Rana Hamouche

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.

Background: Mechanical ventricular unloading and systemic circulatory support with left ventricular assist devices (LVADs) enable myocardial recovery in a subset of advanced heart failure (HF) patients, but predictors and mechanisms of recovery are not well understood. Integrating clinical and molecular data may improve identification of patients most likely to recover and uncover biologically relevant targets in HF. Methods: We collected and analyzed left ventricular apical myocardial tissue and clinical data from 208 patients undergoing LVAD implantation across five centers. Pre-implant transcriptomic profiles (22,373 mRNA transcripts) were integrated with 59 clinical variables using supervised machine learning with repeated cross-validation to identify and prioritize features associated with myocardial recovery, defined as a binary outcome based on improvement in left ventricular ejection fraction (LVEF ≥40%) and left ventricular end-diastolic diameter (LVEDD ≤5.9 cm). We also modeled functional (LVEF) and structural (LVEDD) improvement as a continuous outcome without any predefined LVEF and LVEDD pathological thresholds. Feature prioritization was followed by validation in human myocardial tissue and mechanistic interrogation in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Results: Integrative models achieved modest discrimination for myocardial recovery as a binary categorical outcome (maximum mean cross-validated area under the curve 0.73±0.15), identifying clinical features such as HF duration, LVEDD, HF pharmacologic therapy, and device configuration. Leucine-rich repeat neuronal 4C-like (LRRN4CL), measured in human myocardium, consistently emerged as a top transcriptomic predictor across both binary and continuous metric models (functional and structural). Higher pre-LVAD LRRN4CL expression was associated with reduced likelihood of myocardial recovery and localized primarily to cardiomyocytes. In iPSC-CMs, LRRN4CL overexpression localized to the sarcoplasmic reticulum, induced transcriptional remodeling characterized by suppression of contractile pathways and activation of stress programs, impaired calcium handling, impaired contraction?relaxation kinetics, and diminished mitochondrial respiratory reserve capacity. Conclusions: Integration of clinical and myocardial transcriptomic data identifies LRRN4CL as a novel marker associated with impaired myocardial recovery following LVAD-mediated ventricular unloading and systemic circulatory support. These findings move beyond predictive modeling, linking integrative computational discovery to cardiomyocyte dysfunction and providing a translational framework for biologically informed risk stratification and therapeutic targeting for myocardial recovery.

Transcriptomic changes in heart failure (HF) patients prior to and following left ventricular assist device (LVAD) support have been extensively studied. Recent studies focused on understanding DNA methylation changes in patients with cardiovascular diseases (CVD) and the role of circulating markers of DNA methylation as clinical predictors of the risk of CVD related morbidity and mortality. In this study, we used paired (pre- and post-LVAD) myocardial samples to examine changes in DNA methylation alongside RNA and protein expression. Our data suggests that patients with no improvement in cardiac function after LVAD therapy, despite showing an improvement in energy production (increased β-oxidation of fatty acid) exhibited persistent activation of profibrotic signaling, increased collagen deposition and cytoskeletal disarray evident from abnormal increase in sarcomeric distance following LVAD support. Contrarily, patients with improvement in cardiac function after LVAD therapy showed activation of pro-inflammatory signaling, collagen degradation and myogenesis. Both RNA sequencing and western blot data showed increased COL1A1 and decreased TPPP3 in post-NR thereby suggesting increased fibrosis and disrupted cytoskeletal signaling as potential barriers to myocardial recovery. Additionally, responders to LVAD therapy showed a significant reversal in myocardial interstitial fibrosis with a preserved sarcomeric architecture. Mice model of HF and recovery also confirmed our human findings, with reduced fibrotic signaling and improved cytoskeletal remodeling signaling observed in mice that showed improvement in cardiac function compared to mice with HF. Overall, our data suggests that altering extracellular matrix regulation and cytoskeletal signaling pathways may contribute to myocardial recovery. Further studies targeting these pathways are required to identify new HF therapeutic targets.

Background: Multidisciplinary teams and regionalized care systems have been suggested to improve cardiogenic shock (CS) outcomes. We sought to identify clinical factors associated with successful outcomes for patients developing CS at an outside healthcare facility (spoke) and being transferred to a quaternary medical center (hub). Methods and Results: Consecutive patients with CS were evaluated (N=1162). Our study cohort comprised 412 patients developing CS at a spoke. Our primary end point was native heart survival (NHS) defined as survival to discharge without receiving advanced heart failure therapies. Secondary end points were survival to discharge, 30‐day and 1‐year survival after discharge, and adverse events. Association of clinical data with NHS was analyzed using logistic regression. Overall, 246 (59.7%) patients achieved NHS, 125 (30.3%) died, and 41 (10.0%) were discharged after advanced heart failure therapies. Of the 287 patients who were discharged (69.7%), 276 (67.0%) were alive at 30 days, and 250 (60.7%) at 1 year. Patients with NHS less commonly had bleeding or vascular complications or acute kidney injury requiring renal replacement therapy compared with patients who died or received advanced heart failure therapies. Significant multivariable factors associated with NHS likelihood included younger age; shorter length of stay and transfer from a secondary compared with a tertiary/quaternary level of care spoke; absence of cardiac arrest, intubation, or type 3 bleeding; lower vasoactive–inotropic score; higher left ventricular ejection fraction at admission to the hub; and shorter CS onset‐to‐temporary mechanical circulatory support deployment time. Conclusions: We identified clinical factors reflecting disease severity and management practices including length of stay and spoke level of care, inotrope/vasopressor utilization, and CS onset‐to‐temporary mechanical circulatory support deployment time, that might inform the management of patients developing CS at a spoke.

Ischemic heart disease and acute myocardial infarction (AMI) is a leading cause of morbidity and mortality. Improvements have been made in coronary interventions to restore blood flow, but ischemia/reperfusion (I/R) injury significantly impacts clinical outcomes. We previously reported that activation of percutaneous mechanical unloading of the left ventricle (LV) with a transvalvular axial-flow device simultaneously with reperfusion improves myocardial salvage. However, the underlying mechanisms, potential adjuvant pharmacological interventions and the timing of the use of LV unloading as a cardioprotective approach in AMI are not well understood. This study investigated a) the mechanisms associated with improved myocardial salvage, b) a pharmacological intervention, and c) the timing of LV unloading. Following 90 minutes of ischemia, adult swine were subjected to reperfusion alone, simultaneous unloading with reperfusion, upfront unloading with delayed reperfusion, upfront reperfusion with delayed unloading, or reperfusion with concurrent use of esmolol and milrinone. Compared to controls, the simultaneous group had a 47% increase in myocardial salvage following AMI. This was associated with increased expression of neutrophil degranulation, macrophage activation, iNOS signaling, wound healing, and PPAR signaling. From these pathways, PPARG (peroxisome proliferator-activated receptor gamma) emerged as a potential cardioprotective gene that was uniquely overexpressed in the simultaneously unloaded and reperfused myocardium. Next, we showed PPARG agonism with rosiglitazone reduces mitochondrial oxygen demand in cardiomyocytes and in vivo, improves myocardial salvage following I/R injury in C57BL6/J mice. Thiazolidinediones (TZDs), such as rosiglitazone could be investigated as therapies combined with simultaneous LV unloading and coronary interventions to mitigate reperfusion injury. GRAPHICAL

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using ¹³ C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart; however, the rapid reintroduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the total myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and redirecting pyruvate toward oxidation can blunt hypertrophy. We hypothesized that this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. After I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ), and Ca ²⁺ , increased pyruvate entry to the TCA cycle, increased oxygen consumption, and improved myocardial salvage and functional outcomes following I/R. Our data suggest normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.

BACKGROUND: Cardiogenic shock (CS) can stem from multiple causes and portends poor prognosis. Prior studies have focused on acute myocardial infarction-CS; however, acute decompensated heart failure (ADHF)-CS accounts for most cases. We studied patients suffering ADHF-CS to identify clinical factors, early in their trajectory, associated with a higher probability of successful outcomes. METHODS: Consecutive patients with CS were evaluated (N=1162). We studied patients who developed ADHF-CS at our hospital (N=562). Primary end point was native heart survival (NHS), defined as survival to discharge without receiving advanced HF therapies. Secondary end points were adverse events, survival, major cardiac interventions, and hospital readmissions within 1 year following index hospitalization discharge. Association of clinical data with NHS was analyzed using logistic regression. RESULTS: Overall, 357 (63.5%) patients achieved NHS, 165 (29.2%) died, and 41 (7.3%) were discharged post advanced HF therapies. Of 398 discharged patients (70.8%), 303 (53.9%) were alive at 1 year. Patients with NHS less commonly suffered cardiac arrest, underwent intubation or pulmonary artery catheter placement, or received temporary mechanical circulatory support, had better hemodynamic and echocardiographic profiles, and had a lower vasoactive-inotropic score at shock onset. Bleeding, hemorrhagic stroke, hemolysis in patients with mechanical circulatory support, and acute kidney injury requiring renal replacement therapy were less common compared with patients who died or received advanced HF therapies. After multivariable adjustments, clinical variables associated with NHS likelihood included younger age, history of systemic hypertension, absence of cardiac arrest or acute kidney injury requiring renal replacement therapy, lower pulmonary capillary wedge pressure and vasoactive-inotropic score, and higher tricuspid annular plane systolic excursion at shock onset (all P <0.05). CONCLUSIONS: By studying contemporary patients with ADHF-CS, we identified clinical factors that can inform clinical management and provide future research targets. Right ventricular function, renal function, pulmonary artery catheter placement, and type and timing of temporary mechanical circulatory support warrant further investigation to improve outcomes of this devastating condition.

BACKGROUND: Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS. METHODS: We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models. RESULTS: This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm ⁻⁵ (interquartile range, 870–1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0–0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm ⁻⁵ decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P =0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P P =0.003). CONCLUSIONS: Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR −5 , high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed.