Although the NASCIS-2 protocol may promote early infectious complications, it has no adverse impact on long-term outcome in patients with ASCIs.

Background - Pathogenic variants in MYBPC3 , encoding cardiac MyBP-C, are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped HCM cohorts have precluded detailed genotype-phenotype correlations. Methods - Patients with HCM and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Variant types and locations were analyzed, morphologic severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, LVAD/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro . Results - Among 4,756 genotyped HCM patients in SHaRe, 1,316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or non-truncating (N=22 unique variants, 191 patients) variants in MYBPC3 . Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5' - 3' quartiles or by founder variant subgroup). Non-truncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, p<0.001 vs. gnomAD common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ~90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type. Conclusions - Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Non-truncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss-of-function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating vs. non-truncating variants.

This study was performed with Dahi salt-sensitive (DS) and Dahi salt-resistant (DR) rats to detect differences hi cardiovascular hemodynamics and renal responses that might be involved hi initiating salt-induced hypertension hi DS rats. The effects of 4 weeks of 8% NaCl diet were studied hi conscious, male DR and DS rats hi which vascular and urinary catheters had been previously implanted. Results were compared with those obtained from control groups of DR and DS rats on 4 weeks of 1% NaCl diet. DR rats on 8% salt diet did not develop hypertension, and cardiac output and blood volume were unchanged; glomerular filtration rate, urinary flow, sodium excretion, and plasma atrial natriuretic factor (ANT) increased. DS rats on 8% salt diet developed hypertension, and cardiac output and blood volume increased; glomerular filtration rate, urinary flow, and sodium excretion did not change, despite an increase hi ANF. DS and DR rats on 1% NaCl diet were subjected to ANF infusion. After ANF infusion DR rats had a decreased blood volume and an increased glomerular filtration rate, urinary flow, and sodium excretion; DS rats showed no significant changes hi blood volume, glomerular filtration rate, urinary flow, or sodium excretion. ANF caused vasodilation hi all regions studied hi DR rats; DS rats showed vasodilation hi all regions except the kidney. After acute volume expansion, although both DR and DS rats responded by an increase hi cardiac output, only DS rats developed prolonged hypertension. This finding suggests an inadequate vasodilatory mechanism in DS rats. In response to acute volume expansion, renal resistance decreased hi DR rats but not hi DS rats. It is concluded that the primary hemodynamic disturbance hi DS rats with salt-Induced hypertension is an increase hi cardiac output caused by blood volume expansion hi the absence of any vasodilation. Comparison of the responses of DS and DR rats to high salt diets, ANF infusion, and acute volume expansion indicates that the salt-induced hypertension in DS rats is initiated by a diminished renal response to ANF. (Hypertension 1989;13:612-621) T his study was performed with Dahi saltsensitive (DS) and Dahi salt-resistant (DR) rats to detect differences in cardiovascular hemodynamics and renal responses that might be involved in initiating salt-induced hypertension in DS rats. On the basis of experimental evidence as