Towards Precision in HF Pharmacotherapy

Norgard, Nicholas B; Hempel, Carolyn

doi:10.1007/s11897-017-0314-3

Cited by 3 publications

(4 citation statements)

References 59 publications

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“…Furthermore, remodeling of t-tubules may facilitate arrhythmias due to altered Ca 2+ handling (Orchard et al, 2013). The t-system is therefore considered as a potential target of therapy, prevention and diagnosis, especially in heart failure (Manfra et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

“…However, what causes junctophilin downregulation or changes in the microtubular system is poorly understood. Possible mechanisms include biomechanical disruption of cytoskeletal proteins and mechanotransduction in response to elevated mechanical stress (Frisk et al, 2016; Manfra et al, 2017). An integrated mechanism was suggested by a study using genetic mosaics, where junctophilin knockdown in a subset of cardiomyocytes led to t-tubule loss only in the context of cardiac stress (Guo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

Seidel

Sankarankutty

Sachse

2017

Progress in Biophysics and Molecular Biology

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The transverse tubular system (t-system) of ventricular cardiomyocytes is essential for efficient excitation-contraction coupling. In cardiac diseases, such as heart failure, remodeling of the t-system contributes to reduced cardiac contractility. However, mechanisms of t-system remodeling are incompletely understood. Prior studies suggested an association with altered cardiac biomechanics and gene expression in disease. Since fibrosis may alter tissue biomechanics, we investigated the local microscopic association of t-system remodeling with fibrosis in a rabbit model of myocardial infarction (MI). Biopsies were taken from the MI border zone of 6 infarcted hearts and from 6 control hearts. Using confocal microscopy and automated image analysis, we quantified t-system integrity (ITT) and the local fraction of extracellular matrix (fECM). In control, fECM was 18±0.3%. ITT was high and homogeneous (0.07±0.006), and did not correlate with fECM (R2=0.05±0.02). The MI border zone exhibited increased fECM within 3mm from the infarct scar (30±3.5%, p<0.01 vs control), indicating fibrosis. Myocytes in the MI border zone exhibited significant t-system remodeling, with dilated, sheet-like components, resulting in low ITT (0.03±0.008, p<0.001 vs control). While both fECM and t-system remodeling decreased with infarct distance, ITT correlated better with decreasing fECM (R2=0.44) than with infarct distance (R2=0.24, p<0.05). Our results show that t-system remodeling in the rabbit MI border zone resembles a phenotype previously described in human heart failure. T-system remodeling correlated with the amount of local fibrosis, which is known to stiffen cardiac tissue, but was not found in regions without fibrosis. Thus, locally altered tissue mechanics may contribute to t-system remodeling.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

Seidel

Sankarankutty

Sachse

2017

Progress in Biophysics and Molecular Biology

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“…3,4 Better understanding of the genetic basis of HF may shed light on the prevention, diagnosis and treatment of HF. 5,6 Recently, genome wide association studies have successfully identified multiple genes associated with the risk of HF. [7][8][9][10] However, only a few studies focused on the association of genetic variation with its prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…As the ageing of population and HF risk factors increase, HF has become a serious challenge for the public health . Better understanding of the genetic basis of HF may shed light on the prevention, diagnosis and treatment of HF …”

Section: Introductionmentioning

confidence: 99%

A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding

Huang

et al. 2019

J Cellular Molecular Medi

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Receptor‐interacting protein kinase 3 (RIP3) is a key determinant of necroptosis and participates in ischaemia—and oxidative stress‐induced necroptosis, myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in RIP3 gene were associated with the risk and prognosis of HF in the Chinese Han population. By re‐sequencing and luciferase assays, we identified a common functional variant in the RIP3 promoter region. The rs3212247‐T allele suppressed RIP3 promoter activity by facilitating transcription factor SOX17 binding, but not the C allele. We further recruited 2961 control participants and 3194 HF patients who underwent a mean follow‐up of 19 months (6‐31 months) for this study. Rs3212247 and another missense variant rs3212254 were genotyped. Although rs3212247 did not significantly associate with increased risk of HF (odds ratio = 1.00, 95% CI = 0.92‐1.08, P = 0.91), it raised the risk for cardiovascular death and cardiac transplantation (hazard ratio = 1.47, 95% CI = 1.13‐1.91, P = 0.004). Moreover, participants carrying the rs3212247 CC genotype had higher plasma levels of RIP3 than those carrying the TT or TC genotype (p for trend = 0.02) in New York Heart Association class III HF group. No association was found between the RIP3 missense variant rs3212254 and risk or prognosis of HF after adjustment for traditional risk factors. In conclusion, genetic variant in RIP3 promoter region is associated with increased RIP3 transcription, thus contributed to the poor prognosis of HF patients. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03461107?term=03461107&cond=Heart+Failure&cntry=CN&rank=1 . Unique identifier: NCT03461107.

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Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

Hsu

2021

Advanced Biology

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Pharmacotherapy has been serving as an effective treatment for HFs to improve symptom, functional capacity, quality of life, and to reduce the frequency of hospitalizations. [8] However, it differs in each HF subtype. Traditionally, angiotensin converting enzyme inhibitors (ACEIs), mineralocorticoid receptor antagonists (MRAs), and β-blockers are typical treatments for HFrEF. Since many hospitalizations and deaths in HFpEF patients are due to noncardiovascular causes, pharmacotherapy mainly focus on relieving of symptoms and easing comorbidities for HFpEF patients.HFpEF with a prevalence range from 31% to 55% has received most attention recently from the clinical and research field [4,9,10] due to lack of effective pharmacological treatment options. Although cardiac regenerative therapeutics have been widely studied in the past two decades [11] for treating both HFrEF and HFpEF, the treatment mechanisms and associated intrinsic cardiac remodeling process are nonspecific to each HF subtype. Besides, additional mechanisms such as metabolic disorders, proinflammatory conditions, and immunologic remodeling also influenced the prognosis of different HFs. [12] In this review, we summarized pathological cardiac remodeling, associated immune reactions, and signaling pathways for HF in general, and discussed the challenges that hamper clinical translation of regenerative therapeutics which holds diagnostic and therapeutic potential. This review helps to reveal the underlying mechanisms that may lead us to generate new clinical-feasible treatment for HFpEF in the future. [13][14][15][16][17][18] Signaling during HF Progression HF ProgressionThe growth of cardiomyocytes occurs in both physiological and pathological hypertrophy. [19] Physiologically, hemodynamic load stimulates normal, postnatal, pregnancy, and exercise-induced cardiac growth. [19] Pathologically, the stimulation from HF risk factors increases heart size, mass, or geometry. In the progression of HF, multiple molecular mechanisms associated with cardiomyocyte survival, death, energy metabolism, oxidative stress, inflammation, calcium transport and neurohormonal activation led to loss of functional cardiomyocytes, development of fibrosis, left ventricular remodeling, and HF prognosis. [20] Heart failure (HF) is one of the leading causes for hospital admissions worldwide. HF patients are classified based on the chronic changes in left ventricular ejection fraction (LVEF) as preserved (LVEF ≥ 50%), reduced (LVEF ≤ 40%), or mid-ranged (40% < LVEF < 50%) HFs. Treatments nowadays can prevent HFrEF progress, whereas only a few of the treatments have been proven to be effective in improving the survival of HFpEF. In this review, numerous mediators involved in the pathogenesis of HF are summarized. The regional upstream signaling and their diagnostic and therapeutic potential are also discussed. Additionally, the recent challenges and development in cardiac regenerative therapy that hold opportunities for future research and clinical translation are discussed.

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Towards Precision in HF Pharmacotherapy

Cited by 3 publications

References 59 publications

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding

Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

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