Ventricular Hypertrophy Research Articles

Obesity cardiomyopathy could contribute to sudden cardiac death: a Japanese epidemiological morphological study

BackgroundWe aimed to clarify the existence and pathological features of obesity cardiomyopathy (OCM) in Japan using our series of autopsy cases.MethodsIn this retrospective autopsy study, OCM was defined as cardiac hypertrophy (≥ 400 g in men, ≥ 320 g in women) of unknown aetiology in individuals with obesity (body mass index [BMI] ≥ 25 kg/m2 according to the Japanese definition of obesity). We compared cases of OCM with those with obesity without cardiac hypertrophy (OB) and normal weight without cardiac hypertrophy (normal control). Macroscopically, heart weight and cardiac parameters, including epicardial adipose tissue, were measured. Fibrosis, cardiomyocyte diameter, and adipose tissue infiltration were analysed microscopically.ResultsOf the 294 cases, we identified 19 cases of OCM (6.5%) and compared them with the OB and normal control groups. Patients with OCM were slightly younger than non-OCM patients (p = 0.081). The median heart weight was significantly heavier in OCM cases than in OB cases (435 g, interquartile range [IQR] 408–515 g vs. 360 g, IQR 341–385 g). Macroscopically, OCM hearts had a “globoid” appearance with a thickened right ventricular outflow tract. Some OCM cases showed focal interstitial fibrosis in the left ventricle. Approximately half the OCM cases were diagnosed with sudden cardiac death (SCD), with significant differences.ConclusionsThe prevalence of OCM may be higher than expected in Japan, and this may be a specific pathological finding. Given that approximately half the cases of OCM were due to SCD, OCM may cause SCD, emphasizing the need to recognise and diagnose OCM.

Fine Tuning ECG Interpretation for Young Athletes: ECG Screening Using Z-score-based Analysis

BackgroundElectrocardiograms (ECGs) in athletes commonly reveal findings related to physiologic adaptations to exercise, that may be difficult to discern from true underlying cardiovascular abnormalities. North American and European societies have published consensus statements for normal, borderline, and abnormal ECG findings for athletes, but these criteria are not based on established correlation with disease states. Additionally, data comparing ECG findings in athletes to non-athlete control subjects are lacking. Our objective was to compare the ECGs of collegiate athletes and non-athlete controls using Z-scores for digital ECG variables to better identify significant differences between the groups and to evaluate the ECG variables in athletes falling outside the normal range.MethodsValues for 102 digital ECG variables on 7206 subjects aged 17–22 years, including 672 athletes, from Hawaii Pacific Health, University of Hawaii, and Rady Children’s Hospital San Diego were obtained through retrospective review. Age and sex-specific Z-scores for ECG variables were derived from normal subjects and used to assess the range of values for specific ECG variables in young athletes. Athletes with abnormal ECGs were referred to cardiology consultation and/or echocardiogram.ResultsAthletes had slower heart rate, longer PR interval, more rightward QRS axis, longer QRS duration but shorter QTc duration, larger amplitude and area of T waves, prevalent R’ waves in V1, and higher values of variables traditionally associated with left ventricular hypertrophy (LVH): amplitudes of S waves (leads V1-V2), Q waves (V6, III) and R waves (II, V5, V6). Z-scores of these ECG variables in 558 (83%) of the athletes fell within − 2.5 and 2.5 range derived from the normal population dataset, and 60 (8.9%) athletes had a Z-score outside the − 3 to 3 range. While 191 (28.4%) athletes met traditional voltage criteria for diagnosis of LVH on ECG, only 53 athletes (7.9%) had Z-scores outside the range of -2.5 to 2.5 for both S amplitude in leads V1-V2 and R amplitude in leads V5-6. Only one athlete was diagnosed with hypertrophic cardiomyopathy with a Z-score of R wave in V6 of 2.34 and T wave in V6 of -5.94.ConclusionThe use of Z-scores derived from a normal population may provide more precise screening to define cardiac abnormalities in young athletes and reduce unnecessary secondary testing, restrictions and concern.

Deubiquitinase USP47 ameliorates cardiac hypertrophy through reducing protein O-GlcNAcylation.

Cardiac hypertrophy is a crucial risk factor for heart failure when the heart is confronted with physiological or pathological stimuli. The ubiquitin-proteasome system (UPS) plays a critical role in the pathogenesis of cardiac hypertrophy. However, as a key component of the UPS, the role of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is not well understood. Here, we observed that the expression level of deubiquitinase USP47 was increased in hypertrophic hearts and angiotensin II (Ang II)-stimulated neonatal rat cardiomyocytes (NRCMs). Adenovirus-mediated gain- and loss-of-function approaches indicated that USP47 overexpression significantly attenuated Ang II-induced cardiac hypertrophy in vitro and in vivo, whereas endogenous USP47 deficiency promoted the pro-hypertrophic effect of Ang II. Further investigation demonstrated that USP47 inhibited O-GlcNAcylation in cardiomyocytes by controlling the expression of O-GlcNAcase (OGA). Mechanistically, USP47 bound, deubiquitinated, and stabilized protein arginine methyltransferase 5 (PRMT5), thus upregulating OGA expression. We found that the restoration of PRMT5 abolished the pro-hypertrophic effects of USP47 silence in vitro. Therefore, our results provide the first evidence of the involvement of USP47 in cardiac hypertrophy and identify USP47 as a potential target for hypertrophic therapy.

Effect of ertugliflozin on left ventricular function in type 2 diabetes and pre-heart failure: the Ertu-GLS randomized clinical trial

BackgroundThe therapeutic effects of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcome are not fully understood. This study aimed to evaluate the efficacy and safety of ertugliflozin on cardiac function in people with type 2 diabetes and pre-heart failure.MethodsWe conducted a 24-week randomized, double-blind, placebo-controlled trial involving individuals with type 2 diabetes inadequately controlled with antidiabetic medications. Participants with left ventricular hypertrophy, E/e’ >15, or impaired left ventricular global longitudinal strain (LVGLS) were randomized 1:1 to receive either ertugliflozin (5 mg once daily) or a placebo. The primary outcome was the change in LVGLS. Secondary outcomes included changes in left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Prespecified exploratory outcomes, including angiotensin-converting enzyme 2 (ACE2) and angiotensin (1–7) levels, were also assessed.ResultsA total of 102 individuals (mean age, 63.9 ± 9.2 years; 38% women) were included. The ertugliflozin group showed a significant improvement in LVGLS (− 15.5 ± 3.1% to − 16.6 ± 2.8%, P = 0.004) compared to the placebo group (− 16.7 ± 2.7% to − 16.4 ± 2.6%, P = 0.509), with a significant between-group difference (P = 0.013). Improvements in LVMI and LVEF were also observed. Additionally, significant reductions in HbA1c, systolic blood pressure, whole-body and visceral fat, uric acid, proteinuria, N-terminal pro–B-type natriuretic peptide, and lipoprotein(a) were noted. ACE2 and angiotensin (1–7) levels significantly increased in the ertugliflozin group compared to the placebo group and correlated with changes in LVGLS [r = 0.456, P < 0.001 for ACE2; r = 0.541, P < 0.001 for angiotensin (1–7)]. Adverse events were similar between the two groups.ConclusionsThis study demonstrated that ertugliflozin has beneficial effects on left ventricular function in individuals with type 2 diabetes and pre-heart failure, and it provided insights into potential underlying mechanisms.Clinical trial registration ClinicalTrials.gov Identifier: NCT03717194.

Correction: Balkrishna et al. Application of Zebrafish Model in the Suppression of Drug-Induced Cardiac Hypertrophy by Traditional Indian Medicine Yogendra Ras. Biomolecules 2020, 10, 600

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Sleep restriction exacerbates cardiac dysfunction in diabetic mice by causing cardiomyocyte death and fibrosis through mitochondrial damage.

Diabetic cardiomyopathy (DCM) is a cardiovascular complication of diabetes mellitus with a poor prognosis and is the leading cause of death in diabetic patients. Sleep deficiency is not only recognized as an important risk factor for the development of type 2 DM, but is also associated with increased morbidity and mortality of cardiovascular disease. The underlying role and mechanisms of sleep restriction (SR) in DCM are far from clear. The KK/Upj-Ay mouse model of T2 DM was used as a study subject, and the small animal ultrasound imaging system was used to detect the function of the heart; immunopathological staining was used to clarify the histo-structural pathological alterations of the heart; and TUNEL staining, qPCR, transmission electron microscopy (TEM), and ELISA kits were used to detect apoptosis, oxidative stress, inflammation, and mitochondrial damage, and related molecular alterations. SR led to a significant increase in mortality, cardiac hypertrophy, necrosis, glycogen deposition and fibrosis further deteriorated in DM KK mice. SR increased cardiomyocyte death in KK mice through the Bax/Bcl2 pathway. In addition to this, SR not only exacerbated the inflammatory response, but also aggravated mitochondrial damage and promoted oxidative stress in KK mice through the PRDM16-PGC-1α pathway. Overall, SR exacerbates structural alterations and dysfunction through inflammation, oxidative stress, and apoptosis in DM KK mice, increasing the risk of death. Clinicians and diabetic patients are prompted to pay attention to sleep habits to avoid accelerating the transition of DCM to heart failure and inducing death due to poor sleep habits.

Potential Roles of IP3 Receptors and Calcium in Programmed Cell Death and Implications in Cardiovascular Diseases.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca2+i) homeostasis. The release of Ca2+ from IP3Rs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IP3Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP3Rs results in the dysregulation of Ca2+ concentration ([Ca2+]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP3Rs, i.e., IP3R1 and IP3R2, have been identified. Notably, IP3R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP3R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP3Rs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IP3R antagonists have emerged as promising strategies against IP3R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP3Rs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases.

Phenotypic expression, genotypic profiling and clinical outcomes of infantile hypertrophic cardiomyopathy: a retrospective study

BackgroundInfantile hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder. Apart from registries in high-income nations, there is a shortage of data on the aetiological basis of infantile HCM in low- and...

Protective Role of (-)-Epicatechin on Trimethylamine-N-Oxide (TMAO)-Induced Cardiac Hypertrophy via SP1/SIRT1/SUMO1 Signaling Pathway.

(-)-Epicatechin (EPI) is beneficial for cardiovascular health. Trimethylamine N-oxide (TMAO), a gut microbe-derived food metabolite, is strongly associated with the risk of cardiovascular diseases. However, the effects and underlying mechanisms of EPI on TMAO-induced cardiac hypertrophy remain unclear. This study aimed to determine whether EPI inhibits TMAO-induced cardiac hypertrophy. Plasma levels of TMAO in control participantsand patients with cardiac hypertrophy were measured and analyzed. Male C57BL/6 mice were randomly divided into control group, TMAO group, EPI group and TMAO + EPI group. According to the groups assignments, mice received intraperitoneal (i.p.) injection of normal saline or i.p. injection of TMAO (150mg/kg/day) for 14days. The EPI group was given intragastric (i.g.) administration of EPI alone (1mg/kg/day) for 21days, and TMAO + EPI group received i.g. administration of EPI for 7days before starting i.p. injection of TMAO, continuing until the end of the TMAO treatment. Histological analyses of the mice's hearts was accessed by H&E and Masson staining. In vitro, H9c2 cells were induced to hypertrophy by TMAO (10µM) for 24h and were pre-treated with or without EPI (10µM) for 1h. Protein level of cardiac hypertrophy markers and Sp1/SIRT1/SUMO1 pathway were determined by western blot. The plasma level of TMAO was 2.66 ± 1.59μmol/L in patients with cardiac hypertrophy and 0.62 ± 0.30μmol/L in control participants. EPI attenuated TMAO-induced hypertrophy in H9c2 cells. In vivo, TMAO induced cardiac hypertrophy and impaired the cardiac function of mice. Pathological staining showed that TMAO induced cardiac hypertrophy and collagen deposition in mice. EPI treatment improved the cardiac function, inhibited the myocardial hypertrophy induced by TMAO. EPI significantly attenuated the TMAO-induced upregulation of ANP and BNP and the downregulation of SP1, SIRT1 and SUMO1 in vivo and in vitro. EPI may suppress TMAO-induced cardiac hypertrophy by activating the Sp1/SIRT1/SUMO1 signaling pathway.

Mineralocorticoid receptor antagonists and heart failure with preserved ejection fraction: current understanding and future prospects.

The mineralocorticoid receptor (MR), part of the steroid hormone receptor subfamily within nuclear hormone receptors, is found in the kidney and various non-epithelial tissues, including the heart and blood vessels. When improperly activated, it can contribute to heart failure processes such as cardiac hypertrophy, fibrosis, stiffening of arteries, inflammation, and oxidative stress. MR antagonists (MRAs) have shown clear clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF). However, in cases of heart failure with preserved ejection fraction (HFpEF), there is considerable diversity due to its complex underlying mechanisms, resulting in conflicting findings regarding the effectiveness of MRAs in relevant studies. The concept of phenomapping presents an encouraging avenue for investigating different intervention targets and novel therapies for HFpEF. Post hoc analysis of the TOPCAT trial identified certain HFpEF phenotypes that responded favorably to spironolactone. Growing clinical and preclinical evidence suggests that non-steroidal MRAs, which exhibit greater receptor selectivity, stronger anti-fibrotic and anti-inflammatory properties, and fewer hormone-related side effects, may emerge as another promising treatment option for HFpEF alongside sodium-glucose co-transporter 2 (SGLT2) inhibitors. This review aims to outline the structural and functional characteristics of MR, discuss the physiological effects of its activation and inhibition, and delve into the potential for personalized MRA therapy based on the concept of HFpEF phenotype.

Distinguishing hypertensive cardiomyopathy from cardiac amyloidosis in hypertensive patients with heart failure: a CMR study with histological confirmation.

Differentiation of the cause of left ventricular hypertrophy (LVH) is challenging in cases with co-existing hypertension. CMR offers assessment of diffuse myocardial abnormalities via T1 mapping with extracellular volume fraction (ECV) and macroscopic fibrosis via late gadolinium enhancement imaging (LGE). The goal of the study was to understand if CMR parameters can differentiate hypertensive cardiomyopathy (HC) from cardiac amyloidosis (CA) in patients with hypertension and heart failure, using endomyocardial biopsy (EMB) as the gold standard. We retrospectively analyzed patients with hypertension, LVH, and heart failure undergoing EMB due to uncertain diagnosis. CMR parameters including cine, LGE characteristics, T1 mapping, and ECV were analyzed. A total of 34 patients were included (mean age 66.5 ± 10.7 years, 79.4% male). The final EMB-based diagnosis was HC (10, 29%), light chain (AL) CA (7, 21%), and transthyretin (ATTR) CA (17, 50%). There was a significant difference in subendocardial LGE (p = 0.03) and number of AHA segments with subendocardial LGE (p = 0.005). The subendocardial LGE pattern was most common in AL-CA (85.7%) and African American with HC (80%). ECV elevation (≥ 29%) was present in all patients with CA (AL-CA: 57.6 ± 5.2%, ATTR-CA: 59.1 ± 15.3%) and HC (37.3 ± 4.5%). Extensive subendocardial LGE pattern is not pathognomonic for CA but might also be present in African American patients with longstanding or poorly controlled HTN. The ECV elevation in HC with HF might be more significant than previously reported with an overlap of ECV values in HC and CA, particularly in younger African American patients.

Evaluation of global and regional myocardial work by echocardiography in patients with Fabry disease

BackgroundThis study aimed to quantitatively evaluate the left ventricular global and regional myocardial work of patients in Fabry disease (FD) by echocardiographic pressure–strain loop (PSL) analysis.ResultsThe study included 48 patients with FD and 48 healthy controls matched for age and sex. According to the presence/absence of left ventricular hypertrophy (LVH), the patients with FD were divided into an LVH + group and an LVH– group. Left ventricular blood pressure was estimated noninvasively according to echocardiographic valvular events and systolic pressure in the brachial artery. Left ventricular myocardial work parameters were acquired by echocardiographic pressure–strain loop analysis.The FD groups had a significantly lower global longitudinal strain (GLS), global work index, global work efficiency (GWE), global constructive work and higher global waste work than the control group (P < .05). Regional analysis showed that all segmental myocardial waste work increased and myocardial work efficiency decreased in the LVH + group than in the LVH– group (P < .05). Segmental longitudinal strain, myocardial work index, and myocardial constructive work were markedly lower in the basal and middle segments (P < .05) and preserved in the apical segments. Multivariate analysis revealed that GWE and GLS were significant related to LVH.ConclusionsMyocardial work analysis can be used to assess global and regional myocardial work in patients with FD. In this study, GLS and GWE were reduced in patients with FD and associated with the presence of LVH. Basal and middle myocardial work decreased in relation to the LVH, while apical myocardial work remained, which added value to explore the distribution of myocardial impairment.

UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMPK-Mediated Induction of Mitophagy.

Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury although its impact on diabetic cardiomyopathy remains elusive. Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanism involved. Adult mice were made diabetic using streptozotocin (STZ) while receiving UCF101 (7.15 mg/kg, i.p.) for 6 consecutive days. STZ evidently evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin1, elevated p62), mitophagy (FUNDC1 and Parkin with elevated TOM20), increased left ventricular (LV) end systolic diameter, dampened fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/relengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effect from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMPK (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, mitophagy inhibitor liensinine and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C. These findings denote that UCF101 rescues diabetes-instigated alterations in cardiac structure and contraction, likely through AMPK-mediated regulation of mitophagy.

Cathepsin L Promotes Pulmonary Hypertension via BMPR2/GSDME-Mediated Pyroptosis.

Pulmonary hypertension (PH) is a fatal progressive disease characterized by pulmonary endothelial injury and occlusive pulmonary vascular remodeling. Lysosomal protease cathepsin L degrades essential molecules to participate in the human pathophysiological process. BMPR2 (bone morphogenetic protein type II receptor) deficiency, an important cause of PH, results from mutational inactivation or excessive lysosomal degradation and induces caspase-3-mediated cell death. Given recent evidence that pyroptosis, as a new form of programmed cell death, is induced by caspase-3-dependent GSDME (gasdermin E) cleavage, we hypothesized that cathepsin L might promote PH through BMPR2/caspase-3/GSDME axis-mediated pyroptosis. Cathepsin L expression was evaluated in the lungs and plasma of patients with pulmonary arterial hypertension. The role of cathepsin L in the progression of PH and vascular remodeling was assessed in vivo. Small interfering RNA, specific inhibitors, and lentiviruses were used to explore the mechanisms of cathepsin L on human pulmonary arterial endothelial cell dysfunction. Cathepsin L expression is elevated in pulmonary artery endothelium from patients with idiopathic pulmonary arterial hypertension and experimental PH models. Genetic ablation of cathepsin L in PH rats relieved right ventricular systolic pressure, pulmonary vascular remodeling, and right ventricular hypertrophy, also restoring endothelial integrity. Mechanistically, cathepsin L promotes caspase-3/GSDME-mediated endothelial cell pyroptosis and represses BMPR2 signaling activity. Cathepsin L degrades BMPR2 via the lysosomal pathway, and restoring BMPR2 signaling prevents the pro-pyroptotic role of cathepsin L in PAECs and experimental PH models. These results show for the first time that cathepsin L promotes the development of PH by degrading BMPR2 to induce caspase-3/GSDME-mediated endothelial pyroptosis.

Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians.

Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.

Rapid onset fibrotic remodeling and ventricular dysfunction induced by phenylephrine involve targeted reprogramming of myocyte and fibroblast transcriptomes.

Catecholamine dysregulation is a common feature of multiple acute and chronic cardiac conditions, including heart failure. To investigate the role of altered α-adrenergic stimulation on cardiac function, we developed a short-term exposure model, administering phenylephrine subcutaneously to mice for one week. Compared to vehicle-injected controls, phenylephrine-treated animals exhibited increased ejection fraction, decreased chamber size, diastolic dysfunction and ventricular hypertrophy in the absence of hypertension. Remarkably, these animals developed extensive fibrotic remodeling of the tissue that plateaued at 24 hours and myocyte hypertrophy localized to regions of fibrotic deposition after 3 days of treatment. Transcriptome analyses of purified myocyte and fibroblast populations from these hearts revealed an unexpected role for myocytes in the production of extracellular matrix. Comparison with other models of cardiac stress, including pressure overload hypertrophy and cytokine activation of fibroblasts, identified stimulus-specific transcriptional circuits associated with cardiac pathology. Given the rapid, robust fibrotic response that preceded myocyte hypertrophy, intercellular communication analyses were conducted to investigate fibroblast to myocyte signaling, identifying potential crosstalk between these cells. These studies thoroughly describe and phenotypically characterize a new model of short-term catecholamine stress and provide an atlas of transcriptional remodeling in myocytes and fibroblasts.

PFKP inhibition protects against pathological cardiac hypertrophy by regulating protein synthesis

Metabolic reprogramming precedes most alterations during pathological cardiac hypertrophy and heart failure (HF). Recent studies have revealed that Phosphofructokinase, platelet (PFKP) has a wealth of metabolic and non-metabolic functions. In this study, we explored the role of PFKP in cardiac hypertrophic growth and HF. The expression level of PFKP was elevated both in pathological cardiac remodeling mouse model challenged by transverse aortic constriction (TAC) surgery and in the neonatal rat cardiomyocytes (NRCMs) stimulated by phenylephrine (PE). In global PFKP knockout (PFKP-KO) mice, cardiac hypertrophy was ameliorated under TAC surgery, while overexpression of PFKP by intravenous injection of adeno-associated virus 9 (AAV9) under the cardiac troponin T (cTnT) promoter worsened myocardial hypertrophy and fibrosis. In NRCMs, small interfering RNA (SiRNA) knockdown or adenovirus (Adv) overexpression of PFKP was employed and the intervention of PFKP showed a similar phenotype. Mechanistically, immunoprecipitation combined with liquid chromatography-tandem mass spectrometry (IP-MS/MS) analysis was used to identify the interacting proteins of PFKP. Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) was identified as the downstream target of PFKP. In the PE-stimulated NRCM hypertrophy model and mouse TAC model, knocking down EIF2S2 after PFKP overexpression reduced the synthesis of new proteins and alleviated the hypertrophy phenotype. Our findings illuminate that PFKP participates in pathological cardiac hypertrophy partly by regulating protein synthesis through EIF2S2, which provides a new clue for the involvement of metabolic intermediates in signal transduction.

Case of Bone Morphogenetic Protein Receptor Type 2 (BMPR2) Mutation Complicated by Pulmonary Hypertension Encountered at Autopsy

Abstract Introduction/Objective Bone morphogenetic protein receptor type 2 is a protein encoded by the BMPR2 gene which regulates cell division and apoptosis. BMPR2 mutations result in monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles, which leads to elevated pulmonary artery pressures, right ventricular failure, and death. Here, we present the case of a 12-year-old male with a known history of pulmonary hypertension secondary to BMPR2 mutation referred for medical autopsy after suffering cardiac arrest and passing away. Methods/Case Report This 12-year-old male was diagnosed with pulmonary hypertension in December 2022 after suffering a syncopal episode while running at recess. Genetic testing was obtained, and he was found to have a BMPR2 mutation. His father was tested and also harbored this mutation, but did not clinically have pulmonary hypertension. The decedent was initiated on ambrisentan, tadalafil, and spironolactone, but continued to present to the Emergency Department periodically for syncopal episodes. In April 2024, he presented to the Medical University of South Carolina in cardiac arrest which began while playing outside. A complete autopsy was performed, including gross and microscopic examination of tissues and postmortem vitreous electrolyte analysis. Gross examination revealed the decedent’s heart was enlarged to 350 grams (normal mean for age = 181 grams). Both cardiac ventricles were dilated and the right ventricle was markedly hypertrophic with a thickness of 1.2 cm. Microscopic sections are pending but will presumptively show significant cardiac myocyte hypertrophy and pulmonary arteriole thickening. Cause of death is pending certification but is presumed to be sudden cardiac death resulting from BMPR2 mutation- related pulmonary hypertension. Results (if a Case Study enter NA) NA Conclusion This case highlights a common genetic presentation of pulmonary arterial hypertension, with approximately 80% of familial cases of pulmonary arterial hypertension harboring BMPR2 mutations. Further research should be done to investigate treatment options and management of this genetic presentation.

Apical Sparing of Longitudinal Strain as a Specific Pattern of Myocardial Fibrosis in Patients with Severe Left Ventricular Hypertrophy: A Comparison between Deformation Imaging and Histological Findings.

Objectives: This study aimed to investigate the correlation between apical sparing of longitudinal strain (LS), as measured by speckle-tracking echocardiography (STE), and the histological presence of myocardial fibrosis (MF), in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods: Twenty-seven HOCM patients who underwent elective Morrow procedures +/- aortic valve replacement (AVR) were included. All patients had standard echocardiography, with STE pre- and post-operatively. Intraoperative probes of the interventricular septum were sent for histological analysis. Correlation of different regional LS patterns with the histological findings of MF and with clinical outcome were analyzed. In addition, a logistic regression and ROC analysis were performed. Results: All patients underwent the Morrow procedure for HOCM, with 33.3% also undergoing AVR. A total of 74.1% showed evidence of MF in the histological analysis. Patients with MF had significantly lower GLS than patients without MF (-12.7 ± 2.7% vs. -23.0 ± 5.7%, p < 0.001). The LS in patients with MF was significantly lower at the basal regions of the LV segments and increased significantly towards the apex as compared to the patients without MF (mean basal-strain %: -10.6 ± 2.6 vs. -17.3 ± 4.6, p < 0.001; mean apical strain %: -21.8 ± 4.8 vs. -16.7 ± 5.6, p = 0.032). In the logistic regression, only the GLS remained as an independent predictor of MF with an Odds ratio of 1.07 (95%-CI: 1.05-1.09, p < 0.001). Conclusions: Our study highlights the significant correlation between GLS and MF in HOCM patients. These findings contribute to the growing understanding of MF in HOCM and may inform future approaches to patient management and risk stratification.

Machine learning to classify left ventricular hypertrophy using ECG feature extraction by variational autoencoder.

Traditional ECG criteria for left ventricular hypertrophy (LVH) have low diagnostic yield. Machine learning (ML) can improve ECG classification. ECG summary features (rate, intervals, axis), R-wave, S-wave and overall-QRS amplitudes, and QRS/QRST voltage-time integrals (VTIs) were extracted from 12-lead, vectorcardiographic X-Y-Z-lead, and root-mean-square (3D) representative-beat ECGs. Latent features were extracted by variational autoencoder from X-Y-Z and 3D representative-beat ECGs. Logistic regression, random forest, light gradient boosted machine (LGBM), residual network (ResNet) and multilayer perceptron network (MLP) models using ECG features and sex, and a convolutional neural network (CNN) using ECG signals, were trained to predict LVH (left ventricular mass indexed in women >95 g/m², men >115 g/m²) on 225,333 adult ECG-echocardiogram (within 45 days) pairs. AUROCs for LVH classification were obtained in a separate test set for individual ECG variables, traditional criteria and ML models. In the test set (n=25,263), AUROC for LVH classification was higher for ML models using ECG features (LGBM 0.790, MLP 0.789, ResNet 0.788) as compared to the best individual variable (VTI QRS-3D 0.677), the best traditional criterion (Cornell voltage-duration product 0.647) and CNN using ECG signal (0.767). Among patients without LVH who had a follow-up echocardiogram >1 (closest to 5) years later, LGBM false positives, compared to true negatives, had a 2.63 (95% CI 2.01, 3.45)-fold higher risk for developing LVH (p<0.0001). ML models are superior to traditional ECG criteria to classify-and predict future-LVH. Models trained on extracted ECG features, including variational autoencoder latent variables, outperformed CNN directly trained on ECG signal.