Christos P. Kyriakopoulos

Cardiogenic shock describes a syndrome of systemic hypoperfusion due to insufficient cardiac output. Therapeutic interventions aim to restore systemic perfusion and oxygen delivery, relieve congestion, and reverse the primary culprit pathologies that precipitate shock. Cardiogenic shock care often emphasizes acute rescue and survival; however, survival does not always equal meaningful recovery. In this review, we propose a recovery-focused framework in which myocardial and end-organ recovery are treated as explicit, measurable targets. Building upon prior frameworks proposed for the management of shock, we organize cardiogenic shock management into four overlapping phases: salvage, optimization, stabilization, and de-escalation. Each phase addresses a distinct clinical question: can the patient be rescued, is perfusion and unloading sufficient to prevent further injury, is meaningful myocardial and end-organ recovery occurring, and is recovery durable enough to withdraw support? We synthesize current strategies and highlight emerging targets and research priorities spanning early identification and triage, integrated macro- and microcirculatory monitoring, phenotype-guided management, targeted metabolic and immunologic therapies, use of mechanical circulatory support as a recovery platform, and structured de-escalation of care.

Persistent activation of cardiac fibroblasts into myofibroblasts drives excessive extracellular matrix deposition, leading to maladaptive myocardial fibrosis, adverse remodeling and heart failure (HF) progression. Adipocyte enhancer binding protein 1 (AEBP1) and Aortic carboxypeptidase-like protein (ACLP, full-length AEBP1 protein coded by AEBP1 ) has been implicated in pathological fibrosis across multiple organs, with tissue-specific knockdown attenuating fibrosis in preclinical models. Although elevated AEBP1 expression has been associated with human HF, its role in myocardial fibrosis progression in vivo remains undefined. Here, we demonstrated that AEBP1 is a critical mediator of myocardial fibrosis and adverse cardiac remodeling. Fibroblast-specific knockout and cardiac-specific knockdown of Aebp1 si gnificantly improved cardiac function and prevented pathological remodeling in murine models of myocardial ischemia and pressure-overload induced injury. In ex vivo human myocardial tissue culture studies, ACLP overexpression in non-failing hearts induced pathological remodeling, whereas AEBP1 knockdown in failing human hearts induced structural reverse remodeling. Mechanistically, we also showed that ACLP regulates key pro-fibrotic transcription factors and genes, including MRTFB, RUNX2, SM22 and COL1A1, thereby orchestrating fibroblast activation. Collectively, these findings establish AEBP1 as a central driver of myocardial fi brosis and highlights its inhibition as a promising therapeutic strategy to mitigate both acute and chronic HF.

BACKGROUND: CPT1 (carnitine palmitoyltransferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown. METHODS: CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9 (AAV9)–mediated CPT1a overexpression (AAV9.cTnT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression. RESULTS: CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. AAV9–mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts ( P <0.05). Delivery of AAV9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation. CONCLUSIONS: The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.

Aims: Cardiogenic shock (CS) is the leading cause of in-hospital mortality in patients suffering acute myocardial infarction (AMI). Despite advances in their management, short- and long-term mortality remain unacceptably high. We assessed short and intermediate-term outcomes for a contemporary cohort of patients with AMI-CS managed at a referral centre with a large catchment area, and sought to identify clinical factors portending a favourable prognosis. Methods and results: Of 1162 consecutive, unselected patients with CS we studied 316 with AMI-CS. Our primary endpoint was native heart survival (NHS) defined as survival to discharge without advanced heart failure (HF) therapies. Our secondary endpoints were adverse events, overall survival, and readmissions up to 1 year following discharge. Association of clinical data with NHS was analysed using logistic regression. Of 316 patients, 168 (53.2%) achieved NHS, 140 (44.3%) died, and 8 (2.5%) were discharged after receiving advanced HF therapies. Overall, 181 patients (57.3%) received temporary mechanical circulatory support (MCS), with 78 (24.7%) receiving intra-aortic balloon pump, 107 (33.9%) percutaneous ventricular assist device, and 62 (19.6%) veno-arterial extracorporeal membrane oxygenation. Of 176 discharged patients (55.7%), 170 (53.8%) were alive at 30 days, and 156 (49.4%) at 1-year post-discharge, while 56 (31.8%) had at least one readmission and 30 (17.0%) one HF-related readmission, by 1-year post-discharge. Patients with NHS were younger, had lower CS severity by SCAI stage, less commonly underwent intubation, or received temporary MCS, had a shorter time from CS onset to MCS deployment, and more commonly underwent coronary intervention with fewer stents deployed, compared to patients who died or underwent advanced HF therapies. Bleeding and vascular complications were less common in patients achieving NHS compared to patients who died or received advanced HF therapies. After multivariable adjustments, clinical variables associated with NHS included: younger age, lower vasoactive-inotropic score, lower serum creatinine, and lactate at shock onset, successful coronary intervention with fewer stents deployed, and absence of intubation, or use of veno-arterial extracorporeal membrane oxygenation (all P ≤ 0.05). Conclusion: We studied a contemporary cohort of patients with AMI-CS and high rates of temporary MCS use, and identified clinical factors associated with a higher likelihood for successful outcomes. The need for transfer to an advanced CS centre, the impact and management of adverse events, and the type and timing of temporary MCS as opposed to intensification of pharmacologic therapy, should be studied as clinical practice targets for improving patient outcomes.