Crespo‐Diaz, Ruben

Left ventricular recovery (LV) in patients with advanced heart failure (HF) supported by a durable left ventricular assist device (LVAD) is uncommon but clinically significant. There is limited understanding on the timing of LV recovery in relation to LVAD implantation. A total of 383 HF patients who underwent LVAD implantation were evaluated for LV functional improvement defined as an absolute increase in left ventricular ejection fraction (LVEF) of greater than or equal to 20% post-LVAD placement. Out of 383 LVAD patients, 39 (10.1%) demonstrated significant LV improvement. Among these, 25 (64%) patients had received LVAD less than or equal to 1 year of HF diagnosis, whereas 14 (36%) patients were implanted greater than 1 year from HF diagnosis. No significant differences in baseline imaging or hemodynamics were found between these two groups. The timing of LVAD implantation and time from LVAD to LVEF improvement was not associated with 5 year outcomes. Survival, free from HF relapse or transplant was 59% in the less than or equal to 1 year and 46% in greater than 1 year HF duration groups ( p = 0.83). Thus, LV functional improvement can occur across a broad spectrum of HF duration, suggesting that the potential for recovery is not limited to those with newly diagnosed disease.

Abstract Introduction Non-cardiovascular end-organ dysfunction is an important determinant of outcomes in cardiac intensive care unit (CICU) patients. We examined the association between in-hospital mortality with the severity and extent of admission liver function test (LFT) abnormalities in a heterogeneous CICU population. Purpose We hypothesized that a greater severity or extent of LFT abnormalities would be associated with higher in-hospital mortality. Methods We included consecutive unique adult CICU patients with available data for one or more of the admission LFT values of interest. Admission laboratory values were defined as those closest to CICU admission. We used the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to categorize the severity of each LFT abnormality from Grade 0 (normal) to Grade 4 (life-threatening). We defined the extent of LFT abnormality as the number of individual LFTs meeting criteria for CTCAE Grade 1 or greater. The primary outcome of interest was all-cause in-hospital mortality. Odds ratio (OR) and 95% confidence interval (CI) values for in-hospital mortality were estimated using logistic regression, before and after multivariable adjustment. Results Of 12,428 unique CICU patients, 5,144 were excluded due to a lack of available data for any admission LFT values. The remaining 7,284 patients comprised the final study population. Among patients with available data for each individual LFT, abnormal values were present in: AST, 2,743/5,733 (47.8%); ALT 1,576/5,512 (28.6%); ALK 611/3,684 (16.6%); and TB 898/5,155 (17.4%). A total of 864 (11.9%) patients died during hospitalization. In-hospital mortality was higher for patients with one or more LFTs meeting criteria for CTCAE Grade 1 or greater (17.9% vs. 6.4%, adjusted OR 1.54 [1.27-1.86], p <0.001). A stepwise increase in in-hospital mortality was observed with increasing CTCAE grade, both overall (adjusted OR 1.25 per each higher CTCAE grade [1.16-1.34], p <0.001); (Figure 1A), and for each individual LFT (Figure 1B). Conclusion Cardiohepatic syndrome is an important predictor of prognosis in CICU patients, as the extent and severity of LFT abnormalities are strongly associated with in-hospital mortality. This is the first large-scale study to examine the association between the magnitude of hepatic biomarker derangement with in-hospital mortality in unselected CICU patients. Patients with markedly elevated LFT values exhibited the highest risk of in-hospital mortality. This analysis advocates for the inclusion of commonly obtained LFTs in future risk-prediction tools for enhanced prognostication.

Abstract Aims Hospitalized patients with heart failure (HF) are a heterogeneous population, with multiple phenotypes proposed. Prior studies have not examined the biological phenotypes of critically ill patients with HF admitted to the contemporary cardiac intensive care unit (CICU). We aimed to leverage unsupervised machine learning to identify previously unknown HF phenotypes in a large and diverse cohort of patients with HF admitted to the CICU. Methods We screened 6008 Mayo Clinic CICU patients with an admission diagnosis of HF from 2007 to 2018 and included those without missing values for common laboratory tests. Consensus k-means clustering was performed based on 10 common admission laboratory values (potassium, chloride, anion gap, blood urea nitrogen, haemoglobin, red blood cell distribution width, mean corpuscular volume, platelet count, white blood cell count and neutrophil-to-lymphocyte ratio). In-hospital mortality was evaluated using logistic regression, and 1 year mortality was evaluated using Cox proportional hazard models after multivariable adjustment. Results Among 4877 CICU patients with HF who had complete admission laboratory data (mean age 69.4 years, 38.4% females), we identified five clusters with divergent demographics, comorbidities, laboratory values, admission diagnoses and use of critical care therapies. We labelled these clusters based on the characteristic laboratory profile of each group: uncomplicated (25.7%), iron-deficient (14.5%), cardiorenal (18.4%), inflamed (22.3%) and hypoperfused (19.2%). In-hospital mortality occurred in 10.7% and differed between the phenotypes: uncomplicated, 2.7% (reference); iron-deficient, 8.1% [adjusted odds ratio (OR) 2.18 (1.38–3.48), P < 0.001]; cardiorenal, 10.3% [adjusted OR 2.11 (1.37–3.32), P < 0.001]; inflamed, 12.5% [adjusted OR 1.79 (1.18–2.76), P = 0.007]; and hypoperfused, 21.9% [adjusted OR 4.32 (2.89–6.62), P < 0.001]. These differences in mortality between phenotypes were consistent when patients were stratified based on demographics, aetiology, admission diagnoses, mortality risk scores, shock severity and systolic function. One-year mortality occurred in 31.5% and differed between the phenotypes: uncomplicated, 11.9% (reference); inflamed, 26.8% [adjusted hazard ratio (HR) 1.56 (1.27–1.92), P < 0.001]; iron-deficient, 33.8% [adjusted HR 2.47 (2.00–3.04), P < 0.001]; cardiorenal, 41.2% [adjusted HR 2.41 (1.97–2.95), P < 0.001]; and hypoperfused, 52.3% [adjusted HR 3.43 (2.82–4.18), P < 0.001]. Similar findings were observed for post-discharge 1 year mortality. Conclusions Unsupervised machine learning clustering can identify multiple distinct clinical HF phenotypes within the CICU population that display differing mortality profiles both in-hospital and at 1 year. Mortality was lowest for the uncomplicated HF phenotype and highest for the hypoperfused phenotype. The inflamed phenotype had comparatively higher in-hospital mortality yet lower post-discharge mortality, suggesting divergent short-term and long-term prognosis.

Background The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. Methods and Results Coronary thrombus aspirates were collected from patients at the time of ST‐segment–elevation myocardial infarction and subjected to array‐based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1‐year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor‐α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor‐α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab‐mediated immune modulation impacts post‐MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P <0.01). Concomitantly, immunoassays of coronary sinus samples quantified lower troponin I levels (41.72±7.34 pg/mL versus 58.11±10.75 pg/mL; P <0.05) and secreted protein analysis revealed upregulation of injury‐modifying interleukin‐2, ‐4, ‐10, ‐12, and ‐18 cytokines in the infliximab‐treated cohort. At 4 weeks (n=12), infliximab treatment resulted in significant protective influence, improving left ventricular ejection fraction (53.9%±5.4% versus 36.2%±5.3%; P <0.001) and reducing scar size (8.31%±10.9% versus 17.41%±12.5%; P <0.05). Conclusions Profiling of coronary thrombus aspirates in patients with ST‐segment–elevation MI revealed highest association for tumor necrosis factor‐α in injury risk. Infliximab‐mediated immune modulation offers an actionable pathway to alter MI‐induced inflammatory response, preserving contractility and limiting adverse structural remodeling.

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation (ECPR) has been shown to improve neurologically favorable survival in patients with refractory out-of-hospital cardiac arrest (OHCA) caused by shockable rhythms. Further refinement of patient selection is needed to focus this resource-intensive therapy on those patients likely to benefit. This study sought to create a selection model using machine learning (ML) tools for refractory cardiac arrest patients undergoing ECPR. DESIGN: Retrospective cohort study. SETTING: Cardiac ICU in a Quaternary Care Center. PATIENTS: Adults 18–75 years old with refractory OHCA caused by a shockable rhythm. METHODS: Three hundred seventy-six consecutive patients with refractory OHCA and a shockable presenting rhythm were analyzed, of which 301 underwent ECPR and cannulation for venoarterial extracorporeal membrane oxygenation. Clinical variables that were widely available at the time of cannulation were analyzed and ranked on their ability to predict neurologically favorable survival. INTERVENTIONS: ML was used to train supervised models and predict favorable neurologic outcomes of ECPR. The best-performing models were internally validated using a holdout test set. MEASUREMENTS AND MAIN RESULTS: Neurologically favorable survival occurred in 119 of 301 patients (40%) receiving ECPR. Rhythm at the time of cannulation, intermittent or sustained return of spontaneous circulation, arrest to extracorporeal membrane oxygenation perfusion time, and lactic acid levels were the most predictive of the 11 variables analyzed. All variables were integrated into a training model that yielded an in-sample area under the receiver-operating characteristic curve (AUC) of 0.89 and a misclassification rate of 0.19. Out-of-sample validation of the model yielded an AUC of 0.80 and a misclassification rate of 0.23, demonstrating acceptable prediction ability. CONCLUSIONS: ML can develop a tiered risk model to guide ECPR patient selection with tailored arrest profiles.

Right ventricular failure (RVF) is a significant cause of mortality in patients undergoing left ventricular assist device (LVAD) implantation. Although right ventricular assist devices (RVADs) can treat RVF in the perioperative LVAD period, liberal employment before RVF is not well established. We therefore compared the survival outcomes between proactive RVAD placement at the time of LVAD implantation with a bailout strategy in patients with RVF. Retrospectively, 75 adult patients who underwent durable LVAD implantation at our institution and had an RVAD placed proactively before LVAD implantation or as a bailout strategy postoperatively due to hemodynamically unstable RVF were evaluated. Patients treated with a proactive RVAD strategy had lower Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) and a higher proportion of these required temporary mechanical circulatory support (MCS) preoperatively. Preoperative hemodynamic profiling showed a low pulmonary artery pulsatility index (PAPi) score of 1.8 ± 1.4 and 1.6 ± 0.94 (p = 0.42) in the bailout RVAD and proactive RVAD groups, respectively. Survival at 3, 6, and 12 months post-LVAD implantation was statistically significantly higher in patients who received a proactive RVAD. Thus, proactive RVAD implantation is associated with short- and medium-term survival benefits compared to a bailout strategy in RVF patients undergoing LVAD placement.

Abstract Stem cell paracrine activity is implicated in cardiac repair. Linkage between secretome functionality and therapeutic outcome was here interrogated by systems analytics of biobanked human cardiopoietic cells, a regenerative biologic in advanced clinical trials. Protein chip array identified 155 proteins differentially secreted by cardiopoietic cells with clinical benefit, expanded into a 520 node network, collectively revealing inherent vasculogenic properties along with cardiac and smooth muscle differentiation and development. Next generation RNA sequencing, refined by pathway analysis, pinpointed miR-146 dependent regulation upstream of the decoded secretome. Intracellular and extracellular integration unmasked commonality across cardio-vasculogenic processes. Mirroring the secretome pattern, infarcted hearts benefiting from cardiopoietic cell therapy restored the disease proteome engaging cardiovascular system functions. The cardiopoietic cell secretome thus confers a therapeutic molecular imprint on recipient hearts, with response informed by predictive systems profiling.