Pulmonary Artery Catheter Use and Risk of In-hospital Death in Heart Failure Cardiogenic Shock.

BACKGROUND: Pulmonary artery catheters (PACs) are increasingly used to guide management decisions in cardiogenic shock (CS). The goal of this study was to determine if PAC use was associated with a lower risk of in-hospital mortality in CS owing to acute heart failure (HF-CS). METHODS AND RESULTS: This multicenter, retrospective, observational study included patients with CS hospitalized between 2019 and 2021 at 15 US hospitals participating in the Cardiogenic Shock Working Group registry. The primary end point was in-hospital mortality. Inverse probability of treatment-weighted logistic regression models were used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CI), accounting for multiple variables at admission. The association between the timing of PAC placement and in-hospital death was also analyzed. A total of 1055 patients with HF-CS were included, of whom 834 (79%) received a PAC during their hospitalization. In-hospital mortality risk for the cohort was 24.7% (n = 261). PAC use was associated with lower adjusted in-hospital mortality risk (22.2% vs 29.8%, OR 0.68, 95% CI 0.50-0.94). Similar associations were found across SCAI stages of shock, both at admission and at maximum SCAI stage during hospitalization. Early PAC use (≤6 hours of admission) was observed in 220 PAC recipients (26%) and associated with a lower adjusted risk of in-hospital mortality compared with delayed (≥48 hours) or no PAC use (17.3% vs 27.7%, OR 0.54, 95% CI 0.37-0.81). CONCLUSIONS: This observational study supports PAC use, because it was associated with decreased in-hospital mortality in HF-CS, especially if performed within 6 hours of hospital admission. CONDENSED ABSTRACT: An observational study from the Cardiogenic Shock Working Group registry of 1055 patients with HF-CS showed that pulmonary artery catheter (PAC) use was associated with a lower adjusted in-hospital mortality risk (22.2% vs 29.8%, odds ratio 0.68, 95% confidence interval 0.50-0.94) compared with outcomes in patients managed without PAC. Early PAC use (≤6 hours of admission) was associated with a lower adjusted risk of in-hospital mortality compared with delayed (≥48 hours) or no PAC use (17.3% vs 27.7%, odds ratio 0.54, 95% confidence interval 0.37-0.81).

Right Ventricular Dysfunction Is Common and Identifies Patients at Risk of Dying in Cardiogenic Shock.

BACKGROUND: Understanding the prognostic impact of right ventricular dysfunction (RVD) in cardiogenic shock (CS) is a key step toward rational diagnostic and treatment algorithms and improved outcomes. Using a large multicenter registry, we assessed (1) the association between hemodynamic markers of RVD and in-hospital mortality, (2) the predictive value of invasive hemodynamic assessment incorporating RV evaluation, and (3) the impact of RVD severity on survival in CS. METHODS AND RESULTS: Inpatients with CS owing to acute myocardial infarction (AMI) or heart failure (HF) between 2016 and 2019 were included. RV parameters (right atrial pressure, right atrial/pulmonary capillary wedge pressure [RA/PCWP], pulmonary artery pulsatility index [PAPI], and right ventricular stroke work index [RVSWI]) were assessed between survivors and nonsurvivors, and between etiology and SCAI stage subcohorts. Multivariable logistic regression analysis determined hemodynamic predictors of in-hospital mortality; the resulting models were compared with SCAI staging alone. Nonsurvivors had a significantly higher right atrial pressure and RA/PCWP and lower PAPI and RVSWI than survivors, consistent with more severe RVD. Compared with AMI, patients with HF had a significantly lower RA/PCWP (0.58 vs 0.66, P = .001) and a higher PAPI (2.71 vs 1.78, P < .001) and RVSWI (5.70 g-m/m2 vs 4.66 g-m/m2, P < .001), reflecting relatively preserved RV function. Paradoxically, multiple RVD parameters (PAPI, RVSWI) were associated with mortality in the HF but not the AMI cohort. RVD was more severe with advanced SCAI stage, although its prognostic value was progressively diluted in stages D and E. Multivariable modelling incorporating the RA/PCWP improved the predictive value of SCAI staging (area under the curve [AUC] 0.78 vs 0.73, P < .001), largely driven by patients with HF (AUC 0.82 vs 0.71, P < .001). CONCLUSIONS: RVD is associated with poor outcomes in CS, with key differences across etiology and shock severity. Further studies are needed to assess the usefulness of RVD assessment in guiding therapy.

Factors associated with Acute Limb Ischemia in Cardiogenic Shock and downstream Clinical Outcomes: Insights from the Cardiogenic Shock Working Group.

BACKGROUND: There are limited data depicting the prevalence and ramifications of acute limb ischemia (ALI) among cardiogenic shock (CS) patients. METHODS: We employed data from the Cardiogenic Shock Working Group (CSWG), a consortium including 33 sites. We constructed a multi-variable logistic regression to examine the association between clinical factors and ALI, we generated another logistic regression model to ascertain the association of ALI with mortality. RESULTS: There were 7,070 patients with CS and 399 (5.6%) developed ALI. Patients with ALI were more likely to be female (40.4% versus 29.4%) and have peripheral arterial disease (13.8% versus 8.3%). Stratified by maximum SCAI shock stage, the rates of ALI were stage B 0.0%, stage C 1.8%, stage D 4.1%, and stage E 10.3%. Factors associated with higher risk for ALI included: peripheral vascular disease OR 2.24 (95% CI: 1.53 - 3.23; p < 0.01) and ≥ 2 mechanical circulatory support (MCS) devices OR 1.66 (95% CI: 1.24 - 2.21, p < 0.01). ALI was highest for VA-ECMO patients (11.6%) or VA-ECMO + IABP/Impella CP (16.6%) yet use of distal perfusion catheters was less than 50%. Mortality was 38.0% for CS patients without ALI but 57.4% for CS patients with ALI. ALI was significantly associated with mortality, adjusted OR 1.40 (95% CI 1.01 - 1.95, p < 0.01). CONCLUSIONS: The rate of ALI was 6% among CS patients. Factors most associated with ALI include peripheral vascular disease and multiple MCS devices. The downstream ramifications of ALI were dire with a considerably higher risk of mortality.

Acute Presentation of Critical Aortic Stenosis, Cardiogenic Shock, and the "Heart Team" Approach to Management.

A 65-year-old male was admitted for cardiogenic shock (ejection fraction: 15%) with severe aortic stenosis and regurgitation. He underwent emergency angiography and mechanical circulatory support. A multidisciplinary heart team discussed treatment options. Ultimately, he underwent successful emergency surgical aortic valve replacement with recovery on extracorporeal membrane oxygenation. (Level of Difficulty: Intermediate.).

Clinical Presentation and In-Hospital Trajectory of Heart Failure and Cardiogenic Shock.

BACKGROUND: Heart failure-related cardiogenic shock (HF-CS) remains an understudied distinct clinical entity. OBJECTIVES: The authors sought to profile a large cohort of patients with HF-CS focused on practical application of the SCAI (Society for Cardiovascular Angiography and Interventions) staging system to define baseline and maximal shock severity, in-hospital management with acute mechanical circulatory support (AMCS), and clinical outcomes. METHODS: The Cardiogenic Shock Working Group registry includes patients with CS, regardless of etiology, from 17 clinical sites enrolled between 2016 and 2020. Patients with HF-CS (non-acute myocardial infarction) were analyzed and classified based on clinical presentation, outcomes at discharge, and shock severity defined by SCAI stages. RESULTS: A total of 1,767 patients with HF-CS were included, of whom 349 (19.8%) had de novo HF-CS (DNHF-CS). Patients were more likely to present in SCAI stage C or D and achieve maximum SCAI stage D. Patients with DNHF-CS were more likely to experience in-hospital death and in- and out-of-hospital cardiac arrest, and they escalated more rapidly to a maximum achieved SCAI stage, compared to patients with acute-on-chronic HF-CS. In-hospital cardiac arrest was associated with greater in-hospital death regardless of clinical presentation (de novo: 63% vs 21%; acute-on-chronic HF-CS: 65% vs 17%; both P < 0.001). Forty-five percent of HF-CS patients were exposed to at least 1 AMCS device throughout hospitalization. CONCLUSIONS: In a large contemporary HF-CS cohort, we identified a greater incidence of in-hospital death and cardiac arrest as well as a more rapid escalation to maximum SCAI stage severity among DNHF-CS. AMCS use in HF-CS was common, with significant heterogeneity among device types. (Cardiogenic Shock Working Group Registry [CSWG]; NCT04682483).

Clinical Course of Patients in Cardiogenic Shock Stratified by Phenotype.

BACKGROUND: Cardiogenic shock (CS) patients remain at 30% to 60% in-hospital mortality despite therapeutic innovations. Heterogeneity of CS has complicated clinical trial design. Recently, 3 distinct CS phenotypes were identified in the CSWG (Cardiogenic Shock Working Group) registry version 1 (V1) and external cohorts: I, "noncongested;" II, "cardiorenal;" and III, "cardiometabolic" shock. OBJECTIVES: The aim was to confirm the external reproducibility of machine learning-based CS phenotypes and to define their clinical course. METHODS: The authors included 1,890 all-cause CS patients from the CSWG registry version 2. CS phenotypes were identified using the nearest centroids of the initially reported clusters. RESULTS: Phenotypes were retrospectively identified in 796 patients in version 2. In-hospital mortality rates in phenotypes I, II, III were 23%, 41%, 52%, respectively, comparable to the initially reported 21%, 45%, and 55% in V1. Phenotype-related demographic, hemodynamic, and metabolic features resembled those in V1. In addition, 58.8%, 45.7%, and 51.9% of patients in phenotypes I, II, and III received mechanical circulatory support, respectively (P = 0.013). Receiving mechanical circulatory support was associated with increased mortality in cardiorenal (OR: 1.82 [95% CI: 1.16-2.84]; P = 0.008) but not in noncongested or cardiometabolic CS (OR: 1.26 [95% CI: 0.64-2.47]; P = 0.51 and OR: 1.39 [95% CI: 0.86-2.25]; P = 0.18, respectively). Admission phenotypes II and III and admission Society for Cardiovascular Angiography and Interventions stage E were independently associated with increased mortality in multivariable logistic regression compared to noncongested "stage C" CS (P < 0.001). CONCLUSIONS: The findings support the universal applicability of these phenotypes using supervised machine learning. CS phenotypes may inform the design of future clinical trials and enable management algorithms tailored to a specific CS phenotype.

Impact of Female Sex on Cardiogenic Shock Outcomes: A Cardiogenic Shock Working Group Report.

BACKGROUND: Studies reporting cardiogenic shock (CS) outcomes in women are scarce. OBJECTIVES: The authors compared survival at discharge among women vs men with CS complicating acute myocardial infarction (AMI-CS) and heart failure (HF-CS). METHODS: The authors analyzed 5,083 CS patients in the Cardiogenic Shock Working Group. Propensity score matching (PSM) was performed with the use of baseline characteristics. Logistic regression was performed for log odds of survival. RESULTS: Among 5,083 patients, 1,522 were women (30%), whose mean age was 61.8 ± 15.8 years. There were 30% women and 29.1% men with AMI-CS (P = 0.03). More women presented with de novo HF-CS compared with men (26.2% vs 19.3%; P < 0.001). Before PSM, differences in baseline characteristics and sex-specific outcomes were seen in the HF-CS cohort, with worse survival at discharge (69.9% vs 74.4%; P = 0.009) and a higher rate of maximum Society for Cardiac Angiography and Interventions stage E (26% vs 21%; P = 0.04) in women than in men. Women were less likely to receive pulmonary artery catheterization (52.9% vs 54.6%; P < 0.001), heart transplantation (6.5% vs 10.3%; P < 0.001), or left ventricular assist device implantation (7.8% vs 10%; P = 0.01). Regardless of CS etiology, women had more vascular complications (8.8% vs 5.7%; P < 0.001), bleeding (7.1% vs 5.2%; P = 0.01), and limb ischemia (6.8% vs 4.5%; P = 0.001). More vascular complications persisted in women after PSM (10.4% women vs 7.4% men; P = 0.06). CONCLUSIONS: Women with HF-CS had worse outcomes and more vascular complications than men with HF-CS. More studies are needed to identify barriers to advanced therapies, decrease complications, and improve outcomes of women with CS.

Treatment Intensity for the Management of Cardiogenic Shock: Comparison Between STEMI and Non-STEMI.

Background: Cardiogenic shock is a leading cause of mortality in patients with acute myocardial infarction. Objectives: The authors sought to compare clinical characteristics, hospital trajectory, and drug and device use between patients with ST-segment elevation myocardial infarction-related cardiogenic shock (STEMI-CS) and those without (non-ST-segment elevation myocardial infarction complicated by cardiogenic shock [NSTEMI-CS]). Methods: We analyzed data from 1,110 adult admissions with cardiogenic shock complicating acute myocardial infarction (AMI-CS) across 17 centers within Cardiogenic Shock Working Group. The primary end point was in-hospital mortality. Results: Our study included 1,110 patients with AMI-CS, of which 731 (65.8%) had STEMI-CS and 379 (34.2%) had NSTEMI-CS. Most patients were male (STEMI-CS: 71.6%, NSTEMI-CS: 66.5%) and White (STEMI-CS: 53.8%, NSTEMI-CS: 64.1%). In-hospital mortality was 41% and was similar among patients with STEMI-CS and NSTEMI-CS (43% vs 39%, P = 0.23). Patients with out-of-hospital cardiac arrest had higher in-hospital mortality in patients with NSTEMI-CS (63% vs 36%, P = 0.006) as compared to patients with STEMI-CS (52% vs 41%, P = 0.16). Similar results were observed for in-hospital cardiac arrest in patients with STEMI-CS (63% vs 33%, P < 0.001) and NSTEMI-CS (60% vs 32%, P < 0.001). Only 27% of patients with STEMI-CS and 12% of NSTEMI-CS received both a drug and temporary mechanical circulatory support device during the first 24 hours, which increased to 78% and 61%, respectively, throughout the course of the hospitalization (P < 0.001 for both). Conclusions: Despite increasing use of inotropic and vasoactive support and mechanical circulatory support throughout the hospitalization, both patients with STEMI-CS and NSTEMI-CS remain at increased risk for in-hospital mortality. Randomized controls trials are needed to elucidate whether timing and sequence of escalation of support improves outcomes in patients with AMI-CS.

Criteria for Defining Stages of Cardiogenic Shock Severity.

BACKGROUND: Risk-stratifying patients with cardiogenic shock (CS) is a major unmet need. The recently proposed Society for Cardiovascular Angiography and Interventions (SCAI) staging system for CS severity lacks uniform criteria defining each stage. OBJECTIVES: The purpose of this study was to test parameters that define SCAI stages and explore their utility as predictors of in-hospital mortality in CS. METHODS: The CS Working Group registry includes patients from 17 hospitals enrolled between 2016 and 2021 and was used to define clinical profiles for CS. We selected parameters of hypotension and hypoperfusion and treatment intensity, confirmed their association with mortality, then defined formal criteria for each stage and tested the association between both baseline and maximum Stage and mortality. RESULTS: Of 3,455 patients, CS was caused by heart failure (52%) or myocardial infarction (32%). Mortality was 35% for the total cohort and higher among patients with myocardial infarction, out-of-hospital cardiac arrest, and treatment with increasing numbers of drugs and devices. Systolic blood pressure, lactate level, alanine transaminase level, and systemic pH were significantly associated with mortality and used to define each stage. Using these criteria, baseline and maximum stages were significantly associated with mortality (n = 1,890). Lower baseline stage was associated with a higher incidence of stage escalation and a shorter duration of time to reach maximum stage. CONCLUSIONS: We report a novel approach to define SCAI stages and identify a significant association between baseline and maximum stage and mortality. This approach may improve clinical application of the staging system and provides new insight into the trajectory of hospitalized CS patients. (Cardiogenic Shock Working Group Registry [CSWG]; NCT04682483).

SCAD: a rare case of cardiac arrest in a young female.

A 43-year-old caucasian female without prior history or family history of cardiac disease presented to a community hospital with severe chest pain and electrocardiographic evidence of an acute left anterior descending (LAD) territory infarction. Duringtransferto ourtertiaryfacility, the patient had a cardiac arrest and was cardioverted in the ambulance. After arrival, the patient suffered a second cardiac arrest, was given CPR, cardioverted, intubated and given volume resuscitation. The patient was stabilized with vasopressors and was taken to the cardiac catherization (cath) lab where an intra-aortic balloon pump (IABP) was inserted. At catherization, the patient was found to have an acute left main coronary artery dissection and had evidence of cardiogenic shock. Prompt treatment including multiple stents, hypothermia protocol (HP), left ventricular assist device (LVAD) and multiple inotropic agents resulted in complete clinical recovery.

Trends in post-heart transplant biopsies for graft rejection versus nonrejection.

With alternatives such as gene profiling available for surveillance after orthotopic heart transplantation, we sought to evaluate the utilization of endomyocardial biopsies (EMBs) for hospitalized patients after heart transplantation. Surveillance EMBs in patients with and without complications were evaluated from the 2004 to 2014 National Inpatient Sample. Over the study period, there was no significant change in the number of EMB procedures performed (P = 0.44). Of 37,955 EMBs, 2283 (6%) were in the setting of graft complications, while 35,672 EMBs were not related to graft complications. EMBs in graft complications did not show a significant increase in length of stay over time (P = 0.06), but had a significant increase in cost over time (P = 0.001). However, those with graft complications had an average of a 5-day longer length of stay (P < 0.001) and costs that were $88,816 (P < 0.001) more expensive compared with those without graft complications. In conclusion, the vast majority of in-hospital EMBs were not related to heart transplantation complications. Nevertheless, EMB hospitalizations with graft complications showed significantly greater length of stay and cost. With the COVID-19 pandemic, it seems more effective to use minimal-contact health surveillance methods rather than invasive EMBs.

Clinical Outcomes Associated With Acute Mechanical Circulatory Support Utilization in Heart Failure Related Cardiogenic Shock.

BACKGROUND: Cardiogenic shock occurring in the setting of advanced heart failure (HF-CS) is increasingly common. However, recent studies have focused almost exclusively on acute myocardial infarction-related CS. We sought to define clinical, hemodynamic, metabolic, and treatment parameters associated with clinical outcomes among patients with HF-CS, using data from the Cardiogenic Shock Working Group registry. METHODS: Patients with HF-CS were identified from the multicenter Cardiogenic Shock Working Group registry and divided into 3 outcome categories assessed at hospital discharge: mortality, heart replacement therapy (HRT: durable ventricular assist device or orthotopic heart transplant), or native heart survival. Clinical characteristics, hemodynamic, laboratory parameters, drug therapies, acute mechanical circulatory support device (AMCS) utilization, and Society of Cardiovascular Angiography and Intervention stages were compared across the 3 outcome cohorts. RESULTS: Of the 712 patients with HF-CS identified, 180 (25.3%) died during their index admission, 277 (38.9%) underwent HRT (durable ventricular assist device or orthotopic heart transplant), and 255 (35.8%) experienced native heart survival without HRT. Patients who died had the highest right atrial pressure and heart rate and the lowest mean arterial pressure of the 3 outcome groups (P<0.01 for all). Biventricular and isolated left ventricular congestion were common among patients who died or underwent HRT, respectively. Lactate, blood urea nitrogen, serum creatinine, and aspartate aminotransferase were highest in patients with HF-CS experiencing in-hospital death. Intraaortic balloon pump was the most commonly used AMCS device in the overall cohort and among patients receiving HRT. Patients receiving >1 AMCS device had the highest in-hospital mortality rate irrespective of the number of vasoactive drugs used. Mortality increased with deteriorating Society of Cardiovascular Angiography and Intervention stages (stage B: 0%, stage C: 10.7%, stage D: 29.4%, stage E: 54.5%, 1-way ANOVA=<0.001). CONCLUSIONS: Patients with HF-CS experiencing in-hospital mortality had a high prevalence of biventricular congestion and markers of end-organ hypoperfusion. Substantial heterogeneity exists with use of AMCS in HF-CS with intraaortic balloon pump being the most common device used and high rates of in-hospital mortality after exposure to >1 AMCS device.

Phenotyping Cardiogenic Shock.

Background Cardiogenic shock (CS) is a heterogeneous syndrome with varied presentations and outcomes. We used a machine learning approach to test the hypothesis that patients with CS have distinct phenotypes at presentation, which are associated with unique clinical profiles and in-hospital mortality. Methods and Results We analyzed data from 1959 patients with CS from 2 international cohorts: CSWG (Cardiogenic Shock Working Group Registry) (myocardial infarction [CSWG-MI; n=410] and acute-on-chronic heart failure [CSWG-HF; n=480]) and the DRR (Danish Retroshock MI Registry) (n=1069). Clusters of patients with CS were identified in CSWG-MI using the consensus k means algorithm and subsequently validated in CSWG-HF and DRR. Patients in each phenotype were further categorized by their Society of Cardiovascular Angiography and Interventions staging. The machine learning algorithms revealed 3 distinct clusters in CS: "non-congested (I)", "cardiorenal (II)," and "cardiometabolic (III)" shock. Among the 3 cohorts (CSWG-MI versus DDR versus CSWG-HF), in-hospital mortality was 21% versus 28% versus 10%, 45% versus 40% versus 32%, and 55% versus 56% versus 52% for clusters I, II, and III, respectively. The "cardiometabolic shock" cluster had the highest risk of developing stage D or E shock as well as in-hospital mortality among the phenotypes, regardless of cause. Despite baseline differences, each cluster showed reproducible demographic, metabolic, and hemodynamic profiles across the 3 cohorts. Conclusions Using machine learning, we identified and validated 3 distinct CS phenotypes, with specific and reproducible associations with mortality. These phenotypes may allow for targeted patient enrollment in clinical trials and foster development of tailored treatment strategies in subsets of patients with CS.

Complete Hemodynamic Profiling With Pulmonary Artery Catheters in Cardiogenic Shock Is Associated With Lower In-Hospital Mortality.

OBJECTIVES: The purpose of this study was to investigate the association between obtaining hemodynamic data from early pulmonary artery catheter (PAC) placement and outcomes in cardiogenic shock (CS). BACKGROUND: Although PACs are used to guide CS management decisions, evidence supporting their optimal use in CS is lacking. METHODS: The Cardiogenic Shock Working Group (CSWG) collected retrospective data in CS patients from 8 tertiary care institutions from 2016 to 2019. Patients were divided by Society for Cardiovascular Angiography and Interventions (SCAI) stages and outcomes analyzed by the PAC-use group (no PAC data, incomplete PAC data, complete PAC data) prior to initiating mechanical circulatory support (MCS). RESULTS: Of 1,414 patients with CS analyzed, 1,025 (72.5%) were male, and 494 (34.9%) presented with myocardial infarction; 758 (53.6%) were in SCAI Stage D shock, and 263 (18.6%) were in Stage C shock. Temporary MCS devices were used in 1,190 (84%) of those in advanced CS stages. PAC data were not obtained in 216 patients (18%) prior to MCS, whereas 598 patients (42%) had complete hemodynamic data. Mortality differed significantly between PAC-use groups within the overall cohort (p < 0.001), and each SCAI Stage subcohort (Stage C: p = 0.03; Stage D: p = 0.05; Stage E: p = 0.02). The complete PAC assessment group had the lowest in-hospital mortality than the other groups across all SCAI stages. Having no PAC assessment was associated with higher in-hospital mortality than complete PAC assessment in the overall cohort (adjusted odds ratio: 1.57; 95% confidence interval: 1.06 to 2.33). CONCLUSIONS: The CSWG is a large multicenter registry representing real-world patients with CS in the contemporary MCS era. Use of complete PAC-derived hemodynamic data prior to MCS initiation is associated with improved survival from CS.

Invasive Hemodynamic Assessment and Classification of In-Hospital Mortality Risk Among Patients With Cardiogenic Shock.

BACKGROUND: Risk stratifying patients with cardiogenic shock (CS) is a major unmet need. The recently proposed Society for Cardiovascular Angiography and Interventions (SCAI) stages as an approach to identify patients at risk for in-hospital mortality remains under investigation. We studied the utility of the SCAI stages and further explored the impact of hemodynamic congestion on clinical outcomes. METHODS: The CS Working Group registry includes patients with CS from 8 medical centers enrolled between 2016 and 2019. Patients were classified by the maximum SCAI stage (B-E) reached during their hospital stay according to drug and device utilization. In-hospital mortality was evaluated for association with SCAI stages and hemodynamic congestion. RESULTS: Of the 1414 patients with CS, the majority were due to decompensated heart failure (50%) or myocardial infarction (MI; 35%). In-hospital mortality was 31% for the total cohort, but higher among patients with MI (41% versus 26%, MI versus heart failure, P<0.0001). Risk for in-hospital mortality was associated with increasing SCAI stage (odds ratio [95% CI], 3.25 [2.63-4.02]) in both MI and heart failure cohorts. Hemodynamic data was available in 1116 (79%) patients. Elevated biventricular filling pressures were common among patients with CS, and right atrial pressure was associated with increased mortality and higher SCAI Stage. CONCLUSIONS: Our findings support an association between the proposed SCAI staging system and in-hospital mortality among patient with heart failure and MI. We further identify that venous congestion is common and identifies patients with CS at high risk for in-hospital mortality. These findings provide may inform future management protocols and clinical studies.

Post-exercise heart rate recovery independently predicts mortality risk in patients with chronic heart failure.

BACKGROUND: Post-exercise heart rate recovery (HRR) is an index of parasympathetic function associated with clinical outcomes in populations with and without documented coronary heart disease. Decreased parasympathetic activity is thought to be associated with disease progression in chronic heart failure (HF), but an independent association between post-exercise HRR and clinical outcomes among such patients has not been established. METHODS AND RESULTS: We measured HRR (calculated as the difference between heart rate at peak exercise and after 1 minute of recovery) in 202 HF subjects and recorded 17 mortality and 15 urgent transplantation outcome events over 624 days of follow-up. Reduced post-exercise HRR was independently associated with increased event risk after adjusting for other exercise-derived variables (peak oxygen uptake and change in minute ventilation per change in carbon dioxide production slope), for the Heart Failure Survival Score (adjusted HR 1.09 for 1 beat/min reduction, 95% CI 1.05-1.13, P < .0001), and the Seattle Heart Failure Model score (adjusted HR 1.08 for one beat/min reduction, 95% CI 1.05-1.12, P < .0001). Subjects in the lowest risk tertile based on post-exercise HRR (>or=30 beats/min) had low risk of events irrespective of the risk predicted by the survival scores. In a subgroup of 15 subjects, reduced post-exercise HRR was associated with increased serum markers of inflammation (interleukin-6, r = 0.58, P = .024; high-sensitivity C-reactive protein, r = 0.66, P = .007). CONCLUSIONS: Post-exercise HRR predicts mortality risk in patients with HF and provides prognostic information independent of previously described survival models. Pathophysiologic links between autonomic function and inflammation may be mediators of this association.

A mechanistic role for cardiac myocyte apoptosis in heart failure.

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 10(5) nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.

LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans.

Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are poorly understood. A rare nonconservative mutation in Wnt coreceptor LRP6 (LRP6(R611C)) has been shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes, and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscle and skin fibroblasts of healthy nondiabetic LRP6(R611C) mutation carriers. LRP6 mutation carriers exhibited hyperinsulinemia and reduced insulin sensitivity compared to noncarrier relatives in response to oral glucose ingestion, which correlated with a significant decline in tissue expression of the insulin receptor and insulin signaling activity. Further investigations showed that the LRP6(R611C) mutation diminishes TCF7L2-dependent transcription of the IR while it increases the stability of IGFR and enhances mTORC1 activity. These findings identify the Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance.

Physiogenomic comparison of edema and BMI in patients receiving rosiglitazone or pioglitazone.

BACKGROUND: The thiazolidinediones (TZDs) improve tissue sensitivity to insulin in patients with type II diabetes, resulting in reduced levels of fasting blood glucose and glycated hemoglobin. However, TZDs unpredictably demonstrate adverse effects of increased body weight, fluid retention, and edema. The balance of efficacy and safety of TZD varies widely from patient to patient. Genetic variability may reveal pathophysiological pathways underlying weight gain associated with TZD therapy and due to adiposity and/or edema. METHODS: We analyzed 384 single nucleotide polymorphisms (SNPs) from 222 cardiovascular and metabolic genes in 87 outpatients with type 2 diabetes receiving thiazolidinedione therapy. Physiogenomic analysis was used to discover associations with body mass index (BMI) and edema. RESULTS: The 5 most significant gene associations found between BMI and SNPs were ADORA1, adenosine A1 receptor (rs903361, p<0.0003), PKM2, pyruvate kinase-muscle (rs2856929, p<0.002); ADIPOR2, adiponectin receptor 2 (rs7975375, p<0.007); UCP2, uncoupling protein 2 (rs660339, p<0.008); and APOH, apolipoprotein H (rs8178847, p<0.010). For edema, the 5 most significant gene associations were NPY, neuropeptide Y (rs1468271, p<0.006); GYS1, glycogen synthase 1-muscle (rs2287754, p<0.013); CCL2, chemokine C-C motif ligand 2 (rs3760396, p<0.015); OLR1, oxidized LDL receptor 1 (rs2742115, p<0.015); and GHRH, growth hormone releasing hormone (rs6032470, p<0.023). After accounting for multiple comparisons, ADORA1 was significantly associated with BMI at a false discovery rate (FDR) of <10%. CONCLUSION: Physiogenomic associations were discovered suggesting mechanistic links between adenosine signaling and BMI, and between vascular permeability and drug-induced edema.