Borlaug, Barry A

Abstract Background A substantial proportion of patients with heart failure (HF) with preserved ejection fraction (HFpEF) present with normal natriuretic peptide (NP) levels. The pathophysiology and natural history for this phenotype remain unclear. Methods and results Consecutive subjects undergoing invasive cardiopulmonary exercise testing for unexplained dyspnoea at Mayo Clinic in 2006–18 were studied. Heart failure with preserved ejection fraction was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg (rest) or ≥25 mmHg (exercise). Patients with HFpEF and normal NP [N-terminal of the pro-hormone B-type natriuretic peptide (NT-proBNP) < 125 ng/L] were compared with HFpEF with high NP (NT-proBNP ≥ 125 ng/L) and controls with normal haemodynamics. Patients with HFpEF and normal (n = 157) vs. high NP (n = 263) were younger, yet older than controls (n = 161), with an intermediate comorbidity profile. Normal NP HFpEF was associated with more left ventricular hypertrophy and worse diastolic function compared with controls, but better diastolic function, lower left atrial volumes, superior right ventricular function, and less mitral/tricuspid regurgitation compared with high NP HFpEF. Cardiac output (CO) reserve with exercise was preserved in normal NP HFpEF [101% predicted, interquartile range (IQR): 75–124%], but this was achieved only at the cost of higher left ventricular transmural pressure (LVTMP) (14 ± 6 mmHg vs. 7 ± 4 mmHg in controls, P < 0.001). In contrast, CO reserve was decreased in high NP HFpEF (85% predicted, IQR: 59–109%), with lower LVTMP (10 ± 8 mmHg) compared with normal NP HFpEF (P < 0.001), despite similar PAWP. Patients with high NP HFpEF displayed the highest event rates, but normal NP HFpEF still had 2.7-fold higher risk for mortality or HF readmissions compared with controls (hazard ratio: 2.74, 95% confidence interval: 1.02–7.32) after adjusting for age, sex, and body mass index. Conclusion Patients with HFpEF and normal NP display mild diastolic dysfunction and preserved CO reserve during exercise, despite marked elevation in filling pressures. While clinical outcomes are not as poor compared with patients with high NP, patients with normal NP HFpEF exhibit increased risk of death or HF readmissions compared with patients without HF, emphasizing the importance of this phenotype.

Background: Left atrial (LA) myopathy is common in patients with heart failure and preserved ejection fraction and leads to the development of atrial fibrillation (AF). We investigated whether the likelihood of LA remodeling, LA dysfunction, altered hemodynamics, and risk for incident AF could be identified from a single 12-lead ECG using a novel artificial intelligence (AI)-enabled ECG analysis. Methods: Patients with heart failure and preserved ejection fraction (n=613) underwent AI-enabled ECG analysis, echocardiography, and cardiac catheterization. Individuals were grouped by AI-enabled ECG probability of contemporaneous AF, taken as an indicator of underlying LA myopathy. Results: Structural heart disease was more severe in patients with higher AI-probability of AF, with more left ventricular hypertrophy, larger LA volumes, and lower LA reservoir and booster strain. Cardiac filling pressures and pulmonary artery pressures were higher in patients with higher AI-probability, while cardiac output reserve was more impaired during exercise. Among patients with sinus rhythm and no prior AF, each 10% increase in AI-probability was associated with a 31% greater risk of developing new-onset AF (hazard ratio, 1.31 [95% CI, 1.20–1.42]; P <0.001). In the population as a whole, each 10% increase in AI-probability was associated with a 12% greater risk of death (hazard ratio, 1.12 [95% CI, 1.08–1.17]; P <0.001) during long-term follow-up, which was no longer significant after adjustments for baseline characteristics. Conclusions: A novel AI-enabled score derived from a single 12-lead ECG identifies the presence of underlying LA myopathy in patients with heart failure and preserved ejection fraction as evidenced by structural, functional, and hemodynamic abnormalities, as well as long-term risk for incident AF. Further research is required to determine the role of the AI-enabled ECG in the evaluation and care of patients with heart failure and preserved ejection fraction.

Abstract Aims Patients with obesity frequently present with dyspnoea. Biomarkers that reflect wall stress are often used to evaluate circulatory congestion and help determine whether dyspnoea is of cardiac causes. Patients with obesity display greater external restraint on the heart, which may alter relationships between intravascular pressures and stress markers. Methods and results Subjects with unexplained dyspnoea ( n = 212) underwent cardiac catheterization with simultaneous echocardiography. Blood sampling was performed in a subset ( n = 58). Relationships between echocardiographic and blood biomarkers of circulatory congestion and directly‐measured haemodynamics were compared between participants with severe obesity [body mass index (BMI) ≥35 kg/m 2 , Group B) and those without (BMI <35 kg/m 2 , Group A). Circulatory congestion was assessed by pulmonary capillary wedge pressure (PCWP), and vascular distending pressure was assessed by left ventricular transmural pressure (LVTMP). As compared to Group A, participants in Group B displayed higher PCWP relative to N‐terminal pro‐B‐type natriuretic peptide, mid‐regional pro‐atrial natriuretic peptide, troponin T, and growth differentiation factor‐15 (all p < 0.01). In contrast, the relationships between LVTMP and the biomarkers were superimposable. Echocardiographic biomarkers revealed the same pattern: PCWP was higher for any E/e′ ratio in Group B compared to Group A, but the relationship between LVTMP and E/e′ was similar. In contrast, levels of C‐terminal pro‐endothelin‐1 and mid‐regional pro‐adrenomedullin were more robustly correlated with PCWP (r = 0.67 and r = 0.62, both p < 0.0001), with no differential relationship based upon BMI. Conclusions Non‐invasive haemodynamic markers underestimate circulatory congestion in patients with obesity, an effect that appears related to uncoupling between cardiac wall stress and intravascular pressures. This may lead to systematic under‐recognition of congestion in patients with obesity.

Objective Mild aortic valve stenosis (AS) and aortic valve (AV) sclerosis are associated with diastolic dysfunction and increased mortality in the general population. This study specifically investigated the impact of mild AV disease in heart failure with preserved ejection fraction (HFpEF). Methods Consecutive patients hospitalised with HFpEF (n=370) underwent assessment of cardiac structure and function and long-term clinical follow-up. Results In the study cohort, 111 had mild AS (30%), 104 AV sclerosis (28%) and 155 a non-calcified AV (42%). Mild-to-moderate AV regurgitation (AR) was present in 64 (17%). Compared with patients with a normal AV, those with AV disease were older, with worse renal function and more atrial fibrillation. E/e′ increased from non-calcified AV to AV sclerosis to mild AS (13.8 (10.8–16.8) vs 15.0 (10.9–20.0) vs 18.0 (12.7–23.3), respectively; p<0.001)). Left ventricular diastolic pressure–volume relationships were shifted leftwards in patients with AS and AV sclerosis, but not influenced by AR. The left ventricular end-diastolic volume normalised at 20 mm Hg was 117±34 mL, 106±30 mL and 112±30 mL in non-calcified AV, AV sclerosis and mild AS, respectively (p=0.023), while 112±32 mL in mild-to-moderate AR. Over 30 months (IQR, 8–61 months), 247 patients died (67%). The presence of mild AV disease was associated with increased mortality, but this was no longer significant after adjusting for age and sex. Conclusions Low-grade AV disease is common among patients hospitalised for HFpEF and is associated with older age, atrial arrhythmia, renal dysfunction, higher left heart filling pressures and increased left ventricular chamber stiffness.

Background Hemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DL CO ) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise. Methods and Results Rebreathe DL CO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath‐by‐breath pulmonary gas exchange were recorded at rest, 20 W, and symptom‐limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m 2 ) achieved a lower symptom‐limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m 2 ). DL CO was lower in patients with HFpEF compared with controls at rest (DL CO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P <0.01) and symptom‐limited maximal exercise (DL CO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P <0.01) because of a lower alveolar‐capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P <0.01; symptom‐limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P <0.01). DL CO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient. Conclusions Lung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar‐capillary membrane. DL CO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

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.

Aims To investigate the prognostic value of diagnostic scores for heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results Consecutive patients with HFpEF admitted for unequivocal decompensated HF treated with intravenous loop diuretics were evaluated ( n = 443; mean age 78 ± 12 years; 60% women). The HFA‐PEFF and H 2 FPEF scores were calculated for all patients with echocardiography data available within 1 year and the population was stratified according to HFA‐PEFF scores 2–4 ( n = 79), 5 ( n = 93), or 6 ( n = 271) and H 2 FPEF score probabilities <90% ( n = 80), 90–95% ( n = 61), and 96–100% ( n = 293). HF readmission rates (95% confidence intervals) increased from 28.9 (22.7–35.0) per 100 patient‐years in HFA‐PEFF 2–4 to 46.0 (38.5–53.5) in HFA‐PEFF 5 and 45.0 (40.1–49.8) in HFA‐PEFF 6. Similarly, HF readmission rates increased with increasing H 2 FPEF probability: <0.90 [31.8 (25.3–38.2) per 100 patient‐years], 0.90–0.95 [41.5 (32.9–50.1)], and 0.96–1.00 [45.9 (41.2–50.6]. Median survival was 65 months (36–89 months) in HFA‐PEFF score 2–4, 45 months (26–59 months) in HFA‐PEFF score 5, and 28 months (22–42 months) in HFA‐PEFF score 6 ( P < 0.001), while the hazard ratio (95% confidence interval) for all‐cause mortality was 1.16 (1.02–1.32) per 0.10 increase in H 2 FPEF probability. Conclusions Among patients hospitalized with HFpEF, higher HFpEF probability according to diagnostic scores is associated with increased risk of subsequent HF readmissions and all‐cause mortality.

Background: Heart failure with preserved ejection fraction is increasing in prevalence, but few effective treatments are available. Elevated left ventricular (LV) diastolic filling pressures represent a key therapeutic target. Pericardial restraint contributes to elevated LV end-diastolic pressure, and acute studies have shown that pericardiotomy attenuates the rise in LV end-diastolic pressure with volume loading. However, whether these acute effects are sustained chronically remains unknown. Methods: Minimally invasive pericardiotomy was performed percutaneously using a novel device in a porcine model of heart failure with preserved ejection fraction. Hemodynamics were assessed at baseline and following volume loading with pericardium intact, acutely following pericardiotomy, and then again chronically after 4 weeks. Cardiac structure was assessed by magnetic resonance imaging. Results: The increase in LV end-diastolic pressure with volume loading was mitigated by 41% (95% CI, 27%–45%, P <0.0001; ΔLV end-diastolic pressure reduced from +9±3 mm Hg to +5±3 mm Hg, P =0.0003, 95% CI, −2.2 to −5.5). The effect was sustained at 4 weeks (+5±2 mm Hg, P =0.28 versus acute). There was no statistically significant effect of pericardiotomy on ventricular remodeling compared with age-matched controls. None of the animals developed hemodynamic or pathological indicators of pericardial constriction or frank systolic dysfunction. Conclusions: The acute hemodynamic benefits of pericardiotomy are sustained for at least 4 weeks in a swine model of heart failure with preserved ejection fraction, without excessive chamber remodeling, pericarditis, or clinically significant systolic dysfunction. These data support trials evaluating minimally invasive pericardiotomy as a novel treatment for heart failure with preserved ejection fraction in humans.