Borlaug, Barry A.

Introduction: Anemia is associated with increased mortality, cardiovascular events, and decreased quality of life in patients with heart failure with preserved ejection fraction (HFpEF). Iron deficiency may contribute to disease severity independent of effects on red cell mass. The hemodynamic consequences of anemia and iron deficiency in HFpEF remain unclear. Methods: We analyzed a cohort of 313 consecutive subjects with HFpEF diagnosed by invasive hemodynamic assessment, and compared echocardiographic and hemodynamic characteristics of anemic versus non-anemic subjects. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Iron deficiency was defined as ferritin <100 ug/L. Results: Compared to patients without anemia, HFpEF patients with anemia displayed higher NT-proBNP, elevated pulmonary artery (PA) pressures at rest and at peak exercise, and lower oxygen consumption at peak exercise (Table). There was no difference in pulmonary capillary wedge pressure (PCWP). Patients with iron deficiency were more likely to be women. At rest, patients with iron deficiency displayed lower left ventricular (LV) mass, higher resting SVRI and lower cardiac index (CI), but there were not significant differences with exercise. Conclusions: Anemia in HFpEF is associated with greater evidence of congestion and more severe pulmonary hypertension, contributing to reduced exercise capacity. Iron deficiency in HFpEF is more common in women and associated with lower cardiac output at rest, but hemodynamics are otherwise similar. Further study is required to understand the mechanisms by which anemia and iron deficiency influence cardiac function and outcomes in HFpEF.

Introduction: Cardiovascular disease remains the leading cause of morbidity and mortality in patients with amyloid light chain (AL) amyloidosis. Current prognostic evaluation in AL cardiomyopathy (AL-CM) largely relies upon disparate proxy measurements to assess mortality. With respect to observed myocardial volume changes between systole and diastole, we describe a single measurement derived from cardiac MRI (CMR) to assess mortality of AL-CM. Methods: A cohort of 129 consecutive patients with AL-CM undergoing CMR with amyloid protocol from the years 2001 - 1997 was reviewed. Myocardial volume change at end systole and end diastole was assessed by disc summation with CMR. The myocardial function index (MFI) was calculated by consolidating blood pool and myocardial volume measures as confluent components of myocardial function utilizing operator tracings. The association of MFI and death was assessed with adjusted hazard ratios (HR) derived by a Cox model. Results: Data at time of CMR was reviewed. The mean age was 60 ±10; 68% subjects were female. Median survival from CMR was 47 months. Mean LVEF was assessed by echocardiography to be 55% ± 12. Mean calculated MFI was 19.8% ±7. Univariate analysis suggested MFI is strongly associated with death (HR 0.004; 95%CI 0.00002-0.0838; p = 0.0003). A multivariate analysis re-demonstrated the strong predictive value of MFI when controlled for age (HR 0.006; 95%CI 0.00003 - 0.1156; p = 0.0006). Conclusion: MFI strongly correlates with mortality in AL-CM. In contrast to previously described assessments of ventricular function (extracellular volume imaging, myocardial perfusion imaging, and myocardial contraction fraction), MFI is easily derived from CMR and considers blood pool and myocardial volumes as confluent components of myocardial function. Further studies are needed to assess MFI amongst patients with varying etiologies of heart failure.

Background: There are no specific treatments for patients with HFpEF and pulmonary hypertension (PH-HFpEF). Increased central and pulmonary venous pressures (CVP, PCWP) are believed to contribute importantly to symptoms at rest and during exercise. Levosimendan (LEVO), a calcium sensitizer/KATP channel activator, is known to reduce CVP and PCWP in patients with reduced LVEF. We hypothesized that LEVO would have similar effects in PH-HFpEF. Methods: 44 PH-HFpEF patients with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II or III symptoms underwent hemodynamic measurements at rest, during passive leg raise (PLR) and during supine bicycle exercise for 3 minutes at 25 Watts (EX) at baseline and following a continuous 24-hour infusion of LEVO (0.1 μg/kg/min) as part of a multicenter clinical trial. Measurements included CVP, mPAP, PCWP, mean arterial pressure (MAP) and cardiac index (CI); pulmonary and systemic vascular resistances (PVR, SVR) were calculated. Hemodynamic tracings were analyzed in a core lab blinded to condition and timepoint. The primary endpoint was the change of PCWP at 25 Watts. Results: Patients averaged 69±9.1 years old, 61.4% were female and had a mPAP of 41.0±9.3 mmHg at rest. LEVO decreased mPAP at rest, CVP and PCWP at rest and EX, and increased CI with EX; there were no significant changes in mPAP, PVR or SVR. Resting and EX hemodynamic data are summarized in the Table. 37 of the 44 patients (84%) were considered hemodynamic “responders” based on a pre-specified ≥4 mmHg decrease of EX PCWP. Conclusions: In patients with PH-HFpEF, a 24 hour levosimendan infusion at 0.1 μg/kg/min decreased CVP and PCWP and increased CI at rest and EX, despite no significant effect on SVR or PVR. A majority of patients exhibited acute hemodynamic response. While the underlying mechanism(s) remain to be clarified, LEVO’s effects on CVP and PCWP warrant further study of this drug as a treatment for PH-HFpEF.

Introduction: A low cardiac power output (CPO), measured invasively, identifies critically ill patients at increased risk of mortality. CPO can also be measured non-invasively with transthoracic echocardiography (TTE), although prognostic data in critically ill patients is not available. Hypothesis: Reduced CPO measured by TTE is associated with increased hospital mortality in cardiac intensive care unit (CICU) patients. Methods: Using a database of CICU patients admitted between 2007 and 2018, we identified patients with TTE within one day (before or after) of CICU admission who had data necessary for calculation of CPO. Multivariable logistic regression determined the relationship between CPO and adjusted hospital mortality. Results: We included 5,585 patients with a mean age of 68.3±14.8 years, including 36.7% females. Admission diagnoses included acute coronary syndrome (ACS) in 57%, heart failure (HF) in 50%, cardiac arrest (CA) in 12%, and cardiogenic shock (CS) in 13%. The mean left ventricular ejection fraction (LVEF) was 47±16%, and the mean CPO was 1.0±0.4 W. CPO was inversely associated with the risk of hospital mortality (Figure A), including among patients with ACS, HF, and CS (Figure B). On multivariable analysis, lower CPO was associated with higher hospital mortality (OR 0.96 per 0.1 W, 95% CI 0.0.93-0.99, p=0.03). Hospital mortality was highest in patients with low CPO coupled with reduced LVEF, increased vasopressor requirements, or higher admission lactate. Hospital mortality was higher among patients with a CPO <0.6 W (adjusted OR 1.57, 95% CI 1.13-2.19, p = 0.007), particularly in the presence of admission lactate level >4 mmol/L (50.9%). Conclusions: Echocardiographic CPO was inversely associated with hospital mortality in CICU patients, particularly among patients with increased lactate and vasopressor requirements. Routine measurement of CPO provides important information beyond LVEF and should be considered in CICU patients.

Introduction: Coronary microvascular dysfunction (CMD) is prevalent in symptomatic patients with no obstructive coronary artery disease. We postulated that exercise capacity and cardiac output augmentation in response to exercise are linked to coronary microvascular function in this patient population. Methods: Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease on angiography (<50% stenosis), and normal left ventricular ejection fraction (>50%) who underwent concurrent clinically indicated coronary reactivity testing and invasive cardiopulmonary exercise testing (CPEX) were included. Microvascular function was assessed by coronary flow reserve (CFR; hyperemic/resting flow) in response to intracoronary adenosine injection. Cardiac output (CO) was calculated at rest and peak exercise using Fick’s formula. CO limitation was defined as a measured (peak CO - resting CO) <80% than the expected [6*absolute ΔVO 2 (Peak VO 2 -Rest VO 2 ) increase in CO in L/min]. The relationship between CFR, maximal exercise capacity, and CO augmentation at peak exercise was explored. Results: Patients were 56.6±10.5 years old and 73% were females. CFR had a modest positive correlation with measured increase in CO (r=0.42; P=0.003) ( Fig 1A ), and with maximal ergometric exercise capacity [in Watts/Kg] (Pearson’s r=0.33, P=0.02) ( Fig 1B ). Patients with, vs. without impaired cardiac limitations during exercise, had significantly lower CFR levels (2.6±0.5 vs 3.1±0.7; P=0.01) ( Fig 2 ). Conclusion: Impaired coronary microvascular function is associated with lower peak exercise capacity and reduced cardiac output augmentation in response to exercise, underscoring the functional ramification of CMD in symptomatic patients.

Introduction: The mechanisms linking obesity to increased mortality in patients with coronavirus-disease 2019 (COVID-19) are unclear. Hypothesis: We hypothesised that obesity would be associated with adverse right ventricular (RV) remodelling and function which might be further exacerbated by COVID-19 associated increases in RV afterload/demand. Methods: We used echocardiography and computed tomography to establish links between RV dimensions and function and bodyweight in patients with severe COVID-19. In obese and non-obese participants without COVID-19, we used cardiovascular magnetic resonance to define the effects of obesity upon RV volumes, energetics, systolic function and stress reserve. Results: In patients with severe COVID-19, increasing bodyweight was associated with disproportionate RV dilatation (n=26, echocardiography, R=0.42, P=0.03, CT n=34, R=0.23, P=0.004) and impairment of RV systolic function (fractional area change (FAC) R=-0.45, P=0.04); obesity (BMI >30kg/m2) was associated with a 32% reduction in RV FAC (P=0.03). Similar associations were seen in a validation cohort (n=91, all P<0.05). In participants without COVID-19, class III obesity (n=54, BMI 47±4 kg/m 2 ) was associated with RV remodelling, impaired cardiac energetics (PCr/ATP ratio 23% lower, P<0.001) and reduction in RV systolic function at rest (by 3±1%, P=0.01), which was related to reduced energetics (R=0.3, P=0.04). Participants with class I-II obesity (BMI 35±5 kg/m 2 , n=27) had impaired RV diastolic filling rate at rest (P<0.001) and blunted RV dobutamine stress systolic response (by 68%, P=0.03) and diastolic response (by 78%, P=0.008). Surgical weight loss in patients obesity (n=37, 34±15kg weight loss) was associated with improvement in RV volume (12±26 ml lower, P=0.006) and function (ejection fraction 2±5% higher, P=0.03). Conclusions: Increasing body weight is associated with both significant alterations in RV volumes, systolic function and stress responses which are mitigated with weight loss and also with disproportionate RV dilatation and dysfunction in severe COVID-19. RV dysfunction is a modifiable mechanism which might link obesity to adverse outcomes in patients with COVID-19 and other disorders stressing the right heart.

Background Impaired right ventricular (RV) pulmonary artery coupling has been associated with higher mortality in patients with chronic heart disease, but few studies have examined this metric in critically ill patients. We sought to evaluate the association between RV pulmonary artery coupling, defined by the ratio of tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP), and mortality in cardiac intensive care unit patients. Methods and Results Using a database of unique cardiac intensive care unit admissions from 2007 to 2018, we included patients with TASV/RVSP ratio measured within 1 day of hospitalization. Hospital mortality was analyzed using multivariable logistic regression, and 1‐year mortality was analyzed using multivariable Cox proportional‐hazards analysis. We included 4259 patients with a mean age of 69±15 years (40.1% women). Admission diagnoses included acute coronary syndrome in 56%, heart failure in 52%, respiratory failure in 24%, and cardiogenic shock in 12%. The mean TASV/RVSP ratio was 0.31±0.14, and in‐hospital mortality occurred in 7% of patients. Higher TASV/RVSP ratio was associated with lower in‐hospital mortality (adjusted unit odds ratio, 0.68 per each 0.1‐unit higher ratio; 95% CI, 0.58–0.79; P <0.001) and lower 1‐year mortality among hospital survivors (adjusted unit hazard ratio, 0.83 per each 0.1‐unit higher ratio; 95% CI, 0.77–0.90; P <0.001). Stepwise decreases in hospital and 1‐year mortality were observed in each higher TASV/RVSP quintile. The TASV/RVSP ratio remained associated with mortality after adjusting for left ventricular systolic and diastolic function. Conclusions A low TASV/RVSP ratio is associated with increased short‐term and long‐term mortality among cardiac intensive care unit patients, emphasizing importance of impaired RV pulmonary artery coupling as a determinant of poor prognosis. Further study is required to determine whether interventions to optimize RV pulmonary artery coupling can improve outcomes.