Epidemiology of Cardiogenic Shock Using the Shock Academic Research Consortium (SHARC) Consensus Definitions.

BACKGROUND: The Shock Academic Research Consortium (SHARC) recently proposed pragmatic consensus definitions to standardize classification of cardiogenic shock (CS) in registries and clinical trials. We aimed to describe contemporary CS epidemiology using the SHARC definitions in a cardiac intensive care unit (CICU) population. METHODS: The Critical Care Cardiology Trials Network (CCCTN) is a multinational research network of advanced CICUs coordinated by the TIMI Study Group (Boston, MA). CS was defined as a cardiac disorder resulting in SBP<90mmHg for ≥30 minutes (or the need for vasopressors, inotropes, or mechanical circulatory support [MCS] to maintain SBP ≥90mmHg) with evidence of hypoperfusion. Primary etiologic categories included acute myocardial infarction-related CS (AMI-CS), heart failure-related CS (HF-CS), and non-myocardial (secondary) CS. Post-cardiotomy CS was not included. HF-CS was further subcategorized as de novo vs. acute-on-chronic HF-CS. Patients with both cardiogenic and non-cardiogenic components of shock were classified separately as mixed CS. RESULTS: Of 8,974 patients meeting shock criteria (2017-2023), 65% had isolated CS and 17% had mixed shock. Among patients with CS (n=5,869), 27% had AMI-CS (65% STEMI), 59% HF-CS (72% acute-on-chronic, 28% de novo), and 14% secondary CS. Patients with AMI-CS and de novo HF-CS were most likely to have had concomitant cardiac arrest (p<0.001). Patients with AMI-CS and mixed CS were most likely to present in more severe shock stages (SCAI D or E; p<0.001). Temporary MCS use was highest in AMI-CS (59%). In-hospital mortality was highest in mixed CS (48%), followed by AMI-CS (41%), similar in de novo HF-CS (31%) and secondary CS (31%), and lowest in acute-on-chronic HF-CS (25%; p<0.001). CONCLUSIONS: SHARC consensus definitions for CS classification can be pragmatically applied in contemporary registries and reveal discrete subpopulations of CS with distinct phenotypes and outcomes that may be relevant to clinical practice and future research.

Continuum of Preshock to Classic Cardiogenic Shock in the Critical Care Cardiology Trials Network Registry.

BACKGROUND: The prognostic implications of phenotypes along the preshock to cardiogenic shock (CS) continuum remain uncertain. OBJECTIVES: This study sought to better characterize pre- or early shock and normotensive CS phenotypes and examine outcomes compared to those with conventional CS. METHODS: The CCCTN (Critical Care Cardiology Trials Network) is a registry of contemporary cardiac intensive care units. Consecutive admissions (N = 28,703 across 47 sites) meeting specific criteria based on hemodynamic variables, perfusion parameters, and investigator-reported CS were classified into 1 of 4 groups or none: isolated low cardiac output (CO), heart failure with isolated hypotension, normotensive CS, or SCAI (Society of Cardiovascular Angiography and Intervention) stage C CS. Outcomes of interest were in-hospital mortality and incidence of subsequent hypoperfusion among pre- and early shock states. RESULTS: A total of 2,498 admissions were assigned to the 4 groups with the following distribution: 4.8% isolated low CO, 4.4% isolated hypotension, 12.1% normotensive CS, and 78.7% SCAI stage C CS. Overall in-hospital mortality was 21.3% (95% CI: 19.7%-23.0%), with a gradient across phenotypes (isolated low CO 3.6% [95% CI: 1.0%-9.0%]; isolated hypotension 11.0% [95% CI: 6.9%-16.6%]; normotensive CS 17.0% [95% CI 13.0%-21.8%]; SCAI stage C CS 24.0% [95% CI: 22.1%-26.0%]; global P < 0.001). Among those with an isolated low CO and isolated hypotension on admission, 47 (42.3%) and 56 (30.9%) subsequently developed hypoperfusion. CONCLUSIONS: In a large contemporary registry of cardiac critical illness, there exists a gradient of mortality for phenotypes along the preshock to CS continuum with risk for subsequent worsening of preshock states. These data may inform refinement of CS definitions and severity staging.

Current practices in the management of temporary mechanical circulatory support: A survey of CICU directors in North America.

INTRODUCTION: Despite the growing use of temporary mechanical circulatory support (tMCS), little data exists to inform management and weaning of these devices. METHODS: We performed an online survey among cardiac intensive care unit directors in North America to examine current practices in the management of patients treated with intraaortic balloon pump and Impella. RESULTS: We received responses from 84% of surveyed centers (n=37). Our survey focused on three key aspects of daily management: 1. Hemodynamic monitoring; 2. Hemocompatibility; and 3. Weaning and removal. We found substantial variability surrounding all three areas of care. CONCLUSION: Our findings highlight the need for consensus around practices associated with improved outcomes in patients treated with tMCS.

Post-intensive cardiac care outpatient long-term outreach clinic (PICCOLO clinic): Defining health care needs and outcomes among coronary care unit survivors.

Objective: Patients who survive critical illness endure complex physical and mental health conditions, referred to as post-intensive care syndrome (PICS). The University of Michigan's post-intensive cardiac care outpatient long-term outreach (PICCOLO) clinic is designed for patients recently admitted to the coronary care unit (CCU). The long-term goal of this clinic is to understand post-CCU patients' needs and design targeted interventions to reduce their morbidity and mortality post-discharge. As a first step toward this goal, we aimed to define the post-discharge needs of CCU survivors. Design setting particpants: We retrospectively reviewed case-mix data (including rates of depression, PTSD, disability, and cognitive abnormalities) and health outcomes for patients referred to the PICCOLO clinic from July 1, 2018, through June 30, 2021 at Michigan Medicine. Results: Of the 134 referred patients meeting inclusion criteria, 74 (55 %) patients were seen in the PICCOLO clinic within 30 days of discharge. Patients seen in the clinic frequently screened positive for depression (PHQ-2 score ≥3, 21.4 %) and cognitive impairment (MOCA <26, 38.8 %). Further, patients also reported high rates of physical difficulty (mean WHODAS 2.0 score 28.4 %, consistent with moderate physical difficulty). Consistent with medical intensive care unit (ICU) patients, CCU survivors experience PICS. Conclusion: This work highlights the feasibility of an outpatient care model and the need to leverage information gathered from this care model to develop treatment strategies and pathways to address symptoms of PICS in CCU survivors, including depression, cognitive impairment, and physical disability.

Modes of Death in Patients with Cardiogenic Shock in the Cardiac Intensive Care Unit: A Report from the Critical Care Cardiology Trials Network.

BACKGROUND: There are limited data on how patients with cardiogenic shock (CS) die. METHODS: The Critical Care Cardiology Trials Network is a research network of cardiac intensive care units coordinated by the Thrombolysis In Myocardial Infarction (TIMI) Study Group (Boston, MA). Using standardized definitions, site investigators classified direct modes of in-hospital death for CS admissions (October 2021 to September 2022). Mutually exclusive categories included 4 modes of cardiovascular death and 4 modes of noncardiovascular death. Subgroups defined by CS type, preceding cardiac arrest (CA), use of temporary mechanical circulatory support (tMCS), and transition to comfort measures were evaluated. RESULTS: Among 1068 CS cases, 337 (31.6%) died during the index hospitalization. Overall, the mode of death was cardiovascular in 82.2%. Persistent CS was the dominant specific mode of death (66.5%), followed by arrhythmia (12.8%), anoxic brain injury (6.2%), and respiratory failure (4.5%). Patients with preceding CA were more likely to die from anoxic brain injury (17.1% vs 0.9%; P < .001) or arrhythmia (21.6% vs 8.4%; P < .001). Patients managed with tMCS were more likely to die from persistent shock (P < .01), both cardiogenic (73.5% vs 62.0%) and noncardiogenic (6.1% vs 2.9%). CONCLUSIONS: Most deaths in CS are related to direct cardiovascular causes, particularly persistent CS. However, there is important heterogeneity across subgroups defined by preceding CA and the use of tMCS.

An Unbiased Screen Identified the Hsp70-BAG3 Complex as a Regulator of Myosin-Binding Protein C3.

Variants in the gene myosin-binding protein C3 (MYBPC3) account for approximately 50% of familial hypertrophic cardiomyopathy (HCM), leading to reduced levels of myosin-binding protein C3 (MyBP-C), the protein product made by gene MYBPC3. Elucidation of the pathways that regulate MyBP-C protein homeostasis could uncover new therapeutic strategies. Toward this goal, we screened a library of 2,426 bioactive compounds and identified JG98, an allosteric modulator of heat shock protein 70 that inhibits interaction with Bcl-2-associated athanogene (BAG) domain co-chaperones. JG98 reduces MyBP-C protein levels. Furthermore, genetic reduction of BAG3 phenocopies treatment with JG-98 by reducing MYBP-C protein levels.. Thus, an unbiased compound screen identified the heat shock protein 70-BAG3 complex as a regulator of MyBP-C stability.

Prognostic significance of haemodynamic parameters in patients with cardiogenic shock.

AIMS: Invasive haemodynamic assessment with a pulmonary artery catheter is often used to guide the management of patients with cardiogenic shock (CS) and may provide important prognostic information. We aimed to assess prognostic associations and relationships to end-organ dysfunction of presenting haemodynamic parameters in CS. METHODS AND RESULTS: The Critical Care Cardiology Trials Network is an investigator-initiated multicenter registry of cardiac intensive care units (CICUs) in North America coordinated by the TIMI Study Group. Patients with CS (2018-2022) who underwent invasive haemodynamic assessment within 24 h of CICU admission were included. Associations of haemodynamic parameters with in-hospital mortality were assessed using logistic regression, and associations with presenting serum lactate were assessed using least squares means regression. Sensitivity analyses were performed excluding patients on temporary mechanical circulatory support and adjusted for vasoactive-inotropic score. Among the 3603 admissions with CS, 1473 had haemodynamic data collected within 24 h of CICU admission. The median cardiac index was 1.9 (25th-75th percentile, 1.6-2.4) L/min/m2 and mean arterial pressure (MAP) was 74 (66-86) mmHg. Parameters associated with mortality included low MAP, low systolic blood pressure, low systemic vascular resistance, elevated right atrial pressure (RAP), elevated RAP/pulmonary capillary wedge pressure ratio, and low pulmonary artery pulsatility index. These associations were generally consistent when controlling for the intensity of background pharmacologic and mechanical haemodynamic support. These parameters were also associated with higher presenting serum lactate. CONCLUSION: In a contemporary CS population, presenting haemodynamic parameters reflecting decreased systemic arterial tone and right ventricular dysfunction are associated with adverse outcomes and systemic hypoperfusion.

Translation of New and Emerging Therapies for Genetic Cardiomyopathies.

The primary etiology of a diverse range of cardiomyopathies is now understood to be genetic, creating a new paradigm for targeting treatments on the basis of the underlying molecular cause. This review provides a genetic and etiologic context for the traditional clinical classifications of cardiomyopathy, including molecular subtypes that may exhibit differential responses to existing or emerging treatments. The authors describe several emerging cardiomyopathy treatments, including gene therapy, direct targeting of myofilament function, protein quality control, metabolism, and others. The authors discuss advantages and disadvantages of these approaches and indicate areas of high potential for short- and longer term efficacy.

Impact of a pharmacist in an interdisciplinary post-cardiac intensive care unit clinic.

BACKGROUND: The complex needs of cardiac patients shortly after discharge from a cardiac intensive care unit (CICU) provides a unique opportunity for a pharmacist to help optimize medication management and guideline-directed medical therapy (GDMT). OBJECTIVE: This study describes the impact of a pharmacist in a multidisciplinary post-CICU clinic. METHODS: We performed a retrospective cohort study of patients ≥18 years of age who completed a visit in the University of Michigan Post Intensive Cardiac Care Outpatient Long-Term Outreach (PICCOLO) Clinic from July 2018 to May 2020. RESULTS: One hundred and six CICU survivors were referred. Of these 12 chose to follow-up with long term care providers. A total of 70 of the remaining 94 (74%) completed a visit. The median age was 65 (54-72) years, 71.4% were male, and 85.7% were Caucasian. The median number of pharmacist interventions at each visit was 4 (3-5), all patients had at least 1 intervention. Interventions included medication dose adjustment (n = 46); GDMT optimization (n = 42); medication change (n = 18); medication addition (n = 23) and cessation (n = 21); lab monitoring (n = 97); refill assistance (n = 16); pillbox provision (n = 8); and medication cost assistance (n = 8). CONCLUSIONS: Pharmacist led interventions in a post CICU clinic resulted in medication changes to optimize therapy, increased laboratory monitoring, medication cost savings for patients, and interventions to facilitate GDMT adherence.

Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.

PURPOSE: Variants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk. METHODS: Among 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS. RESULTS: We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ -1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding. CONCLUSION: STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.

Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations. METHODS: Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro. RESULTS: Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5'-3' quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, P<0.001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type. CONCLUSIONS: Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.

Utilization of Cardiac Rehabilitation Among Cardiac Intensive Care Unit Survivors.

Cardiac rehabilitation (CR) is associated with decreased mortality and rehospitalization rates for patients with a variety of cardiac conditions. Although CR referral rates for STEMI patients have improved, rates for heart failure have remained low. Many of these patients are admitted to the cardiac intensive care unit (CICU). However, it is unknown how often CICU survivors qualify for cardiac rehabilitation, how often they are referred, and why eligible patients are not referred. This is a retrospective single-center study of 417 consecutive patients admitted to CICU for >48 hours from March 30, 2016 to March 30, 2017. We excluded patients with in-hospital mortality or those discharged AMA, to hospice or transferred. Chart abstraction was used to determine CR indications based on known American College of Cardiology/American Heart Association guidelines. If CR was indicated, medical records through September 2017 were reviewed to determine both referral and participation rates. In the absence of a referral, medical records were reviewed for potential barriers. A total of 296 CICU survivors were identified upon discharge with 185 (63%) having guideline-directed indications for CR referral. The most common indications were heart failure with reduced ejection fraction (HFrEF, 38%), cardiothoracic surgery (26%), and STEMI (23%). Upon discharge, only 30% of patients were referred to CR. The referral rate increased by 33% to 63% by 18 months postdischarge. CR referrals were most frequently placed following STEMI (91%), NSTEMI (80%), and postpercutaneous coronary intervention (80%). Only 35% of HFrEF discharges were referred to CR. Of patients not referred to CR, no explanation for a lack of referral was documented 87% of the time. In conclusion, nearly 2 of 3 patients discharged from the CICU had CR indications, most commonly HFrEF. CR referrals are frequently not placed and reason for nonreferral is rarely documented. CICU admission may provide a defined event to prompt referral.

Pharmacological chaperone for α-crystallin partially restores transparency in cataract models.

Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.

Identification of key hinge residues important for nucleotide-dependent allostery in E. coli Hsp70/DnaK.

DnaK is a molecular chaperone that has important roles in protein folding. The hydrolysis of ATP is essential to this activity, and the effects of nucleotides on the structure and function of DnaK have been extensively studied. However, the key residues that govern the conformational motions that define the apo, ATP-bound, and ADP-bound states are not entirely clear. Here, we used molecular dynamics simulations, mutagenesis, and enzymatic assays to explore the molecular basis of this process. Simulations of DnaK's nucleotide-binding domain (NBD) in the apo, ATP-bound, and ADP/Pi-bound states suggested that each state has a distinct conformation, consistent with available biochemical and structural information. The simulations further suggested that large shearing motions between subdomains I-A and II-A dominated the conversion between these conformations. We found that several evolutionally conserved residues, especially G228 and G229, appeared to function as a hinge for these motions, because they predominantly populated two distinct states depending on whether ATP or ADP/Pi was bound. Consistent with the importance of these "hinge" residues, alanine point mutations caused DnaK to have reduced chaperone activities in vitro and in vivo. Together, these results clarify how sub-domain motions communicate allostery in DnaK.