Circulatory support escalation is often required during cardiogenic shock (CS) treatment. Currently, no large-scale data is available to inform how escalation strategies integrate in contemporary CS management and affect...Circulatory support escalation is often required during cardiogenic shock (CS) treatment. Currently, no large-scale data is available to inform how escalation strategies integrate in contemporary CS management and affect outcomes. We assessed the frequency, outcomes, and prognostic implications of escalation from a retrospective international registry of CS patients from 4 cardiac intensive care units. Escalation was defined as any incremental change in the circulatory support strategy after an initial bundle of care was established for at least 4 hours. Among 602 consecutive CS patients, escalation was required in 30%. Patients were escalated to inotropes/vasopressors (36%), IABP (39%), Impella (14%) or V-A ECMO (11%). Escalation was associated with a higher hospital mortality rate (43% vs 21%; <0.001; OR 3.42; 95% CI 2.21-3.35) and a greater transition to heart replacement therapies (23% vs 5%; <0.001; OR 6.01; 95% CI 3.31-11.27), when adjusted for age, sex, chronic kidney disease, markers of CS severity on admission, CS etiology, and admission source. Escalation was associated with a higher risk of complications including acute kidney injury, major bleeding, and stroke. These outcomes occurred more frequently with high-profile mechanical circulatory support (Impella, V-A ECMO). Complications mediated 24% (95%CI 9-40%) of the association between escalation and hospital death. Escalated patients were successfully discharged alive in 42%. Age, SCAI B to C stage at escalation, TAPSE at escalation, and mean urinary output ≥1 mL/kg/hour in the 6 hours preceding escalation were independently associated with successful escalation when adjusted for sex, chronic kidney disease, and markers of CS severity on admission and at time of escalation. Circulatory support escalation is prevalent in patients treated for CS. Escalation is associated with a higher risk of hospital death, complications and transition to HRT, consistently with the intrinsically higher risk profile and expected trajectory of escalated patients. However, outcomes may differ according to the specific escalation strategy. Resorting to escalation in younger patients, in less severe CS stages, when the right ventricular function and urinary output are still preserved is associated with a higher chance of subsequent survival.
Gupta DK, Stevenson LW, Garner EM
… +6 more, Maulion C, Nian H, Wright PR, Turcu AF, Wei S, Brown NJ
Circ Heart Fail
· 2026 Jun · PMID 42028604
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BACKGROUND: Symptomatic hypotension can limit sacubitril/valsartan therapy. Neprilysin inhibition may augment vasodilators, such as bradykinin. We hypothesized that bradykinin contributes to blood pressure (BP) lowering...BACKGROUND: Symptomatic hypotension can limit sacubitril/valsartan therapy. Neprilysin inhibition may augment vasodilators, such as bradykinin. We hypothesized that bradykinin contributes to blood pressure (BP) lowering with sacubitril/valsartan in stable ambulatory patients with heart failure and reduced ejection fraction <50%. METHODS: In a randomized, double-blind crossover trial, participants received intravenous infusion of the bradykinin B2 receptor inhibitor icatibant and a matching placebo for 6 hours following sacubitril/valsartan dosing at acute initiation (n=36) and after 8 weeks of chronic therapy (n=30). The primary end point was maximal change in mean arterial pressure (MAP). Plasma natriuretic peptides, urine cyclic GMP, urine volume, sodium excretion, renal plasma flow, and renovascular resistance were measured. RESULTS: The first dose of sacubitril/valsartan (50 mg) significantly lowered MAP by a mean maximum of ≈10 mm Hg, which was similar during icatibant and placebo. Within 6 hours after the first sacubitril/valsartan dose, plasma ANP (atrial natriuretic peptide [1-28]) and urine cGMP/creatinine increased significantly, whereas B-type NP (1-32) and NT-proBNP (N-terminal pro B-type natriuretic peptide) did not. Icatibant partially blunted the rise in urine cGMP/creatinine, but did not affect other parameters. After 8 weeks of sacubitril/valsartan titrated to maximally tolerated doses, baseline ANP (1-28) remained increased, and baseline MAP and NT-proBNP were decreased compared with before sacubitril/valsartan initiation. MAP decreased further after dose administration of sacubitril/valsartan, and the mean maximal reduction in MAP was significantly attenuated during icatibant compared with placebo (9 versus 12 mm Hg; =0.013). Icatibant also decreased renal plasma flow and increased renal vascular resistance after chronic dosing, without affecting heart rate, urine volume, urine sodium, cGMP/creatinine, or natriuretic peptides. CONCLUSIONS: BP lowering with sacubitril/valsartan occurs with both acute and chronic dosing. ANP (1-28) appears to mediate the initial BP reduction, whereas bradykinin contributes to BP lowering after dosing during chronic therapy. Clarifying these mechanisms may inform clinical management to optimize the benefit of this important heart failure and reduced ejection fraction therapy. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04113109.
Breathett K, Knapp SM, Bedrick EJ
… +5 more, Tedford RJ, Dunlay SM, Mohammed SF, Colvin MM, Daly R
Circ Heart Fail
· 2026 Apr · PMID 42013188
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BACKGROUND: Among accepted US heart organs, listing centers accept organ offers earliest for White women, followed by Black women, White men, and Black men. Understanding the relationships of center- and geographic-level...BACKGROUND: Among accepted US heart organs, listing centers accept organ offers earliest for White women, followed by Black women, White men, and Black men. Understanding the relationships of center- and geographic-level decisions is necessary to understand waitlist disparities. We sought to determine whether listing center and geography are associated with the first heart organ acceptance by candidate race, since race demographics vary regionally across the United States. METHODS: Using the United Network for Organ Sharing data sets, we identified first organ offers for Black and White candidates listed for heart transplant (October 18, 2018 to September 30, 2024) and compared models with and without listing center effects adjusted for candidate-, donor-, and offer-level variables. RESULTS: Among 20 668 candidates (31.6% Black, 68.4% White, 26.5% women), the adjusted odds of first offer acceptance were lower for Black candidates compared with White candidates (odds ratio, 0.84 [95% CI, 0.76-0.94]; =0.001) when listing center was not included in the model; but after adjusting for listing center effects, odds were similar by race (odds ratio, 0.98 [95% CI, 0.88-1.10]; =0.78). There were no clear geographic patterns by center, but centers with lower proportions of Black candidates had higher acceptance rates. CONCLUSIONS: Variability in overall acceptance rate among listing centers explains the lower first offer acceptance for Black compared with White heart candidates. Baseline acceptance rates were linked to the center-level proportion of Black candidates but not geography. Investigation of strategies to systemically improve early acceptance of good heart organs may reduce Black and White disparities in wait time duration.
BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) outflow tract obstruction, which increases afterload and chronically activates the Anrep response, a compensatory (afte...BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) outflow tract obstruction, which increases afterload and chronically activates the Anrep response, a compensatory (afterload-driven) state of hyperdynamic systole, prolonged systolic ejection time, and increased myocardial workload. We investigated whether the myosin inhibitor mavacamten reverses this state, comparing its effects to the anatomic relief achieved by alcohol septal ablation. METHODS: Thirty-six patients with symptomatic oHCM were treated with mavacamten. Of these, 29 who achieved a resting LV outflow tract gradient <50 mm Hg at 3 months (responders) underwent echocardiography-derived pressure-volume analysis before and after therapy. For comparison, a separate cohort of 13 patients with oHCM underwent identical pressure-volume analysis before and 3 months post-alcohol septal ablation. Anrep-related indices were quantified: afterload (LV end-systolic pressure [LVESP] and effective arterial elastance [Ea]), contractility (end-systolic elastance [Ees] and end-systolic volume at 150 mm Hg [ESV]), and systolic ejection time. Myocardial workload (stroke work, potential energy, and pressure-volume area) and diastolic function (LV end-diastolic pressure [LVEDP], end-diastolic volume [EDV], and volume at an LVEDP of 15 mm Hg [V]) were also assessed. RESULTS: At baseline, all patients showed chronic activation of the Anrep response: elevated afterload (high LVESP and Ea), hypercontractility (high Ees and low ESV), and prolonged systolic ejection time, accompanied by increased mechanical workload (elevated stroke work, potential energy, and pressure-volume area). After 3 months, both mavacamten responders and alcohol septal ablation responders showed comparable ventricular unloading: reductions in afterload and contractility, shortened systolic ejection time, and decreased myocardial workload, all while preserving stroke volume. Diastolic indices improved (increased EDV and V, and decreased LVEDP). Conversely, in mavacamten nonresponders (persistent LV outflow tract gradient ≥50 mm Hg at 3 months), Anrep-related indices and myocardial workload did not change. CONCLUSIONS: In oHCM, chronic Anrep activation maintains cardiac output against elevated afterload at high energetic cost. Our finding that mavacamten and alcohol septal ablation produce comparable hemodynamic corrections establishes the reversal of this afterload-driven state as a central mechanistic target of therapy in oHCM.
Patel ZA, Ospina MK, Mittelstaedt R
… +18 more, Peller J, Samani S, Marchell C, Ohlrich K, Gunn B, Varrone M, Dodson K, Bull L, Jennifer H, Gregoski MJ, Silkowski M, Esposito M, Tedford RJ, McMurray JD, Witer L, Kilic A, Houston BA, Carnicelli AP
Circ Heart Fail
· 2026 Apr · PMID 41969084
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BACKGROUND: Temporary mechanical support (tMCS) devices are often placed for cardiogenic shock (CS) at regional referral centers (RRCs) before transfer to CS hub centers (HCs). We sought to assess for differences in devi...BACKGROUND: Temporary mechanical support (tMCS) devices are often placed for cardiogenic shock (CS) at regional referral centers (RRCs) before transfer to CS hub centers (HCs). We sought to assess for differences in device-related adverse events (DRAEs) and outcomes between patients with tMCS placement for CS at an RRC before transfer to an HC compared with initial tMCS device placement at an HC. METHODS: All patients with tMCS for CS from August 2021 to August 2024 at a single center were stratified by location of initial tMCS device placement. Baseline characteristics, adjudicated DRAEs, mortality, and unfavorable outcomes (death before discharge, heart transplant, or durable left ventricular assist device) were compared. DRAE rates were calculated as events/patient-week on tMCS. Multivariable logistic regression was performed to account for baseline differences. Kaplan-Meier and Cox regression were performed to compare mortality. RESULTS: A total of 398 patients (77% HC-implanted, 23% RRC-implanted) were identified. RRC-implanted patients more commonly experienced cardiac arrest and had more advanced CS. DRAE prevalence was higher in RRC-implanted patients (any DRAE in 64% versus 33%), including bleeding (29% versus 12%), hemolysis (30% versus 18%), and vascular injury (22% versus 5%); <0.05 for all. The overall DRAE rate was 0.33 events/patient-week and was numerically higher among RRC-implanted than HC-implanted patients (0.65 versus 0.24 events/patient-week). RRC-implanted patients had higher unadjusted in-hospital mortality (odds ratio, 2.52 [95% CI, 1.52-4.18]; <0.001) and unfavorable outcomes (odds ratio, 2.55 [95% CI, 1.52-4.27]; <0.001). This finding was significant after adjustment for baseline differences, but not after adjustment for CS severity and cardiac arrest (in-hospital mortality odds ratio, 1.72 [95% CI, 0.95-3.12]; =0.07; unfavorable outcome odds ratio, 1.60 [95% CI, 0.87-2.92]; =0.13). CONCLUSIONS: Initial tMCS placement for CS at an RRC with transfer to an HC is associated with a higher DRAE prevalence and worse outcomes than initial tMCS placement at a CS HC. The higher mortality in RRC-implanted patients may be due to greater CS severity.
BACKGROUND: Guideline-directed medical therapy (GDMT) is central to the care of heart failure with reduced ejection fraction, yet no standard metric exists to quantify its implementation. METHODS: We conducted a scoping...BACKGROUND: Guideline-directed medical therapy (GDMT) is central to the care of heart failure with reduced ejection fraction, yet no standard metric exists to quantify its implementation. METHODS: We conducted a scoping review to catalogue and characterize all published heart failure GDMT scores and summarize their application in clinical studies. We searched MEDLINE, Embase, the Central Register of Controlled Trials (CENTRAL), and Web of Science from October 2020 to March 2025. RESULTS: From 544 records, we included 26 studies (19 cohorts, 7 randomized trials; 354 281 patients). Of the 26 studies, 25 (96%) utilized different scores, including 13 adaptations of the Optimal Medical Therapy score originally proposed by the Heart Failure Collaboratory in 2020. All counted RASi (renin-angiotensin system inhibitors), beta-blockers, and mineralocorticoid receptor antagonists; 18 separated sacubitril-valsartan from other RASi, 15 incorporated sodium-glucose cotransporter-2 inhibitors, and 8 captured additional drug classes. Only 2 scores were adjusted for contraindications or intolerance. Across studies, GDMT scores served as a descriptor (N=14), covariate (N=11), predictor of future outcomes (N=12), and end point for GDMT optimization interventions (N=8). CONCLUSIONS: Multiple, disparate scores have been developed to quantify heart failure with reduced ejection fraction GDMT optimization, undermining the original intent. Key gaps in scores include heterogeneous weighting of drug classes and doses, minimal incorporation of intolerance to identify maximum-tolerated therapy, and heterogeneous incorporation of therapies beyond quadruple therapy. Future studies should focus on clear reporting and justification of the selected GDMT score, and the use of existing scores that incorporate relevant contemporary agents.
Physician compensation models in the United States are diverse, shaped by practice settings, specialties, and institutional factors. A notable shift in academic medical centers has been the transition from salary-based c...Physician compensation models in the United States are diverse, shaped by practice settings, specialties, and institutional factors. A notable shift in academic medical centers has been the transition from salary-based compensation to relative value unit (RVU)-based models. While this shift may align compensation with clinical productivity and facilitate budgetary planning, it has profound implications for physician satisfaction, burnout, and clinical practice, particularly in primarily cognitive/nonprocedural based specialties like advanced heart failure (AHF). This article explores the benefits and drawbacks of the RVU model, with a focus on its application in AHF care. The RVU system, designed to measure physician work, practice expenses, and malpractice risk, is associated with efficiency incentives but also risks prioritizing quantity over quality, especially in multidisciplinary fields like AHF. Patients with AHF often have multiple comorbidities requiring extensive management and care coordination across multiple subspecialties, outside of the work effort captured by a clinic visit. The RVU model may undervalue the comprehensive, longitudinal care AHF specialists provide. Through a detailed examination of inpatient and outpatient AHF management, we argue that the RVU model may inadequately capture the full scope of AHF care, which may contribute to systemic challenges, physician burnout, and a decline in interest in AHF subspecialty training. Hence, we call for a reconsideration of AHF physician compensation and productivity measurement that more accurately reflects the full breadth of comprehensive AHF care.
BACKGROUND: Although adeno-associated virus (AAV) gene-replacement therapy is a potentially transformative therapy for severe genetic diseases, its cardiac immunotoxicity may challenge broad clinical use. METHODS: Medica...BACKGROUND: Although adeno-associated virus (AAV) gene-replacement therapy is a potentially transformative therapy for severe genetic diseases, its cardiac immunotoxicity may challenge broad clinical use. METHODS: Medical Literature Analysis and Retrieval System Online, Embase, and PubMed databases were searched from January 2005 to March 2025. Studies including patients treated with AAV-replacement therapy were deemed eligible. Prespecified items (type of vector, dose, timing, and clinical significance of the adverse event) were extracted by 2 independent observers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman (International Prospective Register of Systematic Reviews [PROSPERO]. VigiBase and the US Food and Drug Administration Adverse Event Reporting System were searched for the occurrence of myocarditis with commercially available AAV-replacement drugs. RESULTS: Eighty studies including 1939 human patients were analyzed. A total of 734 adverse events were reported over 2122 patient-years of pooled observation. Seventy-one cases of myocarditis were identified. The pooled incidence rate per 100 patient-years was 8.6 (95% CI, 5.8-10.7; =63.2%). Events occurred in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and X-linked myotubular myopathy, with recombinant AAVs and adeno-associated virus serotype 8. All received an intravenous dose >10 vector genomes per kilogram body weight. Myocardial injury peaked in week 1 after injection (90% [95% CI, 85.7%-96.2%]; =43.2%), whereas myocarditis occurred mostly after week 2 (55% [95% CI, 48.7%-65.2%]; =33.1%), with no cases after the first month. Most myocarditis/myocardial injury did not have a relevant clinical impact (62, 87%), with only 8 (12%) cases having transient left ventricular dysfunction. The latter recovered during the follow-up. The only death occurred in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction. Myocarditis occurred in relation to delandistrogene moxeparvovec (1/16 [6%]) and onasemnogene abeparvovec (14/217 [6%]) in the Food and Drug Administration Adverse Event Reporting System and VigiBase. CONCLUSIONS: Immune-mediated myocarditis/myocardial injury after systemic AAV gene therapy occurred in <10 per 100 patient-years (peaking at weeks 1-3) and was usually clinically mild, with a minority showing transient dysfunction. All events followed intravenous doses >1×10 vector genomes per kilogram body weight, clustered in neuromuscular programs, and were associated with certain recombinant capsids/serotypes. These data support intensive early cardiac monitoring, cautious dose selection, and delivery strategies to minimize systemic exposure. REGISTRATION:URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251046546).