229 results on '"Drakos SG"'
Search Results
2. Recurrent Episodes of ST-Elevation Myocardial Infarction in a 19-Year-Old Male with Fontan Circulation
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Martinez Hd, Kemeyou L, Lal Ak, Drakos Sg, and Alghammass Ma
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medicine.medical_specialty ,St elevation myocardial infarction ,business.industry ,Internal medicine ,Cardiology ,medicine ,cardiovascular diseases ,General Medicine ,business ,Fontan circulation - Abstract
We describe a case of a 19-year-old male with history of single ventricle physiology status post-Fontan procedure at the age of two who developed thromboembolic phenomena involving his splenic, renal and coronary arteries resulting in multiple infarcts and recurrent in-hospital acute ST-Segment Elevation Myocardial Infarction (STEMI) treated by emergent Percutaneous Coronary Intervention (PCI). This case highlights multiple aspects and challenges of managing young patients with congenital heart disease.
- Published
- 2021
3. PRIOR HLA-ALLOSENSITIZATION AND LEFT VENTRICULAR ASSIST DEVICE TYPE AFFECT DEGREE OF POST-IMPLANTATION HLA-ALLOSENSITIZATION
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Drakos, SG, Kfoury, AG, Kotter, JR, Reid, BB, Clayson, SE, Selzman, CH, Stehlik, J, Fisher, PW, Merida, M, Eckels, DD, Brunisholz, K, Horne, BD, Stoker, S, Li, DY, and Renlund, DG
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Adult ,Heart Failure ,Male ,HLA Antigens ,Antibody Formation ,Heart Transplantation ,Humans ,Female ,Heart-Assist Devices ,Middle Aged ,Article ,Antibodies ,Retrospective Studies - Abstract
Left ventricular assist device (LVAD) implantation before heart transplantation has been associated with formation of antibodies directed against human leukocyte antigens (HLA), often referred to as sensitization. This study investigated whether prior sensitization or LVAD type affected the degree of post-implantation sensitization. The records of consecutive HeartMate (HM) I and HM II LVAD patients were reviewed. Panel reactive antibody (PRA) was assessed before LVAD implantation and biweekly thereafter. Sensitization was defined as PRA10%, and high-degree sensitization was defined as PRA90%. An HM LVAD was implanted in 64 patients, and 11 received a HM II LVAD as a bridge to transplant. Ten HM I patients (16%) were sensitized before LVAD implantation (HM I-S), and 54 (84%) were not (HM I-Non-S). Nine HM I-S patients (90%) became highly sensitized (PRA90%) compared with 9 HM I-Non-S patients (16.7%; p0.001). The PRA remained elevated (90%) in 8 of the 9 (88.9%) highly sensitized HM I-S patients vs 5 of the 9 (55.6%) HM I-Non-S highly sensitized patients. The PRA levels in the rest of the HM I-S highly sensitized patients declined from 93% +/- 4% to 55% +/- 15% (p = 0.01). Among the 11 HM II patients, 1 (9%) was sensitized before LVAD implantation (PRA, 40%) and the PRA moderately increased to 80%. No other HM II patient became sensitized after implantation. Thus, 1 of 11 (9%) HM II patients became sensitized compared with 29 of 64 (45%) HM I patients (p = 0.04). Pre-sensitized patients are at higher risk for becoming and remaining highly HLA-allosensitized after LVAD implantation. The HeartMate II LVAD appears to cause less sensitization than HeartMate I.
- Published
- 2009
4. Prevalence and prognostic significance of anemia in patients with congestive heart failure treated with standard vs high doses of enalapril
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Terrovitis, JV Anastasiou-Nana, MI Alexopoulos, GP Tsolakis, EJ Margari, ZJ Drakos, SG Tsagalou, EP Papazoglou, P and Efentakis, S Nanas, JN
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hemic and lymphatic diseases - Abstract
Background: Anemia is common in patients with congestive heart failure (CHF), although its etiology and pathophysiology remain largely unexplained. The purpose of this study was to examine the prognostic significance of a low hematocrit (Hct) in patients with CHF and the possible role of angiotensin-converting enzyme inhibition in anemia development. Methods: Hct was measured at the time of enrollment of 160 patients with CHF, mean age 56 12 years, in New York Heart Association (NYHA) functional class 2.6 +/- 0.7 and with left ventricular ejection fraction of 20 +/- 9%. They were randomized to standard (mean: 17.9 +/- 4.3 mg/day) or high (mean: 42 +/- 19.3 mg/day) doses of enalapril. The follow-up duration was 2 years. Cox regression models were used to identify prognostic factors, and correlations among individual variables were tested. Results: Mean baseline Hct was 42.7 +/- 5%. In multivariate analyses, low Hct (p = 0.036), older age (p = 0.022) and low systolic blood pressure (p = 0.032) were independent predictors of death within 2 years. A correlation was found between baseline Hct and NYHA class (Spearman’s correlation coefficient: -0.183, p = 0.008). A significant decrease in Hct from 43.2 +/- 4.9% at baseline to 40.7 +/- 4.4% at 2 years was observed in the group treated with high doses of enalapril (p < 0.001). Conclusions: Low baseline Hct predicted poor 2-year prognosis in patients with CHF. Enalapril administered in high doses increased the incidence of anemia in this population. The underlying pathophysiologic mechanism and effects of maintaining a normal Hct on clinical outcomes remain to be determined.
- Published
- 2006
5. Comparison of pulsatile with nonpulsatile mechanical support in a porcine model of profound cardiogenic shock
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Drakos, SG Charitos, CE Ntalianis, A Terrovitis, JV and Siafakas, KX Dolou, P Pierrakos, C Charitos, E Karelas, J Nanas, JN
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cardiovascular system - Abstract
The aim of this study was to examine whether pulsatility by intraaortic balloon counterpulsation (IABP) is an important adjunct to the treatment of profound cardiogenic shock (CS) with a widely used, nonpulsatile centrifugal pump (CP). In each of 18 anesthetized, open chest pigs, the outflow cannula of the CP was inserted in the aortic arch through the right external carotid artery, and the inflow cannula of the CP was placed in the left atrium. A 40 cc IABP was subsequently placed in the descending aorta through the left external carotid artery. CS was induced by occlusion of coronary arteries and the infusion of propranolol and crystalloid fluid. Mean aortic pressure, pulse pressure, aortic end diastolic pressure, left ventricular end diastolic pressure, right atrial pressure, and heart rate were monitored. Cardiac output and left anterior descending artery flow were measured with a transit time ultrasound flowmeter. During profound CS, life sustaining hemodynamics were maintained only with the support of the assist devices. Hemodynamic support with the CP was associated with a nearly nonpulsatile flow and a pulse pressure of 7 +/- 4 mm Hg, which increased to 33 +/- 10 mm Hg (p = 0.000) after combining the CP with the IABP. Compared with the hemodynamic support offered by the CP alone, addition of the IABP increased mean aortic pressure from 40 +/- 15 to 50 +/- 16 mm Hg (p = 0.000), cardiac output from 810 +/- 194 to 1,200 +/- 234 ml/min (p = 0.003), and left anterior descending artery flow from 26 10 to 39 14 ml/min (p = 0.001). In profound CS, mechanical support provided by a continuous flow CP is enhanced by the added pulsatility of the IABP.
- Published
- 2005
6. Myocardial ischaemic preconditioning in the pig has no effect on the ventricular fibrillation and defibrillation thresholds
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Anastasiou-Nana, MI Tsagalou, EP Mavrikakis, EM Siafakas, KX and Tsolakis, EJ Drakos, SG Dalianis, A Karelas, J and Terrovitis, JV Nanas, JN
- Abstract
Introduction: The effects of myocardial ischaemia preconditioning in pigs on the vulnerability to ventricular fibrillation during subsequent ischaemic events are controversial. This study examined the time course of changes in ventricular fibrillation (VFT) and defibrillation (DFT) thresholds during transient myocardial ischaemia after a 45 min preconditioning period. Methods and results: In five open-chest pigs, VFT was measured after 3 min of regional myocardial ischaemia, at time 0, 2, 15, 30, 60 and 90 min (Control group). In seven other pigs (Test group), VFT was measured before (time 0) and 2, 15, 30, 60 and 90 min after ischaemic preconditioning by three consecutive 5 min periods of regional coronary occlusion, followed by 10 min of reperfusion. DFT was measured by increasing the stored energy systematically until successful defibrillation. Ischaemic preconditioning caused no significant change in the effective refractory period (ERP), VFT or DFT over the 90 min of the experiments. In the Control group, ERP remained stable for 30 min, though was significantly lower at 90 min (178 +/- 28 ms) than at baseline (204 +/- 32 ms, P = 0.007). VFT and DFF remained unchanged throughout the experiments, and no difference was observed in ERP, VFT and DFT between the two groups at any time during the experiment. Conclusion: No changes were observed in the refractory duration, ventricular vulnerability or defibrillation energy requirements up to 90 min after ventricular ischaemic preconditioning in the pig. (c) 2004 Elsevier Ireland Ltd. All rights reserved.
- Published
- 2005
7. Time course of fibrillation and defibrillation thresholds after an intravenous bolus of amiodarone - an experimental study
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Tsagalou, EP Anastasiou-Nana, MI Charitos, CE Siafakas, CX and Drakos, SG Ntalianis, A Terrovitis, JV Mavrikakis, EM and Doufas, A Nanas, JN
- Abstract
Experimental studies have described an increase in ventricular fibrillation threshold (VFT) by intravenous amiodarone. The aim of this study was to examine the early time course of changes in VFT and defibrillation thresholds (DFT) after an intravenous bolus of amiodarone in an experimental pig model of transient myocardial ischemia. Methods and results: VFT and relative effective ventricular refractory period (ERP) were measured in 15 anaesthetized open-chest pigs after 3 min of regional coronary ischaemia before (time 0) and 2, 15, 30, 60, and 90 min after the intravenous injection of normal saline (group A, n = 5) or amiodarone, 5 mg/kg over 15 s (group B, n = 10). DFT was measured by increasing the strength of DC shocks until defibrillation was accomplished. Amiodarone caused an increase in VFT, starting at 2 min after the infusion (11.4 +/- 8.4 mA versus 9.2 +/- 4.6 mA, P = 0.113), became significant at 15 min (13.7 +/- 6.5 mA, P = 0.009) continued to rise at 30 min (34.2 +/- 28.7 mA, P = 0.03) and reached a plateau at 60 min (50.3 +/- 37.8 mA, P = 0.008). An increase was also observed in the ERP (204 +/- 25 ms at 2 min versus 197 +/- 26 ms at baseline, P = 0.074, 211 +/- 38 ms at 15 min, P = 0.084, 212 +/- 40 ms at 30 min, P = 0.037, 220 +/- 34 ms at 60 min, P = 0.002, and 227 32 ms at 90 min, P = 0.008). No change was observed in DFT after amiodarone administration. No significant change in VFT, ERP, or DFT occurred in the control group. Conclusion: In this porcine model, the intravenous administration of amiodarone increased VFT and ERP over 60 min after the injection, without effect on DFT. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
- Published
- 2004
8. Moderate systemic hypotension during reperfusion reduces the coronary blood flow and increases the size of myocardial infarction in pigs
- Author
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Nanas, JN Tsolakis, E Terrovitis, JV Eleftheriou, A and Drakos, SG Dalianis, A Charitos, CE
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cardiovascular system ,circulatory and respiratory physiology - Abstract
Study objectives: To examine the effects of low arterial BP (ABP) during reperfusion on the extent of myocardial infarction and on coronary blood flow (CBF) in an occlusion/reperfusion experimental model. Design: Prospective, randomized animal study. Setting: University hospital. Participants: Normal pigs that were anesthetized, intubated, and mechanically ventilated. Interventions: Twenty-seven open-chest pigs underwent occlusion of the mid left anterior descending (LAD) coronary artery for I h followed by reperfusion for 2 h. During reperfusion, the animals were randomly assigned to either continuous infusion of nitroglycerin in therapeutic doses and fluid infusion at rates to maintain a mean ABP greater than or equal to 80 mm Hg (group 1, n = 13), or continuous nitroglycerin infusion at rates to maintain a mean ABP between 60 mm Hg and 75 mm Hg (group 2, n = 14). Measurements and results: The hemodynamics and the coronary ABP distal to the occlusion were recorded throughout the experiment. In addition, the LAD CBF and peak hyperemia CBF before occlusion and during reperfusion periods were measured by transit-time flowmetry. At the end of the experiment, the infareted left ventricular myocardial size was measured. There were no significant hemodynamic differences, including the distal coronary arterial pressure, between the two groups before or during the LAD artery occlusion period. During reperfusion, mean ABP was 90 +/- 3 min Hg in group 1 vs 69 +/- 3 mm Hg in group 2 (p < 0.001). In group 1, the infarcted myocardium represented 50.3 +/- 4.3% of the myocardium at risk, vs 69.4 +/- 7.2% in group 2 (p < 0.001). During reperfusion, CBF and peak hyperemia CBF were significantly higher in group 1 than in group 2. Conclusions: Low ABP during reperfusion increases the size of myocardial infarction and decreases CBF.
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- 2004
9. Effects of high doses versus standard doses of enalapril on endothelial cell function in patients with chronic congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy
- Author
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Drakos, SG Papamichael, CM Alexopoulos, GP Anastasiou-Nana, MI Stathopoulos, JV Nanas, JN
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- 2003
10. Exacerbation of variant angina by metoprolol resulting in syncope due to transient atrioventricular block
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Drakos, SG Anastasiou-Nana, MI Nanas, JN
- Published
- 2002
11. Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United network for organ sharing thoracic organ allocation policy justified?
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Wever-Pinzon O, Drakos SG, Kfoury AG, Nativi JN, Gilbert EM, Everitt M, Alharethi R, Brunisholz K, Bader FM, Li DY, Selzman CH, Stehlik J, Wever-Pinzon, Omar, Drakos, Stavros G, Kfoury, Abdallah G, Nativi, Jose N, Gilbert, Edward M, Everitt, Melanie, Alharethi, Rami, and Brunisholz, Kim
- Abstract
Background: Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list.Methods and Results: We analyzed mortality and morbidity in 33,073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status 1B patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001).Conclusions: Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts. [ABSTRACT FROM AUTHOR]- Published
- 2013
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12. Bridge to recovery: understanding the disconnect between clinical and biological outcomes.
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Drakos SG, Kfoury AG, Stehlik J, Selzman CH, Reid BB, Terrovitis JV, Nanas JN, Li DY, Drakos, Stavros G, Kfoury, Abdallah G, Stehlik, Josef, Selzman, Craig H, Reid, Bruce B, Terrovitis, John V, Nanas, John N, and Li, Dean Y
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- 2012
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13. Intra-aortic balloon counterpulsation and delayed revascularization for myocardial infarction and shock in the absence of primary angioplasty: a treatment strategy with or without thrombolysis?
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Drakos SG, Anastasiou-Nana MI, Terrovitis JV, Tsagalou EP, Kanakakis J, Ntalianis A, Lazaris N, Maroulidis G, Venetsanakos J, Bonios M, and Nanas JN
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- 2008
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14. Effects of high doses versus standard doses of enalapril on endothelial cell function in patients with chronic congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy.
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Drakos SG, Papamichael CM, Alexopoulos GP, Anastasiou-Nana MI, Stathopoulos JV, Nanas JN, Drakos, Stavros G, Papamichael, Christos M, Alexopoulos, George P, Anastasiou-Nana, Maria I, Stathopoulos, John V, and Nanas, John N
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- 2003
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15. Myocardial Krüppel-Like Factor 5 Abundance Holds Prognostic Value for Myocardial Recovery of Patients With Heart Failure Following Mechanical Unloading and Circulatory Support.
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Siokatas G, Hamouche R, Maneta E, Selzman C, Hatzistergos KE, Drakos SG, and Drosatos K
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- Humans, Male, Prognosis, Female, Middle Aged, Recovery of Function, Kruppel-Like Transcription Factors metabolism, Myocardium metabolism, Myocardium pathology, Biomarkers blood, Aged, Heart Failure physiopathology, Heart Failure therapy, Heart-Assist Devices
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- 2024
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16. Pathophysiologic Vasodilation in Cardiogenic Shock and Its Impact on Mortality.
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Chavez MA, Anderson M, Kyriakopoulos CP, Scott M, Dranow E, Maneta E, Hamouche R, Taleb I, Leon J, Kogelschatz B, Goldstein J, Billia F, Baran DA, Tehrani B, Goodwin M, Selzman CH, Tonna JE, Fang JC, Drakos SG, and Hanff TC
- Abstract
Background: Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS., Methods: We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models., Results: This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm
-5 (interquartile range, 870-1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0-0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm-5 decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P =0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P <0.001). A blunted pressor response was associated with a nearly 2-fold mortality increase (adjusted hazard ratio, 1.74; P =0.003)., Conclusions: Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR <800 dynes•s•cm-5 , high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed.- Published
- 2024
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17. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
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Visker JR, Cluntun AA, Velasco-Silva JN, Eberhardt DR, Cedeno-Rosario L, Shankar TS, Hamouche R, Ling J, Kwak H, Hillas JY, Aist I, Tseliou E, Navankasattusas S, Chaudhuri D, Ducker GS, Drakos SG, and Rutter J
- Abstract
The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
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- 2024
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18. Impact of Diabetes and Glycemia on Cardiac Improvement and Adverse Events Following Mechanical Circulatory Support.
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Kyriakopoulos CP, Taleb I, Tseliou E, Sideris K, Hamouche R, Maneta E, Nelson M, Krauspe E, Selko S, Visker JR, Dranow E, Goodwin ML, Alharethi R, Wever-Pinzon O, Fang JC, Stehlik J, Selzman CH, Hanff TC, and Drakos SG
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- Humans, Male, Female, Middle Aged, Aged, Prospective Studies, Stroke Volume, Treatment Outcome, Recovery of Function, Risk Factors, Time Factors, Heart-Assist Devices adverse effects, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 complications, Glycated Hemoglobin metabolism, Heart Failure mortality, Heart Failure blood, Heart Failure therapy, Heart Failure physiopathology, Ventricular Function, Left, Blood Glucose metabolism
- Abstract
Background: Type 2 diabetes is prevalent in cardiovascular disease and contributes to excess morbidity and mortality. We sought to investigate the effect of glycemia on functional cardiac improvement, morbidity, and mortality in durable left ventricular assist device (LVAD) recipients., Methods and Results: Consecutive patients with an LVAD were prospectively evaluated (n=531). After excluding patients missing pre-LVAD glycated hemoglobin (HbA1c) measurements or having inadequate post-LVAD follow-up, 375 patients were studied. To assess functional cardiac improvement, we used absolute left ventricular ejection fraction change (ΔLVEF: LVEF post-LVAD-LVEF pre-LVAD). We quantified the association of pre-LVAD HbA1c with ΔLVEF as the primary outcome, and all-cause mortality and LVAD-related adverse event rates (ischemic stroke/transient ischemic attack, intracerebral hemorrhage, gastrointestinal bleeding, LVAD-related infection, device thrombosis) as secondary outcomes. Last, we assessed HbA1c differences pre- and post-LVAD. Patients with type 2 diabetes were older, more likely men suffering ischemic cardiomyopathy, and had longer heart failure duration. Pre-LVAD HbA1c was inversely associated with ΔLVEF in patients with nonischemic cardiomyopathy but not in those with ischemic cardiomyopathy, after adjusting for age, sex, heart failure duration, and left ventricular end-diastolic diameter. Pre-LVAD HbA1c was not associated with all-cause mortality, but higher pre-LVAD HbA1c was shown to increase the risk of intracerebral hemorrhage, LVAD-related infection, and device thrombosis by 3 years on LVAD support ( P <0.05 for all). HbA1c decreased from 6.68±1.52% pre-LVAD to 6.11±1.33% post-LVAD ( P <0.001)., Conclusions: Type 2 diabetes and pre-LVAD glycemia modify the potential for functional cardiac improvement and the risk for adverse events on LVAD support. The degree and duration of pre-LVAD glycemic control optimization to favorably affect these outcomes warrants further investigation.
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- 2024
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19. American Heart Association Cardiogenic Shock Registry: Design and Implementation.
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Morrow DA, Jessup M, Abraham WT, Acker M, Aringo A, Batchelor W, Chikwe J, Costello S, Drakos SG, Farmer S, Gelijns A, Gillette N, Hochman JS, Isler M, Kapur NK, Kilic A, Kormos R, Lewis EF, Lindenfeld J, Lombardi P, Mancini D, Rao SV, Rutan C, Samsky M, and Krucoff MW
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- Humans, United States, Treatment Outcome, Benchmarking, Research Design, Time Factors, Electronic Health Records, Program Development, Hospital Mortality, Registries, Shock, Cardiogenic diagnosis, Shock, Cardiogenic therapy, Shock, Cardiogenic mortality, Shock, Cardiogenic physiopathology, Shock, Cardiogenic etiology, American Heart Association, Quality Indicators, Health Care, Quality Improvement
- Abstract
Background: Cardiogenic shock is a morbid complication of heart disease that claims the lives of more than 1 in 3 patients presenting with this syndrome. Supporting a unique collaboration across clinical specialties, federal regulators, payors, and industry, the American Heart Association volunteers and staff have launched a quality improvement registry to better understand the clinical manifestations of shock phenotypes, and to benchmark the management patterns, and outcomes of patients presenting with cardiogenic shock to hospitals across the United States., Methods: Participating hospitals will enroll consecutive hospitalized patients with cardiogenic shock, regardless of etiology or severity. Data are collected through individual reviews of medical records of sequential adult patients with cardiogenic shock. The electronic case record form was collaboratively designed with a core minimum data structure and aligned with Shock Academic Research Consortium definitions. This registry will allow participating health systems to evaluate patient-level data including diagnostic approaches, therapeutics, use of advanced monitoring and circulatory support, processes of care, complications, and in-hospital survival. Participating sites can leverage these data for onsite monitoring of outcomes and benchmarking versus other institutions. The registry was concomitantly designed to provide a high-quality longitudinal research infrastructure for pragmatic randomized trials as well as translational, clinical, and implementation research. An aggregate deidentified data set will be made available to the research community on the American Heart Association's Precision Medicine Platform. On March 31, 2022, the American Heart Association Cardiogenic Shock Registry received its first clinical records. At the time of this submission, 100 centers are participating., Conclusions: The American Heart Association Cardiogenic Shock Registry will serve as a resource using consistent data structure and definitions for the medical and research community to accelerate scientific advancement through shared learning and research resulting in improved quality of care and outcomes of shock patients., Competing Interests: Dr Jessup, S. Costello, Jennifer Hall, M. Isler, C. Rutan are employees of the American Heart Association. A. Aringo is a recent employee of the American Heart Association. David Morrow is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals Inc., Roche, Siemens Healthcare Diagnostics Inc., Softcell Medical Limited, The Medicines Company, Zora Biosciences; as well he has received consulting fees from Abbott, ARCA Biopharma, InCarda, Inflammatix, Merck, Novartis, and Roche Diagnostics. Dr Drakos serves as a consultant for Abbott Laboratories and is receiving research support from Novartis, National Heart Lung and Blood Institute, AHA, US Department of Veterans Affairs Merit and the Nora Eccles Treadwell Foundation. Dr Kilic serves as a speaker/consultant for Abiomed, Abbott, Livanova, and 3ive. Dr Kormos is an employee of Abbott Laboratories. Dr Lindenfeld is receiving research support from AstraZeneca and Volumetrix and consulting fees from Abbott, Alleviant,AstraZeneca, Axon, Boston Scientific, CVRx, Merck, Medtronic, Whiteswell, Vascular Dynamics, VWave. Dr Lombardi is an employee of Getinge.
- Published
- 2024
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20. Therapeutic Options in Ambulatory Advanced Heart Failure: A Moving Target.
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Dunlay SM, Hanff TC, and Drakos SG
- Abstract
Competing Interests: Funding Support and Author Disclosures Dr Hanff has received research support from The International Society for Heart and Lung Transplantation sponsored by Abiomed. Dr Drakos has served as a consultant to Abbott and has received research support from Novartis. Dr Dunlay has reported that she has no relationships relevant to the contents of this paper to disclose.
- Published
- 2024
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21. Reperfusion Injury in Patients With Acute Myocardial Infarction: JACC Scientific Statement.
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Welt FGP, Batchelor W, Spears JR, Penna C, Pagliaro P, Ibanez B, Drakos SG, Dangas G, and Kapur NK
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- Humans, Myocardial Infarction physiopathology, Myocardial Reperfusion methods, ST Elevation Myocardial Infarction physiopathology, ST Elevation Myocardial Infarction therapy, Myocardial Reperfusion Injury physiopathology, Myocardial Reperfusion Injury etiology
- Abstract
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., Competing Interests: Funding Support and Author Disclosures Dr Welt has served as a consultant to Xenter Inc and Faraday Pharmaceuticals. Dr Drakos has served as a consultant to Abbott Laboratories; and has received research support from Novartis. Dr Kapur has received consulting/speaker fees from Abbott, Abiomed, Boston Scientific, Edwards, Getinge, LivaNova, Teleflex, and Zoll; and has received institutional research grants from Abbott, Abiomed, Boston Scientific, Getinge, LivaNova, and Teleflex. All other authors have reported that they have no relationships relevant to contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)
- Published
- 2024
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22. Cardiac Reverse Remodeling Mediated by HeartMate 3 Left Ventricular Assist Device: Comparison to Older Generation Devices.
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Yin MY, Maneta E, Kyriakopoulos CP, Michaels AT, Genovese LD, Indaram MB, Wever-Pinzon O, Singh R, Tseliou E, Taleb I, Nemeh HW, Alharethi R, Tang DG, Goldstein J, Hanff TC, Selzman CH, Cowger J, Kanwar M, Shah P, and Drakos SG
- Abstract
Currently, the fully magnetically levitated left ventricular assist device (LVAD) HeartMate 3 (HM3) is the only commercially available device for advanced heart failure (HF) patients. However, the left ventricular (LV) functional and structural changes following mechanical unloading and circulatory support (MCS) with the HM3 have not been investigated. We compared the reverse remodeling induced by the HM3 to older generation continuous-flow LVADs. Chronic HF patients (n = 405) undergoing MCS with HeartWare Ventricular Assist Device (HVAD, n = 115), HM3 (n = 186), and HeartMate II (HM2, n = 104) at four programs were included. Echocardiograms were obtained preimplant and at 1, 3, 6, and 12 months following LVAD implantation. There were no differences in the postimplant serial LV ejection fraction (LVEF) between the devices. The postimplant LV internal diastolic diameter (LVIDd) was significantly lower for HM2 at 3 and 6 months compared with HVAD and HM3. The proportion of patients achieving "cardiac reverse remodeling responder" status (defined as LVEF improvement to ≥40% and LVIDD ≤5.9 cm) was 11.9%, and was similar between devices. HeartMate 3 appears to result in similar cardiac reverse remodeling as older generation CF-LVADs, suggesting that the fully magnetically levitated device technology could provide an effective platform to further study and promote cardiac reverse remodeling., Competing Interests: S.G.D. serves as a consultant for Abbott Laboratoriesand has received research support from Novartis. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)
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- 2024
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23. Hospital Readmissions in Patients Supported with Durable Centrifugal-Flow Left Ventricular Assist Devices.
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Kyriakopoulos CP, Selzman CH, Giannouchos TV, Mylavarapu R, Sideris K, Elmer A, Vance N, Hanff TC, Kagawa H, Stehlik J, Drakos SG, and Goodwin ML
- Abstract
Background: Centrifugal-flow left ventricular assist devices (CF-LVADs) have improved morbidity and mortality for their recipients. Hospital readmissions remain common, negatively impacting quality of life and survival. We sought to identify risk factors associated with hospital readmissions among patients with CF-LVADs. Methods : Consecutive patients receiving a CF-LVAD between February 2011 and March 2021 were retrospectively evaluated using prospectively maintained institutional databases. Hospital readmissions within three years post-LVAD implantation were dichotomized into heart failure (HF)/LVAD-related or non-HF/LVAD-related readmissions. Multivariable Cox regression models augmented using a machine learning algorithm, the least absolute shrinkage and selection operator (LASSO) method, for variable selection were used to estimate associations between HF/LVAD-related readmissions and pre-, intra- and post-operative clinical variables. Results: A total of 204 CF-LVAD recipients were included, of which 138 (67.7%) had at least one HF/LVAD-related readmission. HF/LVAD-related readmissions accounted for 74.4% (436/586) of total readmissions. The main reasons for HF/LVAD-related readmissions were major bleeding, major infection, HF exacerbation, and neurological dysfunction. Using pre-LVAD variables, HF/LVAD-related readmissions were associated with substance use, previous cardiac surgery, HF duration, pre-LVAD inotrope dependence, percutaneous LVAD/VA-ECMO support, LVAD type, and the left ventricular ejection fraction in multivariable analysis (Harrell's concordance c-statistic; 0.629). After adding intra- and post-operative variables in the multivariable model, LVAD implant hospitalization length of stay was an additional predictor of readmission. Conclusions: Using machine learning-based techniques, we generated models identifying pre-, intra-, and post-operative variables associated with a higher likelihood of rehospitalizations among patients on CF-LVAD support. These models could provide guidance in identifying patients with increased readmission risk for whom clinical strategies to mitigate this risk may further improve LVAD recipient outcomes.
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- 2024
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24. Bridge-to-transplant temporary mechanical circulatory support and risk of allosensitization.
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Sideris K, Lázár-Molnár E, Kyriakopoulos CP, Taleb I, Hurst D, Ugolini S, Selzman CH, Brinker L, Drakos SG, Tonna JE, Geer L, Goodwin ML, Wever-Pinzon O, Hanff TC, Fang JC, Carter S, and Stehlik J
- Subjects
- Humans, Male, Female, Middle Aged, Follow-Up Studies, Adult, Risk Factors, Prognosis, Retrospective Studies, Heart Failure surgery, Heart Failure therapy, Graft Rejection etiology, Heart-Assist Devices, Heart Transplantation, Isoantibodies immunology, Isoantibodies blood
- Abstract
Introduction: Since the 2018 change in the US adult heart allocation policy, more patients are bridged-to-transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization., Methods: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant., Results: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra-aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno-arterial extra-corporeal membrane oxygenation group (n = 9)-p = .039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p = .044), were more likely to be sensitized at baseline - 3 of 9 (33.3%) compared to 2 out of 32 (6.3%) (p = .028) and received more transfusions with red blood cells (6 (66.6%) vs. 8 (25%), p = .02) and platelets (6 (66.6%) vs. 5 (15.6%), p = .002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p = .57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS-p = .028., Conclusions: Our findings suggest that patients bridged-to-transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)
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- 2024
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25. Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.
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Agarwal A, Beddhu S, Boucher R, Rao V, Ramkumar N, Rodan AR, Fang J, Wynne BM, Drakos SG, Hanff T, Cheung AK, and Fang JC
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- Humans, Male, Female, Aged, Pilot Projects, Middle Aged, Natriuresis drug effects, Diuretics pharmacology, Diuretics administration & dosage, Cyclic GMP metabolism, Cyclic GMP urine, Aged, 80 and over, Heart Failure physiopathology, Heart Failure metabolism, Stroke Volume, Furosemide pharmacology, Furosemide administration & dosage, Sodium metabolism, Sodium urine, Natriuretic Peptide, Brain blood, Natriuretic Peptide, Brain metabolism, Kidney metabolism, Kidney physiopathology, Kidney drug effects
- Abstract
The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
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- 2024
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26. Integrating molecular and clinical variables to predict myocardial recovery.
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Visker JR, Brintz BJ, Kyriakopoulos CP, Hillas Y, Taleb I, Badolia R, Shankar TS, Amrute JM, Ling J, Hamouche R, Tseliou E, Navankasattusas S, Wever-Pinzon O, Ducker GS, Holland WL, Summers SA, Koenig SC, Hanff TC, Lavine KJ, Murali S, Bailey S, Alharethi R, Selzman CH, Shah P, Slaughter MS, Kanwar MK, and Drakos SG
- Abstract
Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, and LRRN4CL (ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population.
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- 2024
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27. Author Correction: Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes.
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Maron BA, Wang RS, Shevtsov S, Drakos SG, Arons E, Wever-Pinzon O, Huggins GS, Samokhin AO, Oldham WM, Aguib Y, Yacoub MH, Rowin EJ, Maron BJ, Maron MS, and Loscalzo J
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- 2024
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28. Back to the basics: The need for an etiological classification of chronic heart failure.
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Triposkiadis F, Xanthopoulos A, Drakos SG, Boudoulas KD, Briasoulis A, Skoularigis J, Tsioufis K, Boudoulas H, and Starling RC
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- Humans, Chronic Disease, Death, Sudden, Cardiac, Precision Medicine, Stroke Volume, Heart Failure diagnosis, Heart Failure etiology, Heart Failure therapy
- Abstract
The left ventricular (LV) ejection fraction (LVEF), despite its severe limitations, has had an epicentral role in heart failure (HF) classification, management, and risk stratification for decades. The major argument favoring the LVEF based HF classification has been that it defines groups of patients in which treatment is effective. However, this reasoning has recently collapsed, since medical treatment with neurohormonal inhibitors, has proved beneficial in most HF patients regardless of the LVEF. In addition, there has been compelling evidence, that the LVEF provides poor guidance for device treatment of chronic HF (implantation of cardioverter defibrillator, cardiac resynchronization therapy) since sudden cardiac death may occur and cardiac dyssynchronization may be disastrous in all HF patients. The same holds true for LV assist device implantation, in which the LVEF has been used as a surrogate for LV size. In this review article we update the evidence questioning the use of LVEF-based HF classification and argue that guidance of chronic HF treatment should transition to more contemporary concepts. Specifically, we propose an etiologic chronic HF classification predominantly based on epidemiological data, which will be foundational for further higher resolution phenotyping in the emerging era of precision medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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29. Need for a Cardiogenic Shock Team Collaborative-Promoting a Team-Based Model of Care to Improve Outcomes and Identify Best Practices.
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Senman B, Jentzer JC, Barnett CF, Bartos JA, Berg DD, Chih S, Drakos SG, Dudzinski DM, Elliott A, Gage A, Horowitz JM, Miller PE, Sinha SS, Tehrani BN, Yuriditsky E, Vallabhajosyula S, and Katz JN
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- Humans, Shock, Cardiogenic diagnosis, Shock, Cardiogenic therapy, Shock, Cardiogenic etiology
- Abstract
Cardiogenic shock continues to carry a high mortality rate despite contemporary care, with no breakthrough therapies shown to improve survival over the past few decades. It is a time-sensitive condition that commonly results in cardiovascular complications and multisystem organ failure, necessitating multidisciplinary expertise. Managing patients with cardiogenic shock remains challenging even in well-resourced settings, and an important subgroup of patients may require cardiac replacement therapy. As a result, the idea of leveraging the collective cognitive and procedural proficiencies of multiple providers in a collaborative, team-based approach to care (the "shock team") has been advocated by professional societies and implemented at select high-volume clinical centers. A slowly maturing evidence base has suggested that cardiogenic shock teams may improve patient outcomes. Although several registries exist that are beginning to inform care, particularly around therapeutic strategies of pharmacologic and mechanical circulatory support, none of these are currently focused on the shock team approach, multispecialty partnership, education, or process improvement. We propose the creation of a Cardiogenic Shock Team Collaborative-akin to the successful Pulmonary Embolism Response Team Consortium-with a goal to promote sharing of care protocols, education of stakeholders, and discovery of how process and performance may influence patient outcomes, quality, resource consumption, and costs of care.
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- 2024
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30. Machine Learning Multicenter Risk Model to Predict Right Ventricular Failure After Mechanical Circulatory Support: The STOP-RVF Score.
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Taleb I, Kyriakopoulos CP, Fong R, Ijaz N, Demertzis Z, Sideris K, Wever-Pinzon O, Koliopoulou AG, Bonios MJ, Shad R, Peruri A, Hanff TC, Dranow E, Giannouchos TV, Krauspe E, Zakka C, Tang DG, Nemeh HW, Stehlik J, Fang JC, Selzman CH, Alharethi R, Caine WT, Cowger JA, Hiesinger W, Shah P, and Drakos SG
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- Humans, Male, Middle Aged, Cohort Studies, Prospective Studies, Risk Factors, Female, Adult, Aged, Cardiovascular System, Heart Failure, Heart-Assist Devices adverse effects
- Abstract
Importance: The existing models predicting right ventricular failure (RVF) after durable left ventricular assist device (LVAD) support might be limited, partly due to lack of external validation, marginal predictive power, and absence of intraoperative characteristics., Objective: To derive and validate a risk model to predict RVF after LVAD implantation., Design, Setting, and Participants: This was a hybrid prospective-retrospective multicenter cohort study conducted from April 2008 to July 2019 of patients with advanced heart failure (HF) requiring continuous-flow LVAD. The derivation cohort included patients enrolled at 5 institutions. The external validation cohort included patients enrolled at a sixth institution within the same period. Study data were analyzed October 2022 to August 2023., Exposures: Study participants underwent chronic continuous-flow LVAD support., Main Outcome and Measures: The primary outcome was RVF incidence, defined as the need for RV assist device or intravenous inotropes for greater than 14 days. Bootstrap imputation and adaptive least absolute shrinkage and selection operator variable selection techniques were used to derive a predictive model. An RVF risk calculator (STOP-RVF) was then developed and subsequently externally validated, which can provide personalized quantification of the risk for LVAD candidates. Its predictive accuracy was compared with previously published RVF scores., Results: The derivation cohort included 798 patients (mean [SE] age, 56.1 [13.2] years; 668 male [83.7%]). The external validation cohort included 327 patients. RVF developed in 193 of 798 patients (24.2%) in the derivation cohort and 107 of 327 patients (32.7%) in the validation cohort. Preimplant variables associated with postoperative RVF included nonischemic cardiomyopathy, intra-aortic balloon pump, microaxial percutaneous left ventricular assist device/venoarterial extracorporeal membrane oxygenation, LVAD configuration, Interagency Registry for Mechanically Assisted Circulatory Support profiles 1 to 2, right atrial/pulmonary capillary wedge pressure ratio, use of angiotensin-converting enzyme inhibitors, platelet count, and serum sodium, albumin, and creatinine levels. Inclusion of intraoperative characteristics did not improve model performance. The calculator achieved a C statistic of 0.75 (95% CI, 0.71-0.79) in the derivation cohort and 0.73 (95% CI, 0.67-0.80) in the validation cohort. Cumulative survival was higher in patients composing the low-risk group (estimated <20% RVF risk) compared with those in the higher-risk groups. The STOP-RVF risk calculator exhibited a significantly better performance than commonly used risk scores proposed by Kormos et al (C statistic, 0.58; 95% CI, 0.53-0.63) and Drakos et al (C statistic, 0.62; 95% CI, 0.57-0.67)., Conclusions and Relevance: Implementing routine clinical data, this multicenter cohort study derived and validated the STOP-RVF calculator as a personalized risk assessment tool for the prediction of RVF and RVF-associated all-cause mortality.
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- 2024
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31. Advanced Heart Failure: Therapeutic Options and Challenges in the Evolving Field of Left Ventricular Assist Devices.
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Antonopoulos M, Bonios MJ, Dimopoulos S, Leontiadis E, Gouziouta A, Kogerakis N, Koliopoulou A, Elaiopoulos D, Vlahodimitris I, Chronaki M, Chamogeorgakis T, Drakos SG, and Adamopoulos S
- Abstract
Heart Failure is a chronic and progressively deteriorating syndrome that has reached epidemic proportions worldwide. Improved outcomes have been achieved with novel drugs and devices. However, the number of patients refractory to conventional medical therapy is growing. These advanced heart failure patients suffer from severe symptoms and frequent hospitalizations and have a dismal prognosis, with a significant socioeconomic burden in health care systems. Patients in this group may be eligible for advanced heart failure therapies, including heart transplantation and chronic mechanical circulatory support with left ventricular assist devices (LVADs). Heart transplantation remains the treatment of choice for eligible candidates, but the number of transplants worldwide has reached a plateau and is limited by the shortage of donor organs and prolonged wait times. Therefore, LVADs have emerged as an effective and durable form of therapy, and they are currently being used as a bridge to heart transplant, destination lifetime therapy, and cardiac recovery in selected patients. Although this field is evolving rapidly, LVADs are not free of complications, making appropriate patient selection and management by experienced centers imperative for successful therapy. Here, we review current LVAD technology, indications for durable MCS therapy, and strategies for timely referral to advanced heart failure centers before irreversible end-organ abnormalities.
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- 2024
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32. Timing of Initiation of Extracorporeal Membrane Oxygenation Support and Outcomes Among Patients With Cardiogenic Shock.
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Jentzer JC, Drakos SG, Selzman CH, Owyang C, Teran F, and Tonna JE
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- Adult, Humans, Female, Male, Shock, Cardiogenic diagnosis, Shock, Cardiogenic therapy, Shock, Cardiogenic etiology, Hospital Mortality, Hospitalization, Retrospective Studies, Extracorporeal Membrane Oxygenation, Heart Arrest etiology
- Abstract
Background: Venoarterial extracorporeal membrane oxygenation (ECMO) provides full hemodynamic support for patients with cardiogenic shock, but optimal timing of ECMO initiation remains uncertain. We sought to determine whether earlier initiation of ECMO is associated with improved survival in cardiogenic shock., Methods and Results: We analyzed adult patients with cardiogenic shock who received venoarterial ECMO from the international Extracorporeal Life Support Organization (ELSO) registry from 2009 to 2019, excluding those cannulated following an operation. Multivariable logistic regression evaluated the association between time from admission to ECMO initiation and in-hospital death. Among 8619 patients (median, 56.7 [range, 44.8-65.6] years; 33.5% women), the median duration from admission to ECMO initiation was 14 (5-32) hours. Patients who had ECMO initiated within 24 hours (n=5882 [68.2%]) differed from those who had ECMO initiated after 24 hours, with younger age, more preceding cardiac arrest, and worse acidosis. After multivariable adjustment, patients with ECMO initiated >24 hours after admission had higher risk of in-hospital death (adjusted odds ratio, 1.20 [95% CI, 1.06-1.36]; P =0.004). Each 12-hour increase in the time from admission to ECMO initiation was incrementally associated with higher adjusted in-hospital mortality rate (adjusted odds ratio, 1.06 [95% CI, 1.03-1.10]; P <0.001). The association between longer time to ECMO and worse outcomes appeared stronger in patients with lower shock severity., Conclusions: Longer delays from admission to ECMO initiation were associated with higher a mortality rate in a large-scale, international registry. Our analysis supports optimization of door-to-support time and the avoidance of inappropriately delayed ECMO initiation.
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- 2024
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33. Hypoxia Attenuates Pressure Overload-Induced Heart Failure.
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Froese N, Szaroszyk M, Galuppo P, Visker JR, Werlein C, Korf-Klingebiel M, Berliner D, Reboll MR, Hamouche R, Gegel S, Wang Y, Hofmann W, Tang M, Geffers R, Wende AR, Kühnel MP, Jonigk DD, Hansmann G, Wollert KC, Abel ED, Drakos SG, Bauersachs J, and Riehle C
- Subjects
- Humans, Mice, Animals, Cardiomegaly metabolism, Myocardium metabolism, Hypoxia complications, Ventricular Remodeling, Disease Models, Animal, Heart Failure etiology, Aortic Valve Stenosis
- Abstract
Background: Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support., Methods and Results: We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts., Conclusions: Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.
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- 2024
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34. Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.
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Visker JR, Cluntun AA, Velasco-Silva JN, Eberhardt DR, Shankar TS, Hamouche R, Ling J, Kwak H, Hillas Y, Aist I, Tseliou E, Navankasattusas S, Chaudhuri D, Ducker GS, Drakos SG, and Rutter J
- Abstract
The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (Δψ), and Ca
2+ , increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury.- Published
- 2024
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35. Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury.
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Balderas E, Lee SHJ, Shankar TS, Yin X, Balynas AM, Kyriakopoulos CP, Selzman CH, Drakos SG, and Chaudhuri D
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Mitochondrial ion channels are essential for energy production and cell survival. To avoid depleting the electrochemical gradient used for ATP synthesis, channels so far described in the mitochondrial inner membrane open only briefly, are highly ion-selective, have restricted tissue distributions, or have small currents. Here, we identify a mitochondrial inner membrane conductance that has strikingly different behavior from previously described channels. It is expressed ubiquitously, and transports cations non-selectively, producing a large, up to nanoampere-level, current. The channel does not lead to inner membrane uncoupling during normal physiology because it only becomes active at depolarized voltages. It is inhibited by external Ca
2+ , corresponding to the intermembrane space, as well as amiloride. This large, ubiquitous, non-selective, amiloride-sensitive (LUNA) current appears most active when expression of the mitochondrial calcium uniporter is minimal, such as in the heart. In this organ, we find that LUNA current magnitude increases two- to threefold in multiple mouse models of injury, an effect also seen in cardiac mitochondria from human patients with heart failure with reduced ejection fraction. Taken together, these features lead us to speculate that LUNA current may arise from an essential protein that acts as a transporter under physiological conditions, but becomes a channel under conditions of mitochondrial stress and depolarization.- Published
- 2023
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36. Durable Mechanical Circulatory Support: JACC Scientific Statement.
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Tedford RJ, Leacche M, Lorts A, Drakos SG, Pagani FD, and Cowger J
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- Humans, Quality of Life, Treatment Outcome, Heart Failure, Heart Transplantation, Heart-Assist Devices, Stroke
- Abstract
Despite advances in medical therapy for patients with stage C heart failure (HF), survival for patients with advanced HF is <20% at 5 years. Durable left ventricular assist device (dLVAD) support is an important treatment option for patients with advanced HF. Innovations in dLVAD technology have reduced the risk of several adverse events, including pump thrombosis, stroke, and bleeding. Average patient survival is now similar to that of heart transplantation at 2 years, with 5-year dLVAD survival now approaching 60%. Unfortunately, greater adoption of dLVAD therapy has not been realized due to delayed referral of patients to advanced HF centers, insufficient clinician knowledge of contemporary dLVAD outcomes (including gains in quality of life), and deprioritization of patients with dLVAD support waiting for heart transplantation. Despite these challenges, novel devices are on the horizon of clinical investigation, offering smaller size, permitting less invasive surgical implantation, and eliminating the percutaneous lead for power supply., Competing Interests: Funding Support and Author Disclosures Dr Tedford has consulting relationships with Medtronic, Abbott, Aria CV Inc, Acceleron/Merck, Alleviant, CareDx, Cytokinetics, Itamar, Edwards Lifesciences, Eidos Therapeutics, Lexicon Pharmaceuticals, and Gradient; is a national principal investigator for the RIGHT-FLOW clinical trial (Edwards Lifesciences); has been a steering committee member for Merck, Edwards, and Abbott; is a research advisory board member for Abiomed; and has done hemodynamic core laboratory work for Merck. Dr Leacche has been a consultant for Abbott and Abiomed. Dr Drakos has been a consultant for Pfizer and Abbott; and receives research support from Novartis, the National Institutes of Health, the American Heart Association, Department of Veterans Affairs, and Treadwell Foundation. Dr Cowger is a paid speaker and receives research-related travel funds (2017) from Abbott; is a paid member of the medical advisory board and steering committee for Tendyne and Cephea valves; is a publication committee member for HeartMate 3 clinical trial; and receives institutional support for clinical trials on HeartMate 3 and Tendyne; is a paid speaker for Medtronic, study steering committee member, and national Principal Investigator (2017-present) for DT-PAS and Apogee trials; is on the advisory board, and has received institutional support for clinical trials from Medtronic; is an advisory board member and steering committee member for the Aortix pilot and pivotal trial (2018-present) for Procyrion; has stock options in the Aortix device; is an unpaid steering committee member for the Cordella device used in the Proactive trial (2019-present); has been a speaker for fellow education activities in 2021, 2022, and 2023 for Zoll (etc); has been a steering committee member for ALIVE trial and speaker/educator for BioVentrix; is a steering committee member for Nuwellis for the Restor-HF trial; is a Data Safety Monitoring Board member for BiVACOR; has been a consultant for CorWave; is a Data Safety Monitoring Board Member for Excor Inc; is deputy editor with MCS focus for the Journal of Heart and Lung Transplantation; and is a member of leadership team for STS Intermacs. Dr Pagani has been a noncompensated ad hoc scientific advisor for Abbott, CH Biomedical, FineHeart, and Medtronic; has been a noncompensated medical monitor for Abiomed; is a member of the Data Safety Monitoring Board for Carmat and the National Heart, Lung, and Blood Institute PumpKIN Study; receives grant funding from the NHLBI and the Agency for Healthcare Research and Quality; and receives partial salary support from Blue Cross/Blue Shield of Michigan as Associate Director of the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative. Dr Lorts is a consultant, paid speaker, and PI of research study for Abbott; has received a research grant from Medtronic; has been a speaker, served on the medical advisory board, and has received a research grant from Abiomed; has received a research grant from SynCardia; has been a consultant for Bayer; has been a principal investigator of the Berlin Excor Active Trial; has received a research grant and has been a consultant for Berlin Heart; and has served on the medical advisory board for Optum., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
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- 2023
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37. Ryanodine Receptor Staining Identifies Viable Cardiomyocytes in Human and Rabbit Cardiac Tissue Slices.
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Pfeuffer AM, Küpfer LK, Shankar TS, Drakos SG, Volk T, and Seidel T
- Subjects
- Animals, Humans, Rabbits, Dextrans, Myocardium, Biomimetics, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel
- Abstract
In terms of preserving multicellularity and myocardial function in vitro, the cultivation of beating myocardial slices is an emerging technique in basic and translational cardiac research. It can be used, for example, for drug screening or to study pathomechanisms. Here, we describe staining for viable cardiomyocytes based on the immunofluorescence of ryanodine receptors (RyRs) in human and rabbit myocardial slices. Biomimetic chambers were used for culture and measurements of contractile force. Fixable fluorophore-conjugated dextran, entering cells with a permeable membrane, was used for death staining. RyRs, nuclei and the extracellular matrix, including the t-system, were additionally stained and analyzed by confocal microscopy and image processing. We found the mutual exclusion of the RyR and dextran signals in cultivated slices. T-System density and nucleus size were reduced in RyR-negative/dextran-positive myocytes. The fraction of RyR-positive myocytes and pixels correlated with the contractile force. In RyR-positive/dextran-positive myocytes, we found irregular RyR clusters and SERCA distribution patterns, confirmed by an altered power spectrum. We conclude that RyR immunofluorescence indicates viable cardiomyocytes in vibratome-cut myocardial slices, facilitating the detection and differential structural analysis of living vs. dead or dying myocytes. We suggest the loss of sarcoplasmic reticulum integrity as an early event during cardiomyocyte death.
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- 2023
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38. Left ventricular functional improvement appears to contribute to lower rates of device thrombosis in patients on durable mechanical circulatory support.
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Kyriakopoulos CP, Horne BD, Sideris K, Taleb I, Griffin RJ, Sheffield E, Alharethi R, Hanff TC, Stehlik J, Selzman CH, and Drakos SG
- Subjects
- Humans, Heart, Heart Ventricles, Ventricular Function, Left, Heart Failure, Thrombosis etiology, Heart-Assist Devices adverse effects
- Abstract
By unloading the failing heart, left ventricular (LV) assist devices (LVADs) provide a favorable environment for reversing adverse structural and functional cardiac changes. Prior reports have suggested that an improved native LV function might contribute to the development of LVAD thrombosis. We used the Interagency Registry for Mechanically Assisted Circulatory Support and found that LV functional improvement is associated with a lower risk for device thrombosis. The risk for cerebrovascular accident and transient ischemic attack was comparable across post-LVAD LV function subgroups, while the risk of hemolysis was lower in subgroups of patients with better LV function on LVAD support., Competing Interests: Disclosure statement Dr Drakos serves as a consultant for Abbott Laboratories and Pfizer, and has received research support from Novartis and Merck. Dr Horne is a member of the scientific advisory boards of Lab Me Analytics and Opsis Health, he has received research support from the Intermountain Research and Medical Foundation, AstraZeneca, and the Patient-Centered Outcomes Research Institute (PCORI), he serves as a consultant to Pfizer (monies paid to Intermountain), and he is an inventor of clinical decision tools that Intermountain Healthcare licensed to CareCentra and Alluceo. The remaining authors have nothing to disclose., (Copyright © 2023 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2023
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39. The 2023 International Society for Heart and Lung Transplantation Guidelines for Mechanical Circulatory Support: A 10- Year Update.
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Saeed D, Feldman D, Banayosy AE, Birks E, Blume E, Cowger J, Hayward C, Jorde U, Kremer J, MacGowan G, Maltais S, Maybaum S, Mehra M, Shah KB, Mohacsi P, Schweiger M, Schroeder SE, Shah P, Slepian M, Tops LF, Alvarez P, Arabia F, Aslam S, Benson-Louis L 4th, Birati E, Buchholz HW, Cedars A, Christensen D, Ciarka A, Coglianese E, Cogswell R, Cook J, Copeland J, Costello JG, Drakos SG, Eghtesady P, Elliot T, Estep JD, Eulert-Grehn JJ, Fabrizio R, Garbade J, Gelow J, Guglin M, Hernandez-Montfort J, Horstmanshof D, John R, Kanwar M, Khaliel F, Kim G, Kumar S, Lavee J, Leache M, Leprince P, Lim S, Loforte A, Maly J, Najjar S, Netuka I, Pamboukian SV, Patel SR, Pinney S, Pluym CV, Potapov E, Robson D, Rochlani Y, Russell S, Sandau K, Sandoval E, Sayer G, Schettle S, Schibilsky D, Schlöglhofer T, Schmitto J, Siddique A, Silvestry S, Slaughter MS, Sun B, Takayama H, Tedford R, Teuteberg JJ, Ton VK, Uriel N, Vierecke J, Zimpfer D, and D'Alessandro D
- Subjects
- Humans, Heart, Lung Transplantation, Heart Transplantation, Heart-Assist Devices, Heart Failure surgery
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- 2023
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40. Prospective Phenotyping of Right Ventricle Function Following Intra-Aortic Balloon Pump Counterpulsation in Left Ventricular Assist Device Candidates: Outcomes and Predictors of Response.
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Bonios MJ, Armenis I, Kogerakis N, Thodou A, Fragoulis S, Georgiadou P, Leontiadis E, Chamogeorgakis T, Drakos SG, and Adamopoulos S
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- Humans, Male, Fibrosis, Heart Ventricles diagnostic imaging, Heart Ventricles surgery, Prospective Studies, Retrospective Studies, Adult, Middle Aged, Female, Counterpulsation, Heart Failure surgery, Heart Failure etiology, Heart-Assist Devices, Ventricular Dysfunction, Right etiology
- Abstract
Intra-aortic balloon pump (IABP) may be applied to optimize advanced heart failure (AHF) patients and improve right ventricular (RV) function before left ventricular assist device (LVAD) implantation. We aimed to evaluate the outcome of this intervention and define RV response predictors. Decompensated AHF patients, not eligible for LVAD because of poor RV function, who required IABP for stabilization were enrolled. Echocardiography and invasive hemodynamics were serially applied to determine fulfillment of prespecified "LVAD eligibility RV function" criteria (right atrium pressure [RA] <12 mm Hg, pulmonary artery pulsatility index [PAPi] >2.00, RA/pulmonary capillary wedge pressure [PCWP] <0.67, RV strain <-14.0%). Right ventricular-free wall tissue was harvested to assess interstitial fibrosis. Eighteen patients (12 male), aged 38 ± 14 years were supported with IABP for 55 ± 51 (3-180) days. In 11 (61.1%), RV improved and fulfilled the prespecified criteria, while seven (38.9%) showed no substantial improvement. Histopathology revealed an inverse correlation between RV interstitial fibrosis and functional benefit following IABP: interstitial fibrosis correlated with post-IABP RA ( r = 0.63, p = 0.037), RA/PCWP ( r = 0.87, p = 0.001), PAPi ( r = -0.83, p = 0.003). Conclusively, IABP improves RV function in certain AHF patients facilitating successful LVAD implantation. Right ventricular interstitial fibrosis quantification may be applied to predict response and guide preoperative patient selection and optimization. http://links.lww.com/ASAIO/A995., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)
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- 2023
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41. Use of a Pulmonary Artery Pressure Sensor to Manage Patients With Left Ventricular Assist Devices.
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Thohan V, Abraham J, Burdorf A, Sulemanjee N, Jaski B, Guglin M, Pagani FD, Vidula H, Majure DT, Napier R, Heywood TJ, Cogswell R, Dirckx N, Farrar DJ, and Drakos SG
- Subjects
- Humans, Pulmonary Artery, Quality of Life, Prospective Studies, Heart Failure diagnosis, Heart Failure therapy, Heart-Assist Devices
- Abstract
Background: Hemodynamic-guided management with a pulmonary artery pressure sensor (CardioMEMS) is effective in reducing heart failure hospitalization in patients with chronic heart failure. This study aims to determine the feasibility and clinical utility of the CardioMEMS heart failure system to manage patients supported with left ventricular assist devices (LVADs)., Methods: In this multicenter prospective study, we followed patients with HeartMate II (n=52) or HeartMate 3 (n=49) LVADs and with CardioMEMS PA Sensors and measured pulmonary artery pressure, 6-minute walk distance, quality of life (EQ-5D-5 L scores), and heart failure hospitalization rates through 6 months. Patients were stratified as responders (R) and nonresponders to reductions in pulmonary artery diastolic pressure (PAD)., Results: There were significant reductions in PAD from baseline to 6 months in R (21.5-16.5 mm Hg; P <0.001), compared with an increase in NR (18.0-20.3; P =0.002), and there was a significant increase in 6-minute walk distance among R (266 versus 322 meters; P =0.025) compared with no change in nonresponder. Patients who maintained PAD <20 compared with PAD ≥20 mm Hg for more than half the time throughout the study (averaging 15.6 versus 23.3 mm Hg) had a statistically significant lower rate of heart failure hospitalization (12.0% versus 38.9%; P =0.005)., Conclusions: Patients with LVAD managed with CardioMEMS with a significant reduction in PAD at 6 months showed improvements in 6-minute walk distance. Maintaining PAD <20 mm Hg was associated with fewer heart failure hospitalizations. Hemodynamic-guided management of patients with LVAD with CardioMEMS is feasible and may result in functional and clinical benefits. Prospective evaluation of ambulatory hemodynamic management in patients with LVAD is warranted., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03247829., Competing Interests: Disclosures Dr Thohan is a consultant for Abbott, Impulse Dynamics, and Battelle and participated in Speaker’s Bureau for Pfizer and Boehringer Ingelheim. Dr Abraham is a consultant for Abbott and Abiomed. A. Burdorf participated in Speaker’s Bureau for Abbott. Dr Pagani works for Scientific Advisory Board for FineHeart Inc. Dr Vidula received research grant funding from Abbott and is supported by National Institutes of Health (NIH) grant 1R01HL155201-01. Dr Heywood received Speaker’s Honoraria and research support from Abbott. Dr Cogswell received Speaker’s Honoraria for Abbott. He is third party employed at Medtronic (spouse). N. Dirckx and Dr Farrar are Abbott Employees. Dr Drakos is a consultant for Abbott. He received research support from Novartis, Merck, NIH, American Heart Association, Department of Veterans Affairs, and Nora Eccles Treadwell Foundation. The other authors report no conflicts.
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- 2023
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42. SMYD1a protects the heart from ischemic injury by regulating OPA1-mediated cristae remodeling and supercomplex formation.
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Szulik MW, Valdez S, Walsh M, Davis K, Bia R, Horiuchi E, O'Very S, Laxman AK, Sandaklie-Nicolova L, Eberhardt DR, Durrant JR, Sheikh H, Hickenlooper S, Creed M, Brady C, Miller M, Wang L, Garcia-Llana J, Tracy C, Drakos SG, Funai K, Chaudhuri D, Boudina S, and Franklin S
- Subjects
- Animals, Mice, Cardiomegaly metabolism, Mitochondria metabolism, Muscle, Skeletal metabolism, Myocytes, Cardiac metabolism
- Abstract
SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury., (© 2023. The Author(s).)
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- 2023
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43. The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation.
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Gatsiou A, Tual-Chalot S, Napoli M, Ortega-Gomez A, Regen T, Badolia R, Cesarini V, Garcia-Gonzalez C, Chevre R, Ciliberti G, Silvestre-Roig C, Martini M, Hoffmann J, Hamouche R, Visker JR, Diakos N, Wietelmann A, Silvestris DA, Georgiopoulos G, Moshfegh A, Schneider A, Chen W, Guenther S, Backs J, Kwak S, Selzman CH, Stamatelopoulos K, Rose-John S, Trautwein C, Spyridopoulos I, Braun T, Waisman A, Gallo A, Drakos SG, Dimmeler S, Sperandio M, Soehnlein O, and Stellos K
- Subjects
- Endothelial Cells metabolism, Cytokine Receptor gp130, Endothelium metabolism, Adenosine Deaminase genetics, Adenosine Deaminase metabolism, RNA, Interleukin-6
- Abstract
Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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44. Myocardial Recovery.
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Chrysakis N, Xanthopoulos A, Magouliotis D, Starling RC, Drakos SG, Triposkiadis F, and Skoularigis J
- Abstract
In this paper, the feasibility of myocardial recovery is analyzed through a literature review. First, the phenomena of remodeling and reverse remodeling are analyzed, approached through the physics of elastic bodies, and the terms myocardial depression and myocardial recovery are defined. Continuing, potential biochemical, molecular, and imaging markers of myocardial recovery are reviewed. Then, the work focuses on therapeutic techniques that can facilitate the reverse remodeling of the myocardium. Left ventricular assist device (LVAD) systems are one of the main ways to promote cardiac recovery. The changes that take place in cardiac hypertrophy, extracellular matrix, cell populations and their structural elements, β-receptors, energetics, and several biological processes, are reviewed. The attempt to wean the patients who experienced cardiac recovery from cardiac assist device systems is also discussed. The characteristics of the patients who will benefit from LVAD are presented and the heterogeneity of the studies performed in terms of patient populations included, diagnostic tests performed, and their results are addressed. The experience with cardiac resynchronization therapy (CRT) as another way to promote reverse remodeling is also reviewed. Myocardial recovery is a phenomenon that presents with a continuous spectrum of phenotypes. There is a need for algorithms to screen suitable patients who may benefit and identify specific ways to enhance this phenomenon in order to help combat the heart failure epidemic.
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- 2023
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45. Defining cardiac functional recovery in end-stage heart failure at single-cell resolution.
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Amrute JM, Lai L, Ma P, Koenig AL, Kamimoto K, Bredemeyer A, Shankar TS, Kuppe C, Kadyrov FF, Schulte LJ, Stoutenburg D, Kopecky BJ, Navankasattusas S, Visker J, Morris SA, Kramann R, Leuschner F, Mann DL, Drakos SG, and Lavine KJ
- Abstract
Recovery of cardiac function is the holy grail of heart failure therapy yet is infrequently observed and remains poorly understood. In this study, we performed single-nucleus RNA sequencing from patients with heart failure who recovered left ventricular systolic function after left ventricular assist device implantation, patients who did not recover and non-diseased donors. We identified cell-specific transcriptional signatures of recovery, most prominently in macrophages and fibroblasts. Within these cell types, inflammatory signatures were negative predictors of recovery, and downregulation of RUNX1 was associated with recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of recovery. Cardiac recovery mediated by BET inhibition in mice led to decreased macrophage and fibroblast Runx1 expression and diminished chromatin accessibility within a Runx1 intronic peak and acquisition of human recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery., Competing Interests: Competing interests The authors declare no competing interests.
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- 2023
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46. GJA1-20k Rescues Cx43 Localization and Arrhythmias in Arrhythmogenic Cardiomyopathy.
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Palatinus JA, Valdez S, Taylor L, Whisenant C, Selzman CH, Drakos SG, Ranjan R, Hong T, Saffitz JE, and Shaw RM
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- Humans, Arrhythmias, Cardiac, Myocardium, Gap Junctions, Connexin 43 genetics, Cardiomyopathies genetics
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- 2023
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47. Heart waitlist survival in adults with an intra-aortic balloon pump relative to other Status 2, Status 1, and inotrope Status 3 patients.
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Hanff TC, Browne A, Dickey J, Gaines H, Harhay MO, Goodwin M, Selzman CH, Fang JC, Drakos SG, and Stehlik J
- Subjects
- Humans, Adult, Retrospective Studies, Intra-Aortic Balloon Pumping adverse effects, Heart Failure, Heart-Assist Devices adverse effects, Heart Transplantation
- Abstract
Background: Intra-aortic balloon pump (IABP) utilization has significantly outpaced other Status 2 eligibility criteria for heart transplant. The risk of waitlist mortality of IABP-supported patients relative to other Status 2 listed patients has not been described., Methods: We performed a retrospective analysis of all adult patients listed Status 2 for heart transplantation under the current U.S. allocation policy, using data from the United Network for Organ Sharing. Patients listed status 1 and status 3 for high-dose inotropes were included for reference. Mortality and waitlist decompensation were modeled as a function of time-varying status in cause-specific Cox survival models., Results: We identified 3638 Status 2 listings, of whom 1676 (46%) were Status 2 due to IABP. Relative to patients supported with IABP, status 2 patients with ventricular tachycardia/fibrillation [VT/VF] (HR 4.0, p < .001), right-or-biventricular assist device configurations (HR 2.3, p = .002), or temporary surgical left ventricular assist devices [LVAD] (HR 2.6, p = .003) had greater risk of waitlist mortality and decompensation. Other Status 2 subgroups had mortality comparable to IABP Status 2. Risk of waitlist mortality and decompensation for IABP Status 2 was similar to Status 3 patients listed for high-dose inotropes (HR 1.2, p = .27) and lower than Status 1 patients (HR 0.7, p = .002)., Conclusions: Waitlist mortality varies significantly by Status 2 eligibility criteria and is highest among patients listed for VT/VF, right-or-biVAD configurations, or temporary surgical LVADs. IABP-supported patients were among those with the lowest Status 2 waitlist mortality risk and comparable to Status 3 inotrope-supported patients., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2023
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48. Interrupted Time Series Analysis of Donor Heart Use Before and After the 2018 UNOS Heart Allocation Policy Change.
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Browne A, Gaines H, Alharethi R, Goodwin M, Selzman CH, Fang JC, Drakos SG, Stehlik J, and Hanff TC
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- Adult, Humans, Tissue Donors, Interrupted Time Series Analysis, Policy, Waiting Lists, Heart Transplantation methods, Tissue and Organ Procurement, Heart Failure
- Abstract
Background: Donor heart scarcity remains the fundamental barrier to increased transplant access. We examined whether 2018 United Network for Organ Sharing (UNOS) policy changes have had an impact on donor heart acceptance rates., Methods and Results: We performed an interrupted time series analysis in UNOS to evaluate for abrupt changes in donor heart-acceptance rates associated with the new policy. All adult donor offers were evaluated between 2015 and 2021 (n = 66,654 donors). Donor volumes and transplants increased during this period, but the donor acceptance rate declined significantly from 31% in quarter 3 of 2018 to 26% acceptance in quarter 3 of 2021 (slope change -0.4% per quarter; P < 0.001). We identified 2 trends associated with this decline: (1) a growing number of donors with high-risk features, and (2) decreased acceptance of donors with certain high-risk features in the new allocation system., Conclusions: Heart transplant volumes have increased in recent years as a result of increased donor volumes, but donor heart acceptance rates began decreasing under the current allocation system. Changes in the donor pool and acceptance patterns for certain donor-risk features may explain this shift and warrant further evaluation to maximize donor heart use., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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49. Distinct Transcriptomic and Proteomic Profile Specifies Patients Who Have Heart Failure With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support.
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Drakos SG, Badolia R, Makaju A, Kyriakopoulos CP, Wever-Pinzon O, Tracy CM, Bakhtina A, Bia R, Parnell T, Taleb I, Ramadurai DKA, Navankasattusas S, Dranow E, Hanff TC, Tseliou E, Shankar TS, Visker J, Hamouche R, Stauder EL, Caine WT, Alharethi R, Selzman CH, and Franklin S
- Subjects
- Humans, Transcriptome, Prospective Studies, Phosphopeptides metabolism, Proteomics, Tissue Donors, Myocardium metabolism, Heart Transplantation, Heart Failure genetics, Heart Failure therapy, Heart Failure metabolism, Heart-Assist Devices
- Abstract
Background: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed "responders"). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown., Methods: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders., Results: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions., Conclusions: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.
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- 2023
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50. Acute Decompensated Heart Failure, Volume, and Acetazolamide.
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Kapelios CJ, Drakos SG, and Fang JC
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- Humans, Acetazolamide therapeutic use, Diuretics, Heart Failure drug therapy, Acid-Base Imbalance
- Published
- 2022
- Full Text
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