Mavacamten is a targeted treatment for hypertrophic cardiomyopathy, a disease caused by genetic variants affecting mainly sarcomeric myosin and its regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here we generate knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which unlike carriers of cMyBP-C truncations, develop pathogenic myocardial remodeling with preserved cMyBP-C levels and localization. Mechanistically, R502W reduces cMyBP-C-myosin affinity and generates sarcomere hypercontractility due to increased Ca[2+] sensitivity and a favored ON structural state of myosin. Even though these pathomechanisms do not overlap with those triggered by truncating MYBPC3 variants, mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient hearts, correlating with the drug's ability to restore OFF myosin in R502W sarcomeres. In R502W human engineered heart tissues, mavacamten also opposes hypercontractility. Hence, our results indicate that mavacamten is effective in treating hypertrophic cardiomyopathy caused by both truncating and missense MYBPC3 variants regardless of their primary pathomechanisms.

Atherosclerosis is a systemic disease of the arterial tree that often assumes variable forms across vascular territories. As a result, atherosclerotic plaques in different vascular beds differ in frequency, composition, stability and propensity to rupture. Here, we argue that this territorial variability is a manifestation of partially predictable principles. Embryological origin and developmental programming create regionally distinct smooth muscle cell lineages and extracellular matrix architectures, predisposing vascular segments to characteristic modes of injury and repair. Local hemodynamic processes and vessel structures further influence this architecture, leading to distinct atherosclerotic plaque evolution. Microvascular and macrovascular calcification contribute to these processes by amplifying local signals, including inflammation and environmental cues, and by driving the chondrogenic and osteogenic transformation of vascular cells. By synthesizing evidence on divergent atherosclerotic and calcification patterns across vascular beds, the concept of territory-adapted imaging and therapy may improve prevention and risk stratification.

Systemic inflammatory responses shape clinical outcomes in acute cardiovascular disease. Because of their functional plasticity and rapid turnover, neutrophils have emerged as dynamic indicators of inflammatory stress. Here we profile the appearance of distinct neutrophil maturation stages in patients with ST-elevation myocardial infarction, heart failure and stroke. Our data reveal the mobilization of immature neutrophils in all groups; however, patients with ST-elevation myocardial infarction exhibited the most pronounced engagement of this response, including the appearance of CD16[low]CD10[neg] preneutrophils (preNeus), the final mitotic neutrophil progenitor, which was associated with disease outcome. Plasma cytokine profiling identified a coordinated inflammatory signature associated with preNeu mobilization, consistent with emergency granulopoiesis. PreNeus were identifiable as immature granulocytes in routine blood count analysis, where they predicted 30-day mortality better than established biomarkers in two clinical cohorts. Immature granulocytes also remained independently associated with survival in multivariate models incorporating risk factors, enabling the immediate identification of vulnerable patients with ST-elevation myocardial infarction upon hospital admission.