Skeletal muscle regeneration following injury is a highly coordinated process that involves transient muscle inflammation, removal of necrotic cellular debris and subsequent replacement of damaged myofibers through secondary myogenesis. However, the molecular mechanisms which coordinate these events are only beginning to be defined. In the current study we demonstrate that Heat shock protein 70 (Hsp70) is increased following muscle injury, and is necessary for the normal sequence of events following severe injury induced by cardiotoxin, and physiological injury induced by modified muscle use. Indeed, Hsp70 ablated mice showed a significantly delayed inflammatory response to muscle injury induced by cardiotoxin, with nearly undetected levels of both neutrophil and macrophage markers 24 hours post-injury. At later time points, Hsp70 ablated mice showed sustained muscle inflammation and necrosis, calcium deposition and impaired fiber regeneration that persisted several weeks post-injury. Through rescue experiments reintroducing Hsp70 intracellular expression plasmids into muscles of Hsp70 ablated mice either prior to injury or post-injury, we confirm that Hsp70 optimally promotes muscle regeneration when expressed during both the inflammatory phase that predominates in the first four days following severe injury and the regenerative phase that predominates thereafter. Additional rescue experiments reintroducing Hsp70 protein into the extracellular microenvironment of injured muscles at the onset of injury provides further evidence that Hsp70 released from damaged muscle may drive the early inflammatory response to injury. Importantly, following induction of physiological injury through muscle reloading following a period of muscle disuse, reduced inflammation in 3-day reloaded muscles of Hsp70 ablated mice was associated with preservation of myofibers, and increased muscle force production at later time points compared to WT. Collectively our findings indicate that depending on the nature and severity of muscle injury, therapeutics which differentially target both intracellular and extracellular localized Hsp70 may optimally preserve muscle tissue and promote muscle functional recovery.

The first description of polyarteritis nodosa (PAN) was in 1852 by Karl Rokitansky, a Pathologist at the University of Vienna.(1) The initial report describes a 23 year-old man who had a five-day history of fever and diarrhea. Since then, the definition of PAN has evolved. The currently accepted definition of PAN comes from the 2012 Chapel Hill Conference which classified PAN as a necrotizing arteritis not associated with anti-neutrophil cytoplasmic antibodies (ANCAs) of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules.(2)

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Background: Although the prognosis and management of severe aortic stenosis has been extensively studied, the risk stratification and outcomes of patients with moderate aortic stenosis remain elusive. Methods: This study included 674 patients from the Cleveland Clinic Health System with moderate aortic stenosis (aortic valve area, 1–1.5 cm 2 ; mean gradient, 20–40 mm Hg; and peak velocity <4 m/s) and an NT-proBNP (N-terminal pro-B-type natriuretic peptide) level within 3 months of index diagnosis. The primary outcome of major adverse cardiovascular events (defined as the composite outcome of progression to severe aortic stenosis requiring aortic valve replacement, heart failure hospitalization, or death) was extracted from the electronic medical record. Results: The mean age was 75.3±12 years, and 57% were men. During a median follow-up of 316 days, the composite end point occurred in 305 patients. There were 132 (19.6%) deaths, 144 (21.4%) heart failure hospitalizations, and 114 (16.9%) patients underwent aortic valve replacement. Elevated NT-proBNP (1.41 [95% CI, 1.01–1.95]; P =0.048), diabetes (1.46 [95% CI, 1.08–1.96]; P =0.01), elevated averaged mitral valve E/e′ ratio (hazard ratio, 1.57 [95% CI, 1.18–2.10]; P <0.01), and presence atrial fibrillation at the time of index echocardiogram (hazard ratio, 1.83 [95% CI, 1.15–2.91]; P =0.01) were each independently associated with an increased hazard for the composite outcome and when taken collectively, each of these factors incrementally increased risk. Conclusions: These results further elucidate the relatively poor short-medium term outcomes and risk stratification of patients with moderate aortic stenosis, supporting randomized trials assessing the efficacy of transcatheter aortic valve replacement in this population.

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