Defining mechanisms of cardiomyocyte proliferation should guide the understanding of endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In the neonatal heart, energy metabolic reprogramming (phenotypic alteration of glucose, fatty acid, and amino acid metabolism) parallels cell cycle arrest of cardiomyocytes. The metabolic reprogramming occurring shortly after birth is associated with alterations in blood oxygen levels, metabolic substrate availability, hemodynamic stress, and hormone release. In the adult heart, myocardial infarction causes metabolic reprogramming but these changes cannot stimulate sufficient cardiomyocyte proliferation to replace those lost by the ischemic injury. Some putative pro-proliferative interventions can induce the metabolic reprogramming. Recent data show that altering the metabolic enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 [pyruvate dehydrogenase kinase 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] is sufficient to partially reverse metabolic reprogramming and promotes adult cardiomyocyte proliferation. How metabolic reprogramming regulates cardiomyocyte proliferation is not clearly defined. The possible mechanisms involve biosynthetic pathways from the glycolysis shunts and the epigenetic regulation induced by metabolic intermediates. Metabolic manipulation could represent a new approach to stimulate cardiac regeneration; however, the efficacy of these manipulations requires optimization, and novel molecular targets need to be defined. In this review, we summarize the features, triggers, and molecular regulatory networks responsible for metabolic reprogramming and discuss the current understanding of metabolic reprogramming as a critical determinant of cardiomyocyte proliferation.

Background: GRACE risk score models are capable of predicting all-cause mortality of non-ST elevation myocardial infarction (NSTEMI) patients. However, its utility for evaluating major adverse cardiovascular events (MACE) in NSTEMI patients with multivessel disease (MVD) remains unclear. Methods and results: This study was designed as a retrospective cohort study that recruited patients with NSTEMI and multivessel disease between September 2013 and December 2018 in Daping Hospital, Chongqing, China. The primary outcome was a composite outcome that included all-cause mortality, recurrent angina, non-fatal myocardial infarction, coronary re-vascularization, and non-fatal strokes. Of the 827 patients with NSTEMI, 32 did not complete follow-up and 430 were excluded because of single-vessel disease. The remaining 365 NSTEMI patients with MVD had a median follow-up of 3.0 (IQR 2.6–3.3) years, 78 patients experienced outcomes. The GRACE risk score predicted the MACE (hazard ratio 1.014, 95% CI 1.006–1.021, P < 0.001). The GRACE risk score performed well in predicting all-cause mortality (c-statistic 0.72, 95% CI 0.59–0.85, P = 0.001) in MVD but was less powerful in predicting MACE (c-statistic 0.69, 95% CI 0.62–0.75, P < 0.001). When combining the GRACE risk score with the SYNTAX score, and blood urea nitrogen for predicting all-cause mortality and MACE events, the c-statistic value increased to 0.82 and 0.81 (P < 0.001). Conclusion: In NSTEMI patients with MVD, the GRACE score showed an acceptable predictive value for all-cause mortality, but it was less powerful in predicting MACE. Blood urea nitrogen may be valuable in assessing long-term cardiovascular events in patients with MVD.

Rationale: Anti-phospholipase A2 receptor (PLA2R) antibody is a highly specific serological marker for primary membranous nephropathy, with a detection rate of <2% in minimal change disease (MCD). This case represents the first report of PLA2R-positive adult MCD complicated by active pulmonary tuberculosis (TB) and systemic osteoarthropathy, highlighting the potential for chronic infection to induce PLA2R antibodies through inflammatory activation or molecular mimicry. Patient concerns: A 73-year-old male with 7-year steroid-dependent nephrotic syndrome developed pulmonary TB and systemic osteoarthropathy during immunosuppressive therapy. Diagnoses: Serial renal biopsies confirmed MCD/focal segmental glomerulosclerosis (FSGS) without membranous nephropathy features. PLA2R antibody was transiently positive (16.6 RU/mL) during active TB but turned negative after anti-TB treatment. TB was confirmed by next-generation sequencing. Interventions: A multidisciplinary strategy was implemented: rifapentine replaced rifampicin to maintain tacrolimus levels; rituximab was administered for refractory proteinuria; and TB was treated with a 9-month regimen. Osteoarthropathy was managed with Tripterygium glycosides and joint injections. Outcomes: Following rituximab administration, 24-hour urinary protein decreased from 6.32 g to 1.5 g. TB was controlled with sputum conversion within 2 months. PLA2R antibody became negative post anti-TB therapy, supporting the hypothesis of infection-induced seropositivity. No renal function decline or TB dissemination occurred. Lessons: This case suggests that chronic infections like TB may transiently induce PLA2R antibodies via inflammatory activation, highlighting the need for dynamic serologic and histopathologic correlation to avoid misdiagnosis in PLA2R-positive non-MN patients. Multidisciplinary management is critical to balance immunosuppression and infection control.