A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

Davis, Jennifer; Davis, Lindsay; Correll, Robert N.; Makarewich, Catherine A.; Schwanekamp, Jennifer A.; Moussavi‐Harami, Farid; Wang, Dan; York, Allen J.; Wu, Haodi; Houser, Steven R.; Seidman, Christine E.; Seidman, Jonathan G.; Regnier, Michael; Metzger, Joseph M.; Wu, Joseph C.; Molkentin, Jeffery D

doi:10.1016/j.cell.2016.04.002

Cited by 203 publications

(249 citation statements)

References 37 publications

Supporting

Mentioning

216

Contrasting

Order By: Relevance

“…As discussed above, failing cardiomyocytes with the PLN R9C/+ mutation shared considerable expression overlap with Cdk8-transgenic samples. Humans with this mutation develop DCM, and patient-derived iPSC cardiomyocytes have a negative tension-time integral consistent with other DCM-causing mutations (52).…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

et al. 2017

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

et al. 2017

View full text Add to dashboard Cite

“…A recent study demonstrates that calcineurin is activated in models of both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) [256]. The HCM phenotype was caused by a mutation in cardiac troponin C (cTnC) that increased both Ca 2+ affinity and tension, whereas the DCM cTnC mutation decreased Ca 2+ affinity and myofilament tension.…”

Section: Not All Calcineurin Activity Is Pathologicalmentioning

confidence: 99%

Calcineurin signaling in the heart: The importance of time and place

Parra

Rothermel

2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure.

show abstract

“…Although attractive, the idea that myosin mutations causing hypercontractility lead to HCM and those causing hypocontractility lead to DCM has not been definitively established (Spudich, 2014). However, changes in calcium sensitivity (higher in HCM, decreased in DCM) have been discussed, and a direct link between calcium sensitivity, which induces heart growth via tension generation, and HCM has recently been established (Davis et al, 2016). …”

Section: Thick Filament Mutations Associated With Hcmmentioning

confidence: 99%

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

et al. 2016

View full text Add to dashboard Cite

The South Asian population, numbered at 1.8 billion, is estimated to comprise around 20% of the global population and 1% of the American population, and has one of the highest rates of cardiovascular disease. While South Asians show increased classical risk factors for developing heart failure, the role of population-specific genetic risk factors has not yet been examined for this group. Hypertrophic cardiomyopathy (HCM) is one of the major cardiac genetic disorders among South Asians, leading to contractile dysfunction, heart failure, and sudden cardiac death. This disease displays autosomal dominant inheritance, and it is associated with a large number of variants in both sarcomeric and non-sarcomeric proteins. The South Asians, a population with large ethnic diversity, potentially carries region-specific polymorphisms. There is high variability in disease penetrance and phenotypic expression of variants associated with HCM. Thus, extensive studies are required to decipher pathogenicity and the physiological mechanisms of these variants, as well as the contribution of modifier genes and environmental factors to disease phenotypes. Conducting genotype-phenotype correlation studies will lead to improved understanding of HCM and, consequently, improved treatment options for this high-risk population. The objective of this review is to report the history of cardiovascular disease and HCM in South Asians, present previously published pathogenic variants, and introduce current efforts to study HCM using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies. The authors ultimately hope that this review will stimulate further research, drive novel discoveries, and contribute to the development of personalized medicine with the aim of expanding therapeutic strategies for HCM.

show abstract

A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

Cited by 203 publications

References 37 publications

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

Calcineurin signaling in the heart: The importance of time and place

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

Contact Info

Product

Resources

About