Exacerbation of dystrophic cardiomyopathy by phospholamban deficiency mediated chronically increased cardiac Ca2+ cycling in vivo.

Cardiomyopathy is a significant contributor to morbidity and mortality in Duchenne muscular dystrophy (DMD). Membrane instability, leading to intracellular Ca2+ mishandling and overload, causes myocyte death and subsequent fibrosis in DMD cardiomyopathy. On a cellular level, cardiac myocytes from mdx mice have dysregulated Ca2+ handling, including increased resting Ca2+ and slow Ca2+ decay, especially evident under stress conditions. Sarco(endo)plasmic reticulum Ca2+ ATPase and its regulatory protein phospholamban (PLN) are potential therapeutic targets for DMD cardiomyopathy owing to their key role in regulating intracellular Ca2+ cycling. We tested the hypothesis that enhanced cardiac Ca2+ cycling would remediate cardiomyopathy caused by dystrophin deficiency. We used a genetic complementation model approach by crossing dystrophin-deficient mdx mice with PLN knockout (PLNKO) mice [termed double-knockout (DKO) mice]. As expected, adult cardiac myocytes isolated from DKO mice exhibited increased contractility and faster relaxation associated with increased Ca2+ transient peak height and faster Ca2+ decay rate compared with control mice. However, compared with wild-type, mdx, and PLNKO mice, DKO mice unexpectedly had reduced in vivo systolic and diastolic function as measured by echocardiography. Furthermore, Evans blue dye uptake was increased in DKO hearts compared with control, mdx, and PLNKO hearts, demonstrating increased membrane damage, which subsequently led to increased fibrosis in the DKO myocardium in vivo. In conclusion, despite enhanced intracellular Ca2+ handling at the myocyte level, DMD cardiomyopathy was exacerbated owing to unregulated chronic increases in Ca2+ cycling in DKO mice in vivo. These findings have potentially important implications for ongoing therapeutic strategies for the dystrophic heart. NEW & NOTEWORTHY This study examined the effects of phospholamban ablation on the pathophysiology of cardiomyopathy in dystrophin-deficient mice. In this setting, contractility and Ca2+ cycling were enhanced in isolated myocytes; however, in vivo heart function was diminished. Additionally, sarcolemmal integrity was compromised and fibrosis was increased. This is the first study, to our knowledge, examining unregulated Ca2+ cycling in the dystrophin-deficient heart. Results from this study have implications for potential therapies targeting Ca2+ handling in dystrophic cardiomyopathy. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/unregulated-ca2-cycling-exacerbates-dmd-cardiomyopathy/ .

Primary Care Clinicians Attitudes and Knowledge of Pharmacogenetics in a Large, Multi-state, Healthcare System.

BACKGROUND: Considerable progress has been made in the way of pharmacogenetic research and the development of clinical recommendations; however, its implementation into clinical practice has been slower than anticipated. We sought to better understand its lack of clinical uptake within primary care. AIM: The primary objective of this survey was to ascertain primary care clinicians' perceptions of pharmacogenetic use and implementation in an integrated health system of metropolitan and rural settings across several states. METHODS: Primary care clinicians (including MDs, DOs, NPs, and PAs) were invited to participate in a survey via email. Questions about pharmacogenetics knowledge and perceptions were presented to assess current understanding and usage of pharmacogenetics in practice. RESULTS: The rate of response for the survey was 17%. Of the 90 respondents, 58% were female, 69% were MDs/DOs, 20% were NPs, and 11% were PAs. Fifty-eight percent of respondents received their clinical degree in or after 2000. Ninety percent of respondents noted that they were uncomfortable ordering a pharmacogenetics test, with 76% stating they were uncomfortable applying the results of a pharmacogenetic test. Notably, 78% of respondents were interested in having pharmacogenetic testing available through Medication Therapy Management (MTM) services, although PAs were significantly less interested as compared to NPs and MD/DOs. Ninety-five percent of respondents were interested in a clinical decision support tool relevant to pharmacogenetic results. CONCLUSIONS: As a whole, prescribing clinicians in primary care clinics are uncomfortable in the ordering, interpreting, and applying pharmacogenetic results to individual patients. However, favorable attitudes towards providing pharmacogenetic testing through existing MTM clinics provides the opportunity for pharmacists to advance existing practices.