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Translational Pediatrics Mar 2024
PubMed: 38590375
DOI: 10.21037/tp-23-527 -
Frontiers in Cardiovascular Medicine 2024Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general population. Left ventricular hypertrophy (LVH) caused by sarcomere mutation is the primary reason of HCM. The histopathology feature is that cardiomyocyte hypertrophy, myocyte disorder and myocardial fibrosis lead to diminished diastolic function, left ventricular outflow tract obstruction (LVOTO) and arrhythmia, all of which result in serious cardiac complications. Previously, HCM was considered a malignant disease that was almost untreatable. With the improvement of medical standards and increasing awareness of HCM, it has become a highly treatable disease in contemporary times, with a significant decrease in mortality rates. However, there are still significant unmet requirements in the therapy of HCM. This paper draws on more than 100 references from the past four decades and summarizes current advances in the treatment of HCM. The article will review the pathogenesis and types, recent development in pharmacotherapy, invasive treatments and gene therapies, as well as dilemma and future development of HCM.
PubMed: 38887447
DOI: 10.3389/fcvm.2024.1387596 -
Clinical and Experimental Hypertension... Dec 2023Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains...
BACKGROUND
Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload.
METHODS
Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA.
RESULTS
We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway.
CONCLUSION
In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload.
Topics: Animals; Mice; Cardiomegaly; Fibrosis; Hypertension; Interleukin-18; Mice, Inbred C57BL; Myocytes, Cardiac; Pyroptosis; Ventricular Remodeling; Gasdermins; Humans
PubMed: 36906959
DOI: 10.1080/10641963.2023.2189138 -
Clinical Kidney Journal Nov 2023Chronic kidney disease (CKD) is characterized by clustered age-independent concentric left ventricular (LV) geometry, geometry-independent systolic dysfunction and age... (Review)
Review
Chronic kidney disease (CKD) is characterized by clustered age-independent concentric left ventricular (LV) geometry, geometry-independent systolic dysfunction and age and heart rate-independent diastolic dysfunction. Concentric LV geometry is always associated with echocardiographic markers of abnormal LV relaxation and increased myocardial stiffness, two hallmarks of diastolic dysfunction. Non-haemodynamic mechanisms such as metabolic and electrolyte abnormalities, activation of biological pathways and chronic exposure to cytokine cascade and the myocardial macrophage system also impact myocardial structure and impair the architecture of the myocardial scaffold, producing and increasing reactive fibrosis and altering myocardial distensibility. This review addresses the pathophysiology of diastole in CKD and its relations with cardiac mechanics, haemodynamic loading, structural conditions, non-haemodynamic factors and metabolic characteristics. The three mechanisms of diastole will be examined: elastic recoil, active relaxation and passive distensibility and filling. Based on current evidence, we briefly provide methods for quantification of diastolic function and discuss whether diastolic dysfunction represents a distinct characteristic in CKD or a proxy of the severity of the cardiovascular condition, with the potential to be predicted by the general cardiovascular phenotype. Finally, the review discusses assessment of diastolic function in the context of CKD, with special emphasis on end-stage kidney disease, to indicate whether and when in-depth measurements might be helpful for clinical decision making in this context.
PubMed: 37915916
DOI: 10.1093/ckj/sfad177 -
Journal of Clinical Medicine Nov 2023Fabry disease (FD) is a genetic lysosomal storage disease with frequent cardiovascular involvement, whose presence is a major determinant of adverse clinical outcomes.... (Review)
Review
Fabry disease (FD) is a genetic lysosomal storage disease with frequent cardiovascular involvement, whose presence is a major determinant of adverse clinical outcomes. As a potentially treatable cause of left ventricular hypertrophy (LVH) and heart failure with preserved ejection fraction, the early recognition of FD is crucial to initiate enzyme replacement therapy and improve long-term prognosis. Multimodality imaging plays a central role in the evaluation of patients with FD and helps in the differential diagnosis of other conditions presenting with LVH. In the present review, we explore the current applications of multimodality cardiac imaging, in particular echocardiography and cardiovascular magnetic resonance, in the diagnosis, prognostic assessment, and follow-up of patients with FD.
PubMed: 38002674
DOI: 10.3390/jcm12227061 -
Heart Failure Reviews Sep 2023The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular... (Review)
Review
The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.
Topics: Humans; Cardiomyopathy, Hypertrophic; Hypertrophy, Left Ventricular; Cardiomyopathies; Phenotype; Fabry Disease; Inflammation
PubMed: 37115472
DOI: 10.1007/s10741-023-10307-4 -
American Journal of Translational... 2024Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations... (Review)
Review
Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations in cardiomyocytes, among which autophagy, a crucial intracellular degradation mechanism, plays a pivotal role. Autophagy facilitates the breakdown of damaged organelles and proteins, thereby maintaining cellular homeostasis. In the context of heart failure, autophagy coexists with apoptosis and necrosis, influencing myocardial hypertrophy and ventricular remodeling. However, its impact on heart failure manifests a dual nature: moderate autophagy aids in cardiac repair, whereas excessive autophagy may exacerbate ventricular remodeling and cell demise. This review delves into the fundamental biology of autophagy, elucidating its involvement in the pathological cascade of heart failure and its correlation with cardiac hypertrophy and ventricular remodeling. Furthermore, an analysis of the interplay between autophagy regulatory factors and heart failure sheds light on the potential therapeutic implications of autophagy in the prevention and management of heart failure. This exploration provides a theoretical foundation for novel treatment strategies in combating heart failure.
PubMed: 38883358
DOI: 10.62347/OBXQ9477 -
Circulation Sep 2023In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these...
BACKGROUND
In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate.
METHODS
This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation).
RESULTS
Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all <0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both <0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; =0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; <0.001), and MVD (reduced stress myocardial blood flow [=0.015] with perfusion defects in 28% versus 0 healthy volunteers [=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, =0.01; stress myocardial blood flow: odds ratio, 2.8, =0.015; subclinical: fractional anisotropy odds ratio, 4.0, =0.001; myocardial perfusion reserve odds ratio, 2.2, =0.049).
CONCLUSIONS
Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.
Topics: Humans; Hypertrophy, Left Ventricular; Sarcomeres; Diffusion Tensor Imaging; Genetic Predisposition to Disease; Mutation; Cardiomyopathy, Hypertrophic; Phenotype; Biomarkers; Fibrosis
PubMed: 37463608
DOI: 10.1161/CIRCULATIONAHA.123.063835