Berg‐Hansen, Kristoffer

Abstract Aims Cardiogenic shock (CS) is characterized by impaired left ventricular (LV) mechanical performance and adverse remodelling. We evaluated whether transthoracic echocardiography (TTE)-derived modified cardiac efficiency (mCE), integrating stroke work and residual LV volume, is associated with short- and long-term mortality in CS and whether its prognostic value differs by shock aetiology. Methods and results In this retrospective cohort study, consecutive adults admitted with CS to the cardiac intensive care unit at Mayo Clinic (2007–2018) were included if TTE was performed within 24 h. mCE was calculated as (stroke volume × estimated LV end-systolic pressure) divided by LV end-systolic volume and categorized into quartiles. Primary outcome was in-hospital mortality; secondary outcome was 1-year mortality. Multivariable logistic and Cox models adjusted for illness severity, comorbidity burden, shock aetiology, cardiac arrest, vasoactive therapy, and mechanical circulatory support. Among 667 patients, median mCE was 48 mmHg (IQR 32–74). In-hospital mortality was 28% and increased stepwise across decreasing mCE quartiles. The lowest quartile had a 2.5-fold higher adjusted odds of in-hospital death (OR 2.53; 95%CI: 1.49–4.37; P < 0.001). One-year mortality was 41%; the lowest quartile had a two-fold higher adjusted hazard of death (HR 2.05; 95%CI: 1.45–2.89; P < 0.001). Associations were stronger in acute coronary syndrome-related CS (interaction P = 0.035 for in-hospital; P = 0.015 for 1-year). Within the lowest quartile, reduced systolic pressure further amplified mortality risk. Conclusion Early TTE-derived mCE was independently associated with short- and long-term mortality in CS, particularly in acute coronary syndrome-related CS, and captured the interaction between ventricular remodelling and mechanical performance underlying high-risk phenotypes.

Abstract Aims Left ventricular (LV) ventricular-arterial coupling (VAC) refers to the ratio of afterload (effective arterial elastance) to contractility (end-systolic elastance) as an integrated marker of cardiac performance. We sought to determine whether the echocardiographic VAC ratio, defined using the ratio of LV end-systolic volume (LVESV) to stroke volume (SV), predicted mortality in the cardiac intensive care unit (CICU). Methods and results Mayo Clinic CICU patients from 2007 and 2018 were included. Ventricular-arterial coupling ratio was calculated as the Teichholz LVESV divided by the SV calculated from LV outflow tract Doppler. The primary outcome was in-hospital mortality and the secondary outcome was all-cause 1-year mortality. A total of 4685 patients were included with a median age of 69 (58, 79) years (37.2% females), with acute coronary syndrome in 54.9% and heart failure in 49.0%. A higher VAC ratio was associated with greater severity of illness, worse echocardiographic findings, and more use of critical care therapies. A total of 329 (7%) patients died during hospitalization. Patients with a higher VAC ratio had higher in-hospital mortality overall and in each admission diagnosis subgroup. After multivariable adjustment, patients with a VAC ratio >2 were at higher risk of in-hospital mortality (adjusted odds ratio 1.63, 95% confidence interval 1.17–2.28, P = 0.010). One-year mortality was higher for patients with a higher VAC ratio, especially VAC >2. Conclusion Ventricular-arterial uncoupling was associated with worse outcomes in an unselected CICU cohort. The echocardiographic VAC ratio is a simple non-invasive bedside measure that can be used for risk prediction in the CICU.

Abstract Aims Cardiogenic shock (CS) is a critical manifestation of severe cardiac dysfunction, necessitating precise evaluation of left ventricular (LV) function by transthoracic echocardiography. The prognostic value of global longitudinal strain (GLS) has not been examined in patients with CS. Therefore, we aimed to assess the prognostic significance of GLS in patients with CS. Methods and results This was a retrospective study of patients with CS from 2007 to 2018 who had a transthoracic echocardiography performed within 24 h of admission. GLS was measured, and conventional parameters were obtained. LV dysfunction was categorized by GLS: > 9.7% (Quartile 1), 7.0% < GLS ≤ 9.7% (Quartile 2), 5.0% < GLS ≤ 7.0% (Quartile 3), and ≤5.0% (Quartile 4). Outcomes included in-hospital and 1-year all-cause mortality. Among 623 patients with CS with the median LVEF of 31% [inter-quartile range (IQR): 24–41%] and the median GLS of 7.0% (IQR: 5.0–9.7%), in-hospital mortality was 29%. Mortality increased across GLS quartiles: Quartile 1: 17%; Quartile 2: 22%; Quartile 3: 35%; and Quartile 4: 42%. GLS remained the only independent echocardiographic predictor of in-hospital mortality after adjusting for clinical covariates (adjusted odds ratio: 1.23 per 1% decrease, 95% confidence interval: 1.04–1.46, P = 0.015). GLS independently predicted 1-year all-cause mortality (P < 0.001). The prognostic value of GLS was superior in cases with acute coronary syndrome. A classification and regression tree analysis identified GLS as the most important echocardiographic variable for predicting in-hospital mortality. Conclusion GLS independently predicted short- and long-term mortality in patients with CS, surpassing conventional echocardiographic parameters in prognostic value, supporting its potential role in risk stratification in this population.

Background: Ventricular-arterial coupling (VAC) refers to the ratio of afterload (effective arterial elastance) to contractility (left ventricular (LV) end-systolic elastance) as an integrated marker of cardiac performance. Echocardiography might be used to evaluate VAC through a simple time-efficient bedside evaluation. Hypothesis: VAC is useful for mortality risk stratification in an unselected cardiac intensive care unit (CICU) cohort. Aims: We sought to determine whether the VAC ratio, defined using the ratio of LV end-systolic volume (LVESV) to stroke volume (SV), predicted mortality in the CICU. Methods: Consecutive patients admitted to the Mayo Clinic CICU between 2007 and 2018 were included. The simplified VAC ratio was calculated as the LVESV calculated from 2D measurements using the Teichholz formula divided by the SV calculated from the LV outflow tract pulsed wave Doppler measurement, with values >1 reflecting ventricular-arterial uncoupling. The main outcome was all-cause in-hospital mortality. Results: We included 4685 patients with a median age of 69 (58-79) years; 37% were females. The median VAC ratio was 1.0 (0.7 to 1.8) and 21% of patients had a VAC ratio >2. Most clinical and echocardiographic variables differed in patients with higher VAC ratio, reflecting greater severity of illness with worse cardiac systolic and diastolic function. A total of 329 (7.0%) patients died during hospitalization. An incremental association was observed between a higher VAC and in-hospital mortality (unadjusted OR 1.22, 95% CI 1.16-1.29, p<0.001). Patients with a VAC ratio >1 (unadjusted OR 2.85, 95% CI 2.22-3.69, p <0.001) and especially those with VAC ratio >2 (unadjusted OR 4.28, 95% CI 3.24-5.69, p<0.001) had higher in-hospital mortality overall and in each admission diagnosis subgroup of interest ( Figure ). After multivariable adjustment, patients with a VAC ratio >2 remained at higher risk of in-hospital mortality (adjusted OR 1.63, 95% CI 1.17-2.28, p = 0.01). Conclusions: Ventricular-arterial uncoupling was associated with worse outcomes in an unselected CICU cohort. The echocardiographic VAC ratio is a simple non-invasive bedside measure that can be used for risk prediction in the CICU.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2D). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2D with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2D and HFpEF remain unknown. METHODS: A total of 24 patients with T2D and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P <0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, –2 to 0) and at peak exercise by 5 mm Hg (95% CI, –9 to –1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise ( P <0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2D and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2D and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT05236335.

BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction. METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents. RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1–0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, −2 mm Hg [95% CI, −4 to −1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (−3 mm Hg [95% CI, −5 to −1] ) and higher mean CO (0.5 L/min [95% CI, 0.1–0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, −98 ng/L [95% CI, −185 to −23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P =0.01), and lower left atrial and ventricular volumes. CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05161650.