Unmet needs in the treatment of hypertrophic cardiomyopathy

2021 ◽  
Author(s):  
Erika Hutt ◽  
Steven E Nissen ◽  
Milind Y Desai
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Unmet Needs ◽  
Interstitial Fibrosis ◽  
Symptom Control ◽  
Management Strategies ◽  
Cardiovascular Disorder ◽  
Controlled Clinical Trials ◽  
Current Management ◽  
Control And Prevention ◽  
Familial Screening

Hypertrophic cardiomyopathy (HCM) is a complex heterogeneous cardiovascular disorder characterized by hypertrophied and disorganized myocytes with varying degrees of interstitial fibrosis. The current management strategies include genetic and familial screening, symptom control and prevention of sudden cardiac death in those at high risk. Until recently, septal reduction therapy and heart transplantation were the only disease modifying treatments available to manage HCM, but emerging pharmacotherapies show promising results in controlled clinical trials. In this article, we will review the unmet needs in the treatment of HCM incorporating novel therapies.

scholarly journals A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kathryn M. Meurs ◽  
Brian G. Williams ◽  
Dylan DeProspero ◽  
Steven G. Friedenberg ◽  
David E. Malarkey ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hypertrophic Cardiomyopathy ◽  
Cardiac Development ◽  
Interstitial Fibrosis ◽  
Cell Cycle Control ◽  
Cardiovascular Disorder ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Causative Mutation ◽  
Cardiomyocyte Proliferation ◽  
Large Gene

Abstract Background Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation. Results A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001). Conclusion This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.

scholarly journals Effects of candesartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Maqsood ◽  
H.A Shakeel ◽  
H.F Shoukat ◽  
M.D Khan ◽  
S.A.Y Shah ◽  
...  
Keyword(s):  
Late Gadolinium Enhancement ◽  
Hypertrophic Cardiomyopathy ◽  
Interstitial Fibrosis ◽  
Angiotensin Receptor Blockers ◽  
Left Ventricular ◽  
Funding Source ◽  
Gadolinium Enhancement ◽  
Percent Change ◽  
Lv Mass ◽  
Significant Difference

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular (LV) hypertrophy in the absence of pressure overload. Manifestations of the disease include heart failure associated with diastolic dysfunction and atrial and ventricular tachyarrhythmias. Pathological features of HCM include myocyte hypertrophy, interstitial fibrosis, and myocyte disarray and are mediated by angiotensin II. Purpose This study aimed to evaluate the effects of candesartan on left ventricular (LV) hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy (HCM). Methods In double-blind fashion, 30 patients (6 women, 24 men; age: 55±11 years) with HCM were randomly assigned to receive placebo (n=13) or candesartan 50 mg twice a day (n=17) for 1 year. To measure LV mass and extent of fibrosis, cardiac magnetic resonance imaging was performed at baseline and 1 year as assessed by late gadolinium enhancement. Results There was a trend toward a significant difference in the percent change in LV mass (median: +5% with placebo vs. −5% with candesartan; p=0.06). There was a significant difference in the percent change in the extent of late gadolinium enhancement, with the placebo group experiencing a larger increase (+30±27% with placebo vs. −22±44% with candesartan; p=0.03). Conclusion Our study concludes reduction of the progression of myocardial hypertrophy and fibrosis with candesartan in patients with hypertrophic cardiomyopathy. Our study population was limited so we warrant larger trials to confirm a place for angiotensin receptor blockers in the management of patients with hypertrophic cardiomyopathy. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): Self funding

Pathophysiology, Diagnosis, and Current Management Strategies for Chest Pain in Patients With Normal Findings on Angiography

2001 ◽  
Vol 76 (8) ◽  
pp. 813-822 ◽  
Author(s):  
Jassim Al Suwaidi ◽  
Stuart T. Higano ◽  
David R. Holmes ◽  
Amir Lerman
Keyword(s):  
Chest Pain ◽  
Management Strategies ◽  
Current Management

Intracellular life cycle of Candidatus Liberibacter asisticus inside psyllid gut cells

2021 ◽  
Author(s):  
Lin Chun-Yi ◽  
Diann Achor ◽  
Amit Levy
Keyword(s):  
Molecular Mechanisms ◽  
Management Strategies ◽  
Bacterial Invasion ◽  
Diaphorina Citri ◽  
Current Management ◽  
Insect Midgut ◽  
Rapid Spread ◽  
Candidatus Liberibacter ◽  
Infected Insect ◽  
Liberibacter Asiaticus

Candidatus Liberibacter asiaticus (CLas), the devastating pathogen related to Huanglongbing (HLB), is a phloem-limited, fastidious, insect-borne bacterium. Rapid spread of HLB disease relies on CLas propagates efficiently in its vector, the Asian citrus psyllid, Diaphorina citri, in a circulative manner. Understanding the intracellular lifecycle of CLas in psyllid midgut is fundamental to improve current management strategies. Using a microscopic approach within CLas-infected insect midgut, we observed the entry of CLas into gut cells inside vesicles by endocytosis, termed Liberibacter containing vacuoles (LCVs). Endocytosis is followed by the formation of endoplasmic reticulum-related and replication permissive vacuoles (rLCVs). rLCVs then further develop into bigger double membrane autophagosome-like structure, termed autophagy-related vacuole (aLCV). Vesicles, containing CLas egress from aLCV and fuse with the cell membrane. Immunolocalization studies showed that CLas employs endo/exocytosis-like mechanisms that mediates bacterial invasion and egress. Upregulation of autophagy-related genes indicated subversion of host autophagy by CLas in psyllid vector to promote infection. These results indicate that CLas interacts with host cellular machineries to undergo a multistage intracellular cycle through endocytic, secretory, autophagic and exocytic pathways via complex machineries. Potential tactics for HLB controlling can be made depending on further investigations on the knowledge of the molecular mechanisms of CLas intracellular cycle.

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