Targeting the sarcomere to correct muscle function

Hwang, Peter M.; Sykes, Brian D.

doi:10.1038/nrd4554

Cited by 111 publications

(125 citation statements)

References 198 publications

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“…Both these processes are thought to contribute to heart failure with preserved ejection and are the subject of novel therapeutic intervention trials to influence them directly45, 46 or indirectly 47…”

Section: Discussionmentioning

confidence: 99%

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Williams

Asrress

Lumley

et al. 2018

JAHA

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BackgroundCold air inhalation during exercise increases cardiac mortality, but the pathophysiology is unclear. During cold and exercise, dual‐sensor intracoronary wires measured coronary microvascular resistance (MVR) and blood flow velocity (CBF), and cardiac magnetic resonance measured subendocardial perfusion.Methods and ResultsForty‐two patients (62±9 years) undergoing cardiac catheterization, 32 with obstructive coronary stenoses and 10 without, performed either (1) 5 minutes of cold air inhalation (5°F) or (2) two 5‐minute supine‐cycling periods: 1 at room temperature and 1 during cold air inhalation (5°F) (randomized order). We compared rest and peak stress MVR, CBF, and subendocardial perfusion measurements. In patients with unobstructed coronary arteries (n=10), cold air inhalation at rest decreased MVR by 6% (P=0.41), increasing CBF by 20% (P<0.01). However, in patients with obstructive stenoses (n=10), cold air inhalation at rest increased MVR by 17% (P<0.01), reducing CBF by 3% (P=0.85). Consequently, in patients with obstructive stenoses undergoing the cardiac magnetic resonance protocol (n=10), cold air inhalation reduced subendocardial perfusion (P<0.05). Only patients with obstructive stenoses performed this protocol (n=12). Cycling at room temperature decreased MVR by 29% (P<0.001) and increased CBF by 61% (P<0.001). However, cold air inhalation during cycling blunted these adaptations in MVR (P=0.12) and CBF (P<0.05), an effect attributable to defective early diastolic CBF acceleration (P<0.05) and associated with greater ST‐segment depression (P<0.05).ConclusionsIn patients with obstructive coronary stenoses, cold air inhalation causes deleterious changes in MVR and CBF. These diminish or abolish the normal adaptations during exertion that ordinarily match myocardial blood supply to demand.

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Section: Discussionmentioning

confidence: 99%

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Williams

Asrress

Lumley

et al. 2018

JAHA

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“…As such, therapeutics targeting the sarcomere to neutralize altered sarcomeric function need to be investigated. Levosimendan and pimobendan target cTnC to increase Ca 2ϩ sensitivity of the myofilaments (17). Levosimendan, in Europe, and Pimobendan, in Japan, are in use clinically to treat heart failure (17,27,30).…”

Section: Discussionmentioning

confidence: 99%

“…Presently, there are several small-molecule cTnC Ca 2ϩ sensitizers in clinical application (17,27). In contrast, very few small-molecule Ca 2ϩ desensitizers have been identified and studied.…”

mentioning

confidence: 99%

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca²⁺-sensitive myofilaments

Thompson

Martindale

Metzger

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Thompson BR, Martindale J, Metzger JM. Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca 2ϩ -sensitive myofilaments. Am J Physiol Heart Circ Physiol 311: H36 -H43, 2016. First published May 13, 2016 doi:10.1152/ajpheart.00981.2015.-The sarcomere is the functional unit of the heart. Alterations in sarcomere activation lead to disease states such as hypertrophic and restrictive cardiomyopathy (HCM/ RCM). Mutations in many of the sarcomeric genes are causal for HCM/RCM. In most cases, these mutations result in increased Ca 2ϩ sensitivity of the sarcomere, giving rise to altered systolic and diastolic function. There is emerging evidence that small-molecule sarcomere neutralization is a potential therapeutic strategy for HCM/ RCM. To pursue proof-of-concept, W7 was used here because of its well-known Ca 2ϩ desensitizer biochemical effects at the level of cardiac troponin C. Acute treatment of adult cardiac myocytes with W7 caused a dose-dependent (1-10 M) decrease in contractility in a Ca 2ϩ -independent manner. Alkalosis was used as an in vitro experimental model of acquired heightened Ca 2ϩ sensitivity, resulting in increased live cell contractility and decreased baseline sarcomere length, which were rapidly corrected with W7. As an inherited cardiomyopathy model, R193H cardiac troponin I (cTnI) transgenic myocytes showed significant decreased baseline sarcomere length and slowed relaxation that were rapidly and dose-dependently corrected by W7. Langendorff whole heart pacing stress showed that R193H cTnI transgenic hearts had elevated end-diastolic pressures at all pacing frequencies compared with hearts from nontransgenic mice. Acute treatment with W7 rapidly restored end-diastolic pressures to normal values in R193H cTnI hearts, supporting a sarcomere intrinsic mechanism of dysfunction. The known off-target effects of W7 notwithstanding, these results provide further proof-of-concept that small-molecule-based sarcomere neutralization is a potential approach to remediate hyper-Ca 2ϩ -sensitive sarcomere function.

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“…In the presence of intracellular calcium, CK-2127107 binds to troponin and disrupts its interaction with actin. Therefore, tropomyosin, another regulatory protein, can no longer block actin-myosin interaction, and triggers muscle contraction (65,66). Through slowing calcium release from troponin in fast skeletal muscle fibers, CK-2127107 sensitizes the sarcomere to calcium and increases muscle contractility (44).…”

Section: Ck-2127107mentioning

confidence: 99%

Recent therapeutic developments of spinal muscular atrophy

Bora¹,

Yeşbek-Kaymaz²,

Bekircan-Kurt³

et al. 2018

Turk J Med Sci

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Targeting the sarcomere to correct muscle function

Cited by 111 publications

References 198 publications

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca²⁺-sensitive myofilaments

Recent therapeutic developments of spinal muscular atrophy

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Targeting the sarcomere to correct muscle function

Cited by 111 publications

References 198 publications

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments

Recent therapeutic developments of spinal muscular atrophy

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Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca²⁺-sensitive myofilaments