apnea in children. Previous studies have suggested that pathogenic infections and local immune system disorders in the adenoids are associated with adenoid hypertrophy. The abnormalities in the number and function of various lymphocyte subsets in the adenoids may play a role in this association. However, changes in the proportion of lymphocyte subsets in hypertrophic adenoids remain unclear. To identify patterns of lymphocyte subsets in hypertrophic adenoids, we used multicolor flow cytometry to analyze the lymphocyte subset composition in two groups of children: the mild to moderate hypertrophy group (n = 10) and the severe hypertrophy group (n = 5). A significant increase in naïve lymphocytes and a decrease in effector lymphocytes were found in severe hypertrophic adenoids. This finding suggests that abnormal lymphocyte differentiation or migration may contribute to the development of adenoid hypertrophy. Our study provides valuable insights and clues into the immunological mechanism underlying adenoid hypertrophy.

Hypertrophic cardiomyopathy in an athlete, occurring under the mask of sports remodeling. Secondary prevention of sudden cardiac death. Analysis of a clinical case

HCMP is a severe heart disease characterized by high rates of sudden mortality, especially in young people. Optimization of the tactics of treatment of children with HCMP in order to improve the prognosis remains one of the urgent tasks of cardiology. A clinical case of a 15-yearold boy with moderate myocardial hypertrophy and an asymptomatic course of HCMP is presented, in connection with which the disease was not diagnosed for a long time. The boy was engaged in professional sports, during the competition he suddenly lost consciousness, clinical death occurred. Only timely resuscitation measures allowed to save the patient’s life. Implantation of a cardioverter defibrillator was performed as a secondary prevention of SCD (class 1 indications). The importance of timely examination of asymptomatic athletes with myocardial hypertrophy for differential diagnosis between HCMP and myocardial remodeling against the background of intense physical exertion (“athlete’s heart”) is emphasized. The importance of solving the issue of the inadmissibility of intense physical exertion, even with an asymptomatic course of HCMP, is shown. It should be remembered that it has been established that intense sports loads act as a trigger for cardiac arrest in patients with HCMP. Retrospective calculation of SCD risk based on HCM risc-SDD calculator/The BCC risk calculator at GCMP showed 3.19 %, which corresponded to a low risk. The possibility of SCD in patients with HCMP is emphasized, even with an estimated low risk, which requires further research to find predictors of an unfavorable outcome.

P120 NEW MALIGNANT MUTATION IN HYPERTROPHIC CARDIOMYOPATHY

Abstract A 62–year–old man diagnosed with non–obstructive hypertrophic cardiomyopathy and dual–chamber pacemaker wearer since the age of 40, for third–degree atrioventricular block, came to our attention for atrial fibrillation (AF) episodes (one complicated by cardiogenic shock and multiorgan failure) and flutter with high ventricular response. For a progressive worsening of the systolic function, and the onset of multiple episodes of sustained ventricular tachycardia, an upgrade to the defibrillator was performed, which, in the following months, intervened appropriately for recurrences of ventricular arrhythmias. The patient was admitted to our ward for exacerbation of heart failure. The echocardiography showed moderate concentric hypertrophy with mild ventricular dilatation and ejection fraction 33%, inferior and inferoseptal wall, and apex akinesia with thrombotic apposition. Due to a sudden deterioration of the clinical conditions, the patient died. After genetic counseling the patient‘s family agreed to genetic testing in the proband. This highlighted the presence of a missense mutation, i.e. the substitution of the cysteine ​​residue with a serine, in the codon 905 of the MYH7 gene, encoding the cardiac isoform of myosin heavy chain. The mutation is probably pathogenetic as it falls in the region where most of the missense variants are clustered and statistically associated with the HCM phenotype. Only in one previous case of HCM was detected a mutation of the same codon, Cys905Phe. Several studies have reported that AF tends to be more prevalent in patients carrying MYH7 mutations and is associated with a substantial risk of heart failure–related mortality, stroke, and severe functional disability. Knowledge of the entire spectrum of MYH7 mutations, especially those related to a high arrhythmic burden or SCD, combined with an accurate clinical and molecular characterization of the patient, can improve the genotype–phenotype correlation by clarifying the mechanism of HCM and allowing a better clinical and therapeutic decision–making of patients.

Absence of Bcl11b in murine heart leads to mitochondrial dysfunction and cardiomyocyte death

B cell lymphoma 11b (Bcl11b/Ctip2) is a zinc finger transcriptional factor involved in a number of physiological processes, including cardiac hypertrophy. In humans, genome-wide association studies show that a common genetic variation in the 3’ region of Bcl11b gene is associated with higher risk of aortic stiffness and increased rate of cardiovascular disease. In mice, Bcl11b invalidation specifically in cardiomyocytes leads to cardiac malfunction, fibrosis augmentation and cell death. Our specific aims are: To investigate the signalling pathways related to cardiac cell death and to assess the sarcomere structure of cardiomyocytes in the absence of Bcl11b. The experiments were conducted using cardiac specific Bcl11b knock-out mice induced by tamoxifen administration 3 and 7 days after the invalidation, cardiac tissues were collected to perform RNA sequencing and subsequently to analyse related molecular pathways using bioinformatic tools. In parallel, cardiomyocytes were purified and isolated by conducting Langendorff perfusion technique to have a better insight into the impact of Bcl11b. A simplified mathematical model, Fourier transform analysis was used to assess sarcomeric length following Bcl11b invalidation in cardiomyocytes. Based on the RNA sequencing results, Bcl11b invalidation has an impact on the regulation of over 2000 genes. Among them, genes related to cell death and mitochondrial functions are the most affected regarding the enrichment scores. Interestingly, a considerable number of genes fall into the “Cuproptosis” pathway, a newly identified, non-apoptotic cell death mechanism. The oxygen consumption of mitochondria was also measured using the Seahorse assay. Bcl11b deletion leads to the decrease in basal level of mitochondrial respiration with no effect on the maximum respiratory capacity. Finally, adult cardiomyocytes in the mutant groups showed a moderate hypertrophy (15% bigger than the control group). However, Fourier transform analysis exhibited stability in the average sarcomere length of these cells. The obtained data suggest that cardiac specific invalidation of Bcl11b induces mitochondrial dysfunction and possibly cell death through the “Cuproptosis” pathway.

Left ventricular remodeling in normotensive Wistar rats exposed to intermittent hypoxia of different duration

Intermittent hypoxia has been studied for many years as a promising non-pharmacological method of cardiovascular disease prevention. Hypoxic effects are accompanied by structural and functional changes in the myocardium. There is a direct link between the duration of hypoxic exposures and the severity of left ventricular myocardial remodeling. A range of histochemical markers of myocardial remodeling (cardiotrophin-1, titin, collagen type 1, annexin V) characterizing parenchymal-stromal relationships in the myocardium has shown high informativeness and prognostic value. The aim of the study was to examine cardiotrophin-1, titin, collagen type 1, annexin V and the morphofunctional state of the left ventricle of the heart in experimental rats exposed to intermittent 15-day (IH15) and 60-day hypoxia (IH60). Materials and methods. Intermittent hypoxia was modeled using 30 normotensive male Wistar rats, 7–8 months old, which were randomly assigned to 3 experimental groups of 10 animals each: 1) INT – a control group – intact animals (196.3 ± 6.8 g); 2) IH15 – 15-day hypoxia (205.6 ± 4.1 g); 3) IH60 – 60-day hypoxia (201.1 ± 5.5 g). The study compared the effects of intermittent hypoxia of varying duration: 15-day and 60-day hypoxia. Experimental modeling of intermittent hypoxia of 2 terms revealed a number of differences between the effects dependent on this factor duration through functional (blood pressure measurement, echocardiography) and immunofluorescent studies. Results. Blood pressure in rats of both groups was in the normotensive range, but an increase in systolic by 10 % and diastolic by 19 % was found in IH60 group compared to IH15 group (p &lt; 0.05). In IH15 group, there was a significant decrease in end-diastolic dimension by 20 %, end-systolic dimension by 22 %, an increase in the thickness of left ventricular posterior wall by 44 % and interventricular septum by 33 % as well as left ventricular mass by 12 %, indicating concentric remodeling of the left ventricle, the development of which was confirmed by a 76 % increase in relative wall thickness compared to that in the control group (p &lt; 0.05). Along with these changes, a decrease in end-diastolic volume by 47 %, end-systolic volume by 48 %, stroke volume by 49 % and cardiac output by 50 % with preserved ejection fraction was revealed (p &lt; 0.05). While the parameters of IH60 rats were characterized by an increase in the thickness of interventricular septum by 33 % and left ventricular posterior wall by 17 %, as well as left ventricle mass by 23 %, relative left ventricular wall thickness was 15 % higher than the control value (p &lt; 0.05). At the same time, diastolic volume was 9 % decreased and systolic volume was 24 % increased (p &lt; 0.05). Also, cardiac output was increased by 58 % compared to that in 15-day hypoxic rats with an 8 % decrease in ejection fraction (p &lt; 0.05). The concentrations of markers in IH60 group exceeded those in IH15, namely: cardiotrophin-1 by 39 %, titin by 70 %, collagen type 1 by 60 % and annexin V by 130 % (p &lt; 0.05). Conclusions. 15-day hypoxia forms concentric left ventricular hypertrophy according to echocardiography findings; the study of marker profile of myocardial remodeling has revealed the development of moderate hypertrophy with increased resilient-elastic properties and decreased intensity of cardiomyocyte death. Remodeling caused by 60-day hypoxia is characterized by the eccentric pattern of changes with severe hypertrophy, significant fibrosis associated with apoptosis of cardiomyocytes. Such morphofunctional state of the myocardium may indicate the initial stages of maladaptation, increasing the risk of heart failure development.

Establishment and digital simulation of upper airway in patients with adenoid hypertrophy

Objective: To analyze the flow field characteristics of the upper airway in patients with different adenoid hypertrophy using computational fluid dynamics (CFD). Methods: From November 2020 to November 2021, the cone-beam CT (CBCT) data of 4 patients [2 males and 2 females,age range 5-7 years, mean (6.0±1.2) years] with adenoid hypertrophy who were hospitalized in the Department of Orthodontics and the Department of Otolaryngology at Hebei Eye Hospital were selected. The degree of adenoid hypertrophy in the 4 patients was divided into normal S1 (A/N<0.6), mild hypertrophy S2 (0.6≤A/N<0.7), moderate hypertrophy S3 (0.7≤A/N<0.9) and severe hypertrophy S4 (A/N≥0.9) according to the ratio of adenoid thickness to the width of nasopharyngeal cavity (A/N). The CFD model of the upper airway was established using ANSYS 2019 R1 software, and the internal flow field of the CFD model was numerically simulated. Eight sections were selected as observation and measurement planes for flow field information. Relevant flow field information includes airflow distribution, velocity variation, and pressure variation. Results: In the S1 model, the maximum pressure difference occurred in the 4th and 5th observation planes (ΔP=27.98). The lowest pressures and the maximum flow rates of S2 and S3 were located in the 6th observation plane. The airflow in S1 and S2 models completely passed through the nasal cavity. In the S3 model, the mouth-to-nasal airflow ratio was close to 2∶1. In S4 model, the airflow completely passed through the mouth; in the S1 and S2 models, hard palates were subjected to a downward positive pressure with a pressure difference of 38.34 and 23.31 Pa, respectively. The hard palates in S3 and S4 models were subjected to a downward negative pressure with a pressure difference of -2.95 and -21.81 Pa, respectively. Conclusions: The CFD model can objectively and quantitatively describe the upper airway airflow field information in patients with adenoid hypertrophy. With the increasing degree of adenoid hypertrophy, the nasal ventilation volume gradually decreased, whereas the oral space ventilation volume gradually increased, and the pressure difference between the upper and lower surfaces of the palate gradually decreased until the pressure became negative.

De Novo Asp219Val Mutation in Cardiac Tropomyosin Associated with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), caused by mutations in thin filament proteins, manifests as moderate cardiac hypertrophy and is associated with sudden cardiac death (SCD). We identified a new de novo variant, c.656A>T (p.D219V), in the TPM1 gene encoding cardiac tropomyosin 1.1 (Tpm) in a young SCD victim with post-mortem-diagnosed HCM. We produced recombinant D219V Tpm1.1 and studied its structural and functional properties using various biochemical and biophysical methods. The D219V mutation did not affect the Tpm affinity for F-actin but increased the thermal stability of the Tpm molecule and Tpm-F-actin complex. The D219V mutation significantly increased the Ca2+ sensitivity of the sliding velocity of thin filaments over cardiac myosin in an in vitro motility assay and impaired the inhibition of the filament sliding at low Ca2+ concentration. The molecular dynamics (MD) simulation provided insight into a possible molecular mechanism of the effect of the mutation that is most likely a cause of the weakening of the Tpm interaction with actin in the "closed" state and so makes it an easier transition to the “open” state. The changes in the Ca2+ regulation of the actin-myosin interaction characteristic of genetic HCM suggest that the mutation is likely pathogenic.