Mechanical Preload Reduction: Harnessing a Cornerstone of Heart Failure Management to Improve Clinical Outcomes.

Decongestion is a cornerstone therapeutic goal for those presenting with decompensated heart failure. Current approaches to clinical decongestion include reducing cardiac preload, which is typically limited to diuretics and hemofiltration. Several new technologies designed to mechanically reduce cardiac preload are in development. In this review, we discuss the pathophysiology of decompensated heart failure; the central role of targeting cardiac preload; emerging mechanical preload reduction technologies; and potential application of these devices.

Innovating to resolve the pressure-oxygenation-paradox created by VA-ECMO could improve outcomes for acute myocardial infarction and cardiogenic shock.

VA-ECMO use is growing exponentially. Recent data shows no clinical benefit with routine use of VA-ECMO in acute myocardial infarction and shock, however clinical experience with ECMO is growing. Two key variables that may impact outcomes with ECMO in acute myocardial infarction and shock include it's effect on systemic pressure and oxygenation. We define the pressure-oxygenaton paradox of ECMO as a potential new avenue for therapeutic discovery.

Reperfusion Injury in Patients With Acute Myocardial Infarction: JACC Scientific Statement.

Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial salvage, but the abrupt return of flow sets off a cascade of injurious processes that can lead to further necrosis. This has been termed myocardial ischemia-reperfusion injury and is the subject of this review. The pathologic and molecular bases for myocardial ischemia-reperfusion injury are increasingly understood and include injury from reactive oxygen species, inflammation, calcium overload, endothelial dysfunction, and impaired microvascular flow. A variety of pharmacologic strategies have been developed that have worked well in preclinical models and some have shown promise in the clinical setting. In addition, there are newer mechanical approaches including mechanical unloading of the heart prior to reperfusion that are in current clinical trials.

Left ventricular unloading in patients supported with veno-arterial extra corporeal membrane oxygenation; an international EuroELSO survey.

INTRODUCTION: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) improves end-organ perfusion in cardiogenic shock but may increase afterload, which can limit cardiac recovery. Left ventricular (LV) unloading strategies may aid cardiac recovery and prevent complications of increased afterload. However, there is no consensus on when and which unloading strategy should be used. METHODS: An online survey was distributed worldwide via the EuroELSO newsletter mailing list to describe contemporary international practice and evaluate heterogeneity in strategies for LV unloading. RESULTS: Of 192 respondents from 43 countries, 53% routinely use mechanical LV unloading, to promote ventricular recovery and/or to prevent complications. Of those that do not routinely unload, 65% cited risk of complications as the reason. The most common indications for unplanned unloading were reduced arterial line pulsatility (68%), pulmonary edema (64%) and LV dilatation (50%). An intra-aortic balloon pump was the most frequently used device for unloading followed by percutaneous left ventricular assist devices. Echocardiography was the most frequently used method to monitor the response to unloading. CONCLUSIONS: Significant variation exists with respect to international practice of ventricular unloading. Further research is required that compares the efficacy of different unloading strategies and a randomized comparison of routine mechanical unloading versus unplanned unloading.

Guide to Lung-Protective Ventilation in Cardiac Patients.

The incidence of acute respiratory insufficiency has continued to increase among patients admitted to modern-day cardiovascular intensive care units. Positive pressure ventilation (PPV) remains the mainstay of treatment for these patients. Alterations in intrathoracic pressure during PPV has distinct effects on both the right and left ventricles, affecting cardiovascular performance. Lung-protective ventilation (LPV) minimizes the risk of further lung injury through ventilator-induced lung injury and, hence, an understanding of LPV and its cardiopulmonary interactions is beneficial for cardiologists.

Body Mass Index and Mortality in Cardiogenic Shock.

We explored the association of body mass index (BMI) with mortality in cardiogenic shock (CS). Using the Cardiogenic Shock Working Group registry, we assessed the impact of BMI on mortality using restricted cubic splines in a multivariable logistic regression model adjusting for age, gender, and race. We also assessed mortality, device use, and complications in BMI categories, defined as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obese (30-39.9 kg/m2), and severely obese (>40 kg/m2) using univariable logistic regression models. Our cohort had 3,492 patients with CS (mean age = 62.1 ± 14 years, 69% male), 58.0% HF-related CS (HF-CS), and 27.8% acute myocardial infarction (AMI) related CS. Body mass index was a significant predictor of mortality in multivariable regression using restricted cubic splines (p < 0.0001, p = 0.194 for nonlinearity). When stratified by categories, patients with healthy weight had lower mortality (29.0%) than obese (35.1%, p = 0.003) or severely obese (36.7%, p = 0.01). In HF-CS cohort, the healthy weight patients had the lowest mortality (21.7%), whereas it was higher in the underweight (37.5%, p = 0.012), obese (29.2%, p = 0.003), and severely obese (29.9%, p = 0.019). There was no difference in mortality among BMI categories in AMI-CS.

Comparison of Mixed Venous Oxygen Saturation and Premembranous Venous Oxygen Saturation in Patients on Peripheral Venous-Arterial Extracorporeal Membrane Oxygenation.

In patients on veno-arterial extracorporeal membrane oxygenation (ECMO) premembranous venous oxygen saturation (Spm-vO2) is continuously displayed on the ECMO console. However, the concordance between Spm-vO2 and mixed venous oxygen saturation (SvO2) remains largely unexplored. Our single-center retrospective study included adult patients who had paired SvO2 and Spm-vO2 readings within 15 minutes of each other, on peripherally cannulated Vf ivc-A ECMO and a pulmonary artery using catheter (PAC). The 82 pairs of observations showed a mean difference of 11.37% (95% limits of agreement -6.0 to 28.74, p < 0.001) between Spm-vO2 and SvO2. Although the two values correlated with each other (r = 0.51, p < 0.01), the difference between the paired measurements was larger at lower values of SvO2 (3.72 ± 6.38% when SvO2 >80%, 11.79±7.46% when SvO2 between 60% and 80%, and 18.81±12.09% when SvO2 <60%). The equation SvO2 = 1.2* Spm-vO2 - 28.03 was obtained by Passing Bablok regression. Cardiac index calculated by Spm-vO2 and SvO2 differed by 0.8L/minute/m2 (95% limits of agreement -0.52 to 2.17, p < 0.001). In peripheral VA-ECMO, Spm-vO2 is consistently higher than SvO2, with more discordance at lower saturation levels. Using Spm-vO2 to estimate cardiac output using Fick method yields inaccurate results.

Circulating Proteome Analysis Identifies Reduced Inflammation After Initiation of Hemodynamic Support with Either Veno-Arterial Extracorporeal Membrane Oxygenation or Impella in Patients with Cardiogenic Shock.

In-hospital mortality associated with cardiogenic shock (CS) remains high despite the use of percutaneous assist devices. We sought to determine whether support with VA-ECMO or Impella in patients with CS alters specific components of the plasma proteome. Plasma samples were collected before device implantation and 72 h after initiation of support in 11 CS patients receiving ECMO or Impella. SOMAscan was used to detect 1305 circulating proteins. Sixty-seven proteins were changed after ECMO (18 upregulated and 49 downregulated, p < 0.05), 38 after Impella (10 upregulated and 28 downregulated, p < 0.05), and only eight proteins were commonly affected. Despite minimal protein overlap, both devices were associated with markers of reduced inflammation and increased apoptosis of inflammatory cells. In summary, ECMO and Impella are associated with reduced expression of inflammatory markers and increased markers of inflammatory cell death. These circulating proteins may serve as novel targets of therapy or biomarkers to tailor AMCS use.

Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. METHODS: We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. RESULTS: Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. CONCLUSIONS: We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Treatment of Acute Myocardial Infarction and Cardiogenic Shock: Outcomes of the RECOVER III Postapproval Study by Society of Cardiovascular Angiography and Interventions Shock Stage.

BACKGROUND: The Society for Cardiovascular Angiography and Interventions proposed a staging system (A-E) to predict prognosis in cardiogenic shock. Herein, we report clinical outcomes of the RECOVER III study for the first time, according to Society for Cardiovascular Angiography and Interventions shock classification. METHODS AND RESULTS: The RECOVER III study is an observational, prospective, multicenter, single-arm, postapproval study of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support. Patients enrolled in the RECOVER III study were assigned a baseline Society for Cardiovascular Angiography and Interventions shock stage. Staging was then repeated within 24 hours after initiation of Impella. Kaplan-Meier survival curve analyses were conducted to assess survival across Society for Cardiovascular Angiography and Interventions shock stages at both time points. At baseline assessment, 16.5%, 11.4%, and 72.2% were classified as stage C, D, and E, respectively. At ≤24-hour assessment, 26.4%, 33.2%, and 40.0% were classified as stage C, D, and E, respectively. Thirty-day survival among patients with stage C, D, and E shock at baseline was 59.7%, 56.5%, and 42.9%, respectively (P=0.003). Survival among patients with stage C, D, and E shock at ≤24 hours was 65.7%, 52.1%, and 29.5%, respectively (P<0.001). After multivariable analysis of impact of shock stage classifications at baseline and ≤24 hours, only stage E classification at ≤24 hours was a significant predictor of mortality (odds ratio, 4.8; P<0.001). CONCLUSIONS: In a real-world cohort of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support, only stage E classification at ≤24 hours was significantly predictive of mortality, suggesting that response to therapy may be more important than clinical severity of shock at presentation.

Delaying reperfusion plus left ventricular unloading reduces infarct size: Sub-analysis of DTU-STEMI pilot study.

INTRODUCTION: The STEMI-DTU pilot study tested the early safety and practical feasibility of left ventricular (LV) unloading with a trans-valvular pump before reperfusion. In the intent-to-treat cohort, no difference was observed for microvascular obstruction (MVO) or infarct size (IS) normalized to either the area at risk (AAR) at 3-5 days or total LV mass (TLVM) at 3-5 days We now report a per protocol analysis of the STEMI-DTU pilot study. METHODS: In STEMI-DTU STUDY 50 adult patients (25 in each arm) with anterior STEMI [sum of precordial ST-segment elevation (ΣSTE) ≥4 mm] requiring primary percutaneous coronary intervention (PCI) were enrolled. Only patients who met all inclusion and exclusion criteria were included in this analysis. Cardiac magnetic resonance (CMR) imaging 3-5 days after PCI quantified IS/AAR and IS/TLVM and MVO. Group differences were assessed using Student's t-tests and linear regression (SAS Version-9.4). RESULTS: Of the 50 patients enrolled, 2 died before CMR imaging. Of the remaining 48 patients those without CMR at 3-5 days (n = 8), without PCI of a culprit left anterior descending artery lesion (n = 2), with OHCA (n = 1) and with ΣSTE < 4 mm (n = 5) were removed from this analysis leaving 32/50 (64 %) patients meeting all inclusion and exclusion criteria (U-IR, n = 15; U-DR, n = 17) as per protocol. Despite longer symptom-to-balloon times in the U-DR arm (228 ± 80 vs 174 ± 59 min, p < 0.01), IS/AAR was significantly lower with 30 min of delay to reperfusion in the presence of active LV unloading (47 ± 16 % vs 60 ± 15 %, p = 0.02) and remained lower irrespective of the magnitude of precordial ΣSTE. MVO was not significantly different between groups (1.5 ± 2.8 % vs 3.5 ± 4.8 %, p = 0.15). Among patients who received LV unloading within 180 min of symptom onset, IS/AAR was significantly lower in the U-DR group. CONCLUSION: In this per-protocol analysis of the STEMI-DTU pilot study we observed that LV unloading for 30 min before reperfusion significantly reduced IS/AAR compared to LV unloading and immediate reperfusion, whereas in the ITT cohort no difference was observed between groups. This observation supports the design of the STEMI-DTU pivotal trial and suggests that strict adherence to the study protocol can significantly influence the outcome.

Outcomes of Patients Transferred to Tertiary Care Centers for Treatment of Cardiogenic Shock: A Cardiogenic Shock Working Group Analysis.

BACKGROUND: Consensus recommendations for cardiogenic shock (CS) advise transfer of patients in need of advanced options beyond the capability of "spoke" centers to tertiary/"hub" centers with higher capabilities. However, outcomes associated with such transfers are largely unknown beyond those reported in individual health networks. OBJECTIVES: To analyze a contemporary, multicenter CS cohort with the aim of comparing characteristics and outcomes of patients between transfer (between spoke and hub centers) and nontransfer cohorts (those primarily admitted to a hub center) for both acute myocardial infarction (AMI-CS) and heart failure-related HF-CS. We also aim to identify clinical characteristics of the transfer cohort that are associated with in-hospital mortality. METHODS: The Cardiogenic Shock Working Group (CSWG) registry is a national, multicenter, prospective registry including high-volume (mostly hub) CS centers. Fifteen U.S. sites contributed data for this analysis from 2016-2020. RESULTS: Of 1890 consecutive CS patients enrolled into the CSWG registry, 1028 (54.4%) patients were transferred. Of these patients, 528 (58.1%) had heart failure-related CS (HF-CS), and 381 (41.9%) had CS related to acute myocardial infarction (AMI-CS). Upon arrival to the CSWG site, transfer patients were more likely to be in SCAI stages C and D, when compared to nontransfer patients. Transfer patients had higher mortality rates (37% vs 29%, < 0.001) than nontransfer patients; the differences were driven primarily by the HF-CS cohort. Logistic regression identified increasing age, mechanical ventilation, renal replacement therapy, and higher number of vasoactive drugs prior to or within 24 hours after CSWG site transfer as independent predictors of mortality among HF-CS patients. Conversely, pulmonary artery catheter use prior to transfer or within 24 hours of arrival was associated with decreased mortality rates. Among transfer AMI-CS patients, BMI > 28 kg/m2, worsening renal failure, lactate > 3 mg/dL, and increasing numbers of vasoactive drugs were associated with increased mortality rates. CONCLUSION: More than half of patients with CS managed at high-volume CS centers were transferred from another hospital. Although transfer patients had higher mortality rates than those who were admitted primarily to hub centers, the outcomes and their predictors varied significantly when classified by HF-CS vs AMI-CS.

Procedural Insights and Clinical Outcomes of a Novel Superior Vena Cava Occlusion Device for Acute Heart Failure: A Single-Center Experience.

The preCARDIA system is a device combining a balloon-mounted catheter and an extracorporeal system designed for intermittent occlusion of the superior vena cava. Studies have established safety and efficacy in acute decompensated heart failure. We present a single-center experience detailing 90 days outcomes and procedural insights. A 24 hours therapy session demonstrated reduced pulmonary wedge pressures and increased urine output, with cardiac output remaining unchanged. There was one readmission and no heart failure-related readmissions at 90 days. The preCARDIA device appears to be a safe mechanical diuretic strategy to manage patients with acute decompensated heart failure beyond current therapeutic strategies.

ALK1 Deficiency Impairs the Wound-Healing Process and Increases Mortality in Murine Model of Myocardial Infarction.

The functional role of TGFß type I receptor, activin-like kinase (ALK)-1 in post-myocardial infarction (MI) cardiac remodeling is unknown. We hypothesize that reduced ALK1 activity reduces survival and promotes cardiac fibrosis after MI. MI was induced in wild-type (WT), and ALK+/- mice by left coronary ligation. After 14 days ALK1+/- mice had reduced survival with a higher rate of cardiac rupture compared to WT mice. ALK1+/- left ventricles (LVs) had increased volumes at the end of systole and at the end of diastole. After MI ALK1+/- LVs had increased profibrotic SMAD3 signaling, type 1 collagen, and fibrosis as well as increased levels of TGFß1 co-receptor, endoglin, VEGF, and ALK1 ligands BMP9 and BMP10. ALK1+/- LVs had decreased levels of stromal-derived factor 1α. These data identify the critical role of ALK1 in post-MI survival and cardiac remodeling and implicate ALK1 as a potential therapeutic target to improve survival after MI.

Loss of Bone Morphogenetic Protein-9 Reduces Survival and Increases MMP Activity After Myocardial Infarction.

No studies have explored a functional role for bone morphogenetic protein (BMP)-9, a transforming growth factor-ß superfamily ligand, in cardiac remodeling after myocardial infarction (MI). Using BMP-9 null mice, we observed that loss of BMP-9 decreases survival and increases cardiac rupture after MI. We further observed that loss of BMP-9 not only increases collagen abundance, but also promotes matrix metalloproteinase-9 activity and collagen degradation after MI. These findings identify BMP-9 as a necessary component of cardiac remodeling after MI and a potentially important target of therapy to improve outcomes after MI.

Cardiogenic Shock Integrated PHenotyping for Event Reduction: A Pilot Metabolomics Analysis.

Cardiogenic shock (CS) portends a dismal prognosis if hypoperfusion triggers uncontrolled inflammatory and metabolic derangements. We sought to investigate metabolomic profiles and temporal changes in IL6, Ang-2, and markers of glycocalyx perturbation from admission to discharge in eighteen patients with heart failure complicated by CS (HF-CS). Biological samples were collected from 18 consecutive HF-CS patients at admission (T0), 48 h after admission (T1), and at discharge (T2). ELISA analytical techniques and targeted metabolomics were performed Seven patients (44%) died at in-hospital follow-up. Among the survivors, IL-6 and kynurenine were significantly reduced at discharge compared to baseline. Conversely, the amino acids arginine, threonine, glycine, lysine, and asparagine; the biogenic amine putrescine; multiple sphingolipids; and glycerophospholipids were significantly increased. Patients with HF-CS have a metabolomic fingerprint that might allow for tailored treatment strategies for the patients' recovery or stabilization.

Early Utilization of Mechanical Circulatory Support in Acute Myocardial Infarction Complicated by Cardiogenic Shock: The National Cardiogenic Shock Initiative.

BACKGROUND: Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with significant morbidity and mortality. Mechanical circulatory support (MCS) devices increase systemic blood pressure and end organ perfusion while reducing cardiac filling pressures. METHODS AND RESULTS: The National Cardiogenic Shock Initiative (NCT03677180) is a single-arm, multicenter study. The purpose of this study was to assess the feasibility and effectiveness of utilizing early MCS with Impella in patients presenting with AMI-CS. The primary end point was in-hospital mortality. A total of 406 patients were enrolled at 80 sites between 2016 and 2020. Average age was 64±12 years, 24% were female, 17% had a witnessed out-of-hospital cardiac arrest, 27% had in-hospital cardiac arrest, and 9% were under active cardiopulmonary resuscitation during MCS implantation. Patients presented with a mean systolic blood pressure of 77.2±19.2 mm Hg, 85% of patients were on vasopressors or inotropes, mean lactate was 4.8±3.9 mmol/L and cardiac power output was 0.67±0.29 watts. At 24 hours, mean systolic blood pressure improved to 103.9±17.8 mm Hg, lactate to 2.7±2.8 mmol/L, and cardiac power output to 1.0±1.3 watts. Procedural survival, survival to discharge, survival to 30 days, and survival to 1 year were 99%, 71%, 68%, and 53%, respectively. CONCLUSIONS: Early use of MCS in AMI-CS is feasible across varying health care settings and resulted in improvements to early hemodynamics and perfusion. Survival rates to hospital discharge were high. Given the encouraging results from our analysis, randomized clinical trials are warranted to assess the role of utilizing early MCS, using a standardized, multidisciplinary approach.

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.