Borlaug, Barry A.

Abstract Background Diastolic reserve decreases with aging. A recently developed artificial intelligence (AI) algorithm can predict age based on 12-lead electrocardiogram (ECG) analysis. Purpose This study aims to use a validated AI algorithm to assess cardiac senescence and investigate the impact of obesity on cardiac aging in heart failure with preserved ejection fraction (HFpEF). Methods This retrospective cohort study includes 403 patients with HFpEF, admitted for treatment with intravenous diuretics. ECG age was assessed by a convolutional neural network as previously validated. Patients were stratified according to the presence of obesity (body mass index >30 kg/m2) and ECG age was compared between groups. The relationship between ECG versus calendar age and structural/functional alterations on echocardiography, as well as the risk of atrial fibrillation (AF) development, was evaluated. Results In 253 (63%) obese patients with HFpEF, calendar age was 8 years younger compared with their non-obese counterparts, but ECG age was only 3 years younger. ECG minus calendar age was higher in obese patients (P-value <0.001; figure) and correlated moderately strong with weight, fat free, and fat mass (r=0.35–0.41; P-value <0.001). Older ECG age was correlated with worse diastolic function, but not with left ventricular afterload (table). Calendar age correlated less strongly with diastolic dysfunction (table). ECG age did predict AF development, independently of calendar age, gender, and presence of obesity [HR (95% CI) = 1.31 (1.06–1.63) per 5-year; P-value=0.015]. Conclusions Obesity accelerates cardiac senescence in HFpEF as reflected by more pronounced diastolic dysfunction and a higher AF risk, which was identified from ECG analysis by a validated AI algorithm. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Belgian American Educational Foundation (B.A.E.F.); Special Research Fund (BOF) of Hasselt University (Hasselt, Belgium).

Background: Reduced left ventricular stroke work index (LVSWI) has been associated with adverse outcomes in several populations of patients with chronic heart disease, but no prior studies have examined this metric in cardiac intensive care unit (CICU) patients. We sought to determine whether a low LVSWI, as measured noninvasively using transthoracic echocardiography, is associated with higher mortality in CICU patients. Methods: Using a database of unique Mayo Clinic CICU admissions from 2007 to 2018, we identified patients with LVSWI measured by transthoracic echocardiography within 1 day of CICU admission. Hospital mortality was analyzed using multivariable logistic regression, and 1-year mortality was analyzed using multivariable Cox proportional-hazards analysis, adjusted for left ventricular ejection fraction and known predictors of hospital mortality. Results: We included 4536 patients with a mean age of 68±14 years (36% women). Admission diagnoses (not mutually exclusive) included acute coronary syndrome in 62%, heart failure in 46%, and cardiogenic shock in 11%. The mean LVSWI was 38±14 g×min/m 2 , and in-hospital mortality occurred in 6% of patients. LVSWI had better discrimination for hospital mortality than left ventricular ejection fraction ( P <0.001 by De Long test). Higher LVSWI was associated with lower in-hospital mortality (adjusted odds ratio, 0.72 per 10 g×min/m 2 higher [95% CI, 0.61–0.84]; P <0.001) and lower 1-year mortality (adjusted hazard ratio, 0.812 per 1 g×min/m 2 higher [95% CI, 0.759–0.868]; P <0.001). Stepwise decreases in hospital and 1-year mortality were observed with higher LVSWI. Conclusions: Low LVSWI, reflecting poor left ventricular systolic and diastolic performance, is associated with increased short-term and long-term mortality among CICU patients. This emphasizes the importance of Doppler transthoracic echocardiography as a predictor of outcomes among critically ill patients. Further study is required to determine whether early interventions to optimize LVSWI can improve outcomes in the CICU setting.

Abstract Aims Central obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear. We hypothesized that sex-specific differences in visceral adipose tissue (VAT) content would differentially relate to haemodynamic severity of HFpEF in women and men. Methods and results Abdominal computed tomography (CT) and invasive haemodynamic exercise testing were performed in 105 subjects with HFpEF (63 women) and 105 age-, sex-, and body mass index-matched controls. Visceral adipose tissue area was quantified by CT. As compared with control women, VAT area was 34% higher in women with HFpEF (186 ± 112 vs. 139 ± 72 cm2, P = 0.006), while VAT area was not significantly different in men with or without HFpEF (294 ± 158 vs. 252 ± 92 cm2, P = 0.1). During exercise, pulmonary capillary wedge pressure (PCWP) increased markedly and to similar extent in both men and women with HFpEF. Women with increased VAT area displayed 33% higher PCWP during exercise compared with women with normal VAT area (28 ± 10 vs. 21 ± 10 mmHg, P = 0.001), whereas exercise PCWP was similar in men with or without excess VAT (24 ± 9 vs. 25 ± 6, P = 0.89). In women, each 100 cm2 increase in VAT area was associated with a 4.0 mmHg higher PCWP (95% CI 2.1, 6.0 mmHg; P &lt; 0.0001), but there was no such relationship in men (interaction P = 0.009). Conclusions These data suggest that accumulation of excess VAT plays a distinct and important role in the pathophysiology of HFpEF preferentially in women. Further research is needed to better understand the mechanisms and treatment implications for visceral fat in HFpEF.

Aims This study uniquely explored the relationship between coronary microvascular function and exercise haemodynamics using concurrent invasive testing. Methods and results Fifty‐one consecutive patients with unexplained cardiac exertion symptoms, non‐obstructive coronary artery disease and normal left ventricular ejection fraction (>50%) underwent haemodynamic exercise assessment and concurrent coronary reactivity testing. Heart failure with preserved ejection fraction (HFpEF) was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg at rest and/or ≥25 mmHg at peak exercise. Endothelium‐independent coronary microvascular dysfunction (CMD) was defined as a coronary flow reserve (CFR) ≤2.5, while endothelium‐dependent CMD was defined as ≤50% increase in coronary blood flow (CBF) in response to intracoronary acetylcholine infusions. Patients with HFpEF ( n = 22) had significantly lower CFR (2.5 ± 0.6 vs. 3.2 ± 0.7; P = 0.0003) and median %CBF increase in response to intracoronary acetylcholine [1 (−35; 34) vs. 64 (−4; 133); P = 0.002] compared to patients without HFpEF ( n = 29). PAWP was significantly higher in patients with endothelium‐independent CMD compared to controls during both rest and exercise. This significant elevation was only present during exercise in patients with endothelium‐dependent CMD compared to controls. CFR had significant inverse correlations with PAWP at rest (r = −0.31; P = 0.03) and peak exercise (r = −0.47, P = 0.001). CFR also had positive correlations with maximal exercise capacity (in W/kg) (r = 0.33, P = 0.02). Conclusions Coronary microvascular function is inversely associated with filling pressures, particularly during exercise. Both types of CMD are associated with higher filling pressures at peak exercise. These findings underscore the potential mechanism and therapeutic target for CMD and HFpEF.

Patients with heart failure with preserved ejection fraction (HFpEF) experience symptoms of exertional dyspnea that may be related to lung fluid accumulation during exercise. A computed tomography (CT)-based method was used to measure exercise-induced changes in extravascular lung fluid content and thoracic blood volumes and to determine the effect of lung fluid on lung diffusing capacity for carbon monoxide (DLCO) in stable subjects with HFpEF and healthy controls. Nine subjects with HFpEF (age = 68 ± 8 yr; body mass index = 32.1 ± 2.6 kg/m2) and eight healthy controls (62 ± 9 yr, 23.8 ± 2.4 kg/m2) performed triplicate rebreathe DLCO/DLNO (lung diffusing capacity for nitric oxide) tests in a supine position at rest and duplicate measurements during two 5-min submaximal exercise stages (15W and 35W) and recovery. Subjects subsequently performed a 5-min exercise bout (35W) inside a CT scanner, and extravascular lung fluid content and thoracic blood volumes were quantified at rest and immediately following exercise from thoracic and contrast perfusion scans, respectively. Subjects with HFpEF had a higher lung fluid content at rest compared with controls (means ± SD, HFpEF: 14.4 ± 1.7%, control: 12.8 ± 1.7%, P = 0.043) and a higher lung fluid content following exercise (15.2 ± 2.0% vs. 12.6 ± 1.5%, P = 0.009). Higher lung fluid content was associated with a lower DLCO and alveolar-capillary membrane conductance (Dm) in subjects with HFpEF (DLCO: R = −0.57, P = 0.022, Dm: R = −0.61, P = 0.012) but not in controls. Pulmonary blood volume was not altered by exercise and was similar between groups. Submaximal exercise elicited a greater accumulation of lung fluid in subjects with HFpEF compared with in controls, and lung fluid content was negatively correlated with lung diffusing capacity and alveolar-capillary membrane conductance in subjects with HFpEF.

Heart failure is characterized by pathologic hemodynamic derangements, including elevated cardiac filling pressures (“backward” failure), which may or may not coexist with reduced cardiac output (“forward” failure). Even when normal during unstressed conditions such as rest, hemodynamics classically become abnormal during stressors such as exercise in patients with heart failure. This has important upstream and downstream effects on multiple organ systems, particularly with respect to the lungs and kidneys. Hemodynamic abnormalities in heart failure are affected by processes that extend well beyond the cardiac myocyte, including important roles for pericardial constraint, ventricular interaction, and altered venous capacity. Hemodynamic perturbations have widespread effects across multiple heart failure phenotypes, ranging from reduced to preserved ejection fraction, acute to chronic disease, and cardiogenic shock to preserved perfusion states. In the lung, hemodynamic derangements lead to the development of abnormalities in ventilatory control and efficiency, pulmonary congestion, capillary stress failure, and eventually pulmonary vascular disease. In the kidney, hemodynamic perturbations lead to sodium and water retention and worsening renal function. Improved understanding of the mechanisms by which altered hemodynamics in heart failure affect the lungs and kidneys is needed in order to design novel strategies to improve clinical outcomes.

Key points Heart failure patients with reduced ejection fraction (HFrEF) exhibit severe limitations in exercise capacity ( peak). One of the primary peripheral mechanisms suggested to underlie exercise intolerance in HFrEF is excessive locomotor muscle group III/IV afferent feedback; however, this has never been investigated in human heart failure. HFrEF patients and controls performed an incremental exercise test to volitional exhaustion to determine peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output, leg blood flow and radial artery and femoral venous blood gases were measured. With fentanyl, compared with placebo, patients with HFrEF achieved a higher peak workload, peak, cardiac output, stroke volume and leg blood flow. These findings suggest that locomotor muscle group III/IV afferent feedback in HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O2 delivery thereby impairing peak and thus exercise capacity. AbstractTo better understand the underlying mechanisms contributing to exercise limitation in heart failure with reduced ejection fraction (HFrEF), we investigated the influence of locomotor muscle group III/IV afferent inhibition via lumbar intrathecal fentanyl on peak exercise capacity ( peak) and the contributory mechanisms. Eleven HFrEF patients and eight healthy matched controls were recruited. The participants performed an incremental exercise test to volitional exhaustion to determine peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output and leg blood flow () were measured via open‐circuit acetylene wash‐in technique and constant infusion thermodilution, respectively. Radial artery and femoral venous blood gases were measured. peak was 15% greater with fentanyl compared with placebo for HFrEF (P < 0.01), while no different in the controls. During peak exercise with fentanyl, cardiac output was 12% greater in HFrEF secondary to significant decreases in systemic vascular resistance and increases in stroke volume compared with placebo (all, P < 0.01). From placebo to fentanyl, leg , and O2 delivery were greater for HFrEF during peak exercise (all, P < 0.01), but not control. These findings indicate that locomotor muscle group III/IV afferent feedback in patients with HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O2 delivery, thereby impairing peak and thus exercise capacity. These findings have important clinical implications as peak is highly predictive of morbidity and mortality in HF.

Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left‐sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP‐protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left‐sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3‐ to 5‐mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.