Reddy, Yogesh N.V.

Introduction: Obesity is prevalent in HFpEF, a syndrome that disproportionality affects women, and is associated with poor exercise tolerance (VO 2 ), reduced quality of life, and greater symptoms. Visceral adipose tissue (VAT), more than general obesity, is related to metabolic and cardiovascular dysfunction common to HFpEF. While fat deposition varies between sexes, these differences and the relation to exercise tolerance remain unclear in HFpEF. Hypothesis: Compared to sex-matched controls, HFpEF patients will demonstrate reduced lean mass, excess VAT, subcutaneous, visceral, and intramuscular fat, and will be associated with reduced VO 2 . Methods: HFpEF females (F) and males (M) (n=78; 37 F/41 M; age 70±9) and non-HFpEF controls (n=50; 30 F/20 M; age 65±5) prospectively underwent body composition measurement via dual-energy x-ray absorptiometry and magnetic resonance imaging (MRI) and cardiopulmonary exercise testing for measurement of peak oxygen consumption (peak VO 2 ). Muscle quality calculated as peak Watts (W) achieved divided by MRI thigh lean mass. Results: HFpEF had greater VAT, subcutaneous (SAT) and intramuscular (IMAT), and poorer muscle quality than controls (all p<0.01). Exercise performance was lower in HFpEF (peak VO 2 : 14±4 vs. 22±6; peak W: 69±29 vs. 116±34; both p<0.01). HFpEF demonstrated increased odds for VAT (OR: 2.02, 95% CI: 1.22-3.37), SAT (OR: 2.05, 95% CI: 1.20-3.49), and IMAT (OR: 2.04, 95% CI: 1.35-3.39) (all p<0.01). Sex-stratification revealed increased odds of excess VAT in HFpEF females (OR: 2.76, 95% CI: 1.16-7.72, p=0.03), SAT in HFpEF males (OR: 3.64, 95% CI: 1.10-12.07, p=0.03), and IMAT in HFpEF females (OR: 2.38, 95%CI: 1.10-5.29, p=0.03) with a trend in males (OR: 1.67, 95%CI: 0.97-2.86, p=0.06). Impaired VO 2 was associated with all AT depots as a combined cohort and among controls (all p<0.01) and linked to poor muscle quality individually for men and women in HFpEF and controls (all p<0.01). Conclusion: HFpEF patients have significantly altered body composition profiles and reduced exercise tolerance compared to controls. Sex differences in regional fat deposition impact peak VO 2 and may serve a distinct role in the pathophysiology of HFpEF.

Introduction: Pulmonary hypertension (PH), defined as an elevated mean pulmonary artery pressure, has been consistently associated with adverse outcomes in hospitalized patients. Limited epidemiologic data exist regarding PH in the cardiac intensive care unit (CICU) population. We used transthoracic echocardiography (TTE) to describe the prevalence, etiology, and outcomes of PH in the CICU. Hypothesis: PH will be associated with higher in-hospital mortality in CICU patients. Methods: CICU patients admitted from 2007 to 2018 who had right ventricular systolic pressure (RVSP) measured via TTE within 1 day of CICU admission were included. PH was defined as an estimated RVSP >35 mmHg. Predictors of in-hospital mortality were determined using multivariable logistic regression. Results: We included 5042 patients with a mean age of 69.4±14.8 (41% females); 81.1% had an admission diagnosis of acute coronary syndrome or heart failure. PH was present in 3085 (61%); the majority (68%) of patients with PH had left heart failure, and 29% had lung disease. In-hospital mortality occurred in 8% and was higher in patients with PH (11% vs. 4%, adjusted OR 1.40, 95% CI 1.03-1.92, p =0.03). PH was associated with higher in-hospital mortality in patients with acute coronary syndrome, heart failure or cardiac arrest (all p <0.01), but not in patients with cardiogenic shock, respiratory failure or sepsis ( Figure ). In-hospital mortality increased as a function of higher RVSP in each admission diagnosis group (adjusted 1.18 per 10 mmHg higher in the entire cohort, 95% CI 1.09-1.28, p <0.001). Conclusions: PH by TTE is very common in the CICU population and remains associated with a higher risk of death during hospitalization even after adjustment. TTE assessment of right heart hemodynamics can predict mortality in CICU patients, with variability across common admission diagnoses. This highlights the importance of PH determined by TTE in hospitalized patients with cardiac critical illness.

Introduction: Arteriovenous fistulas(AVF) have been associated with high output heart failure but little is known about their effect on patients initiating hemodialysis. We sought to describe echocardiographic changes and identify those with incident heart failure after AVF creation. Methods: This was a retrospective analysis of all patients undergoing AVF creation over a 15 year period from 2000-2014 at the Mayo Clinic in Rochester, MN. Patients undergoing echocardiogram <3 months (median 40 days) before AVF creation and >6 months (median 2.5 years) following surgery were included. Patients with independent modifiers of LV structural changes (such as revascularization or myocardial infarction) were excluded by chart review. Clinical heart failure was defined by Framingham criteria. Results: From 2000-2014, 2236 patients underwent creation of AVFs and 137 patients met inclusion criteria. There was a longitudinal decrease in systolic function as evident by a drop in ejection fraction(-2%, p=0.047) with decrease in s’ tissue Doppler velocity(-0.6 cm/s, p=0.055) and increase in HR(+5 beats/min, p=0.003). There was also an increase in the prevalence of RV dilation(20 to 40%, p=0.002) and RV dysfunction(12 to 29%, p=0.002). With initiation of dialysis and decrease in weight (-7.3kg) and estimated plasma volume (-303ml) (both p<0.0001), there was a decrease in LV end diastolic dimension (-2mm, p=0.006). Despite better volume control, left atrial volume index increased (+5ml/m2, p=0.004). On multivariate Cox regression, worsening RV dilation [HR 1.8 (1.06-3.09),p=0.03] was independently associated with mortality. Incident heart failure developed in 43%(28/65) with no pre-existing HF, of whom 75% had HFPEF and 25% HFrEF. The development of new systolic HF (but not HFPEF) was associated with increased age and sex adjusted mortality [HR 3.0(1.0-7.9), p=0.045]. Conclusions: AVF creation is associated with worsening biventricular function and left atrial and RV dilatation, despite reduction in LV size. These changes are coupled with high incidence of new, unexplained heart failure. Further research is needed to identify the hemodynamic mechanisms underlying heart failure development in patients with ESRD requiring dialysis access.

Aims Despite the common occurrence of coronary artery disease (CAD) and heart failure (HF) with preserved ejection fraction (HFpEF), there is limited evidence to guide revascularization. Methods and Results We investigated the long‐term outcomes of coronary artery bypass grafting (CABG) in patients with HF and significant CAD across the spectrum of ejection fraction, using a large national cohort of patients from the Veteran Affairs (VA) Medical Centers in the US. Patients with HF were stratified into groups, HFpEF, HF with mid‐range ejection fraction (HFmrEF), and HF with reduced ejection fraction (HFrEF) and compared to patients with no preoperative HF. We analysed 10 396 patients. Despite an increased hazard in the first year following revascularization, the long‐term survival (median follow‐up 6.6 years; interquartile range 3.7–10.1) of HFpEF post‐CABG was similar to controls (hazard ratio 0.85, 95% confidence interval 0.68‐1.06), but survival progressively declined with HFmrEF and HFrEF. Similar trends were seen with recurrent HF hospitalization with lower risk with baseline HFpEF (43.9 ± 6.9/100 patient‐years) compared to HFmrEF (65.9 ± 3.8/100 patient‐years) and HFrEF (93.4 ± 4.8/100 patient‐years). Although HFpEF patients had lower mortality and HF hospitalization post‐CABG compared to patients with a lower ejection fraction, they experienced the highest rates of future myocardial infarction. Conclusion Although HFpEF patients with CAD have greater short‐term risk post‐CABG, their long‐term survival is comparable to controls. However, they are at increased risk for HF hospitalizations and myocardial infarction. These data support the safety of CABG in HFpEF patients and suggest continuum of mortality risk for ischaemic HF when stratified by baseline ejection fraction before revascularization.

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) &lt; 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 &lt; 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 &lt; 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.

Abstract Aims Pulmonary hypertension (PH) has been consistently associated with adverse outcomes in hospitalized patients. Limited epidemiologic data exist regarding PH in the cardiac intensive care unit (CICU) population. Here, we describe the prevalence, aetiology, and outcomes of PH in the CICU. Methods and results Cardiac intensive care unit patients admitted from 2007 to 2018 who had right ventricular systolic pressure (RVSP) measured via transthoracic echocardiography near CICU admission were included. PH was defined as RVSP &gt;35 mmHg, and moderate-to-severe PH as RVSP ≥50 mmHg. Predictors of in-hospital mortality were determined using multivariable logistic regression. Among 5042 patients (mean age 69.4 ± 14.8 years; 41% females), PH was present in 3085 (61%). The majority (68%) of patients with PH had left heart failure, and 29% had lung disease. In-hospital mortality occurred in 8.3% and was more frequent in patients with PH [10.9% vs. 4.2%, adjusted odds ratio (OR) 1.40, 95% confidence interval (CI) 1.03–1.92, P = 0.03], particularly patients with moderate-to-severe PH (14.4% vs. 6.2%, adjusted OR 1.65, 95% CI 1.27–2.14, P &lt; 0.001). In-hospital mortality increased incrementally as a function of higher RVSP (adjusted 1.18 per 10 mmHg increase, 95% CI 1.09–1.28, P &lt; 0.001). Patients with higher RVSP or moderate-to-severe PH had increased in-hospital mortality across admission diagnoses (all P &lt; 0.05). Conclusions Pulmonary hypertension is very common in the CICU population and appears to be independently associated with a higher risk of death during hospitalization, although the strength of this association varies according to the underlying admission diagnosis. These data highlight the importance of PH in patients with cardiac critical illness.

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.

Abstract Background Atrial fibrillation (AF) is common in patients with heart failure and preserved ejection fraction (HFpEF) and associated with left atrial (LA) myopathy, reduced exercise capacity and poor outcomes. However, the mechanisms underlying exercise intolerance in HFpEF with AF are not well-characterized. Purpose To test hypotheses that patients with HFpEF and AF (HFpEF-AF) would display greater acute impairments in right heart-pulmonary vascular coupling during exercise, leading to greater elevations in left and right heart filling pressures and increased lung congestion as compared to patients with HFpEF and no AF (HFpEF-no-AF) and control subjects free of heart failure and AF. As corollary hypotheses, we also posited that these changes would lead to greater ventricular interdependence during exercise in HFpEF-AF, and that pulmonary hypertension in HFpEF-AF was not simply ascribable to the LA dysfunction that accompanies AF, which would provide greater impetus to pursue restoration of sinus rhythm. Methods Subjects with HFpEF-AF (n=35), HFpEF-no-AF (n=85), and controls free of heart failure or AF (n=28) underwent cardiopulmonary exercise testing with invasive hemodynamic assessment and simultaneous echocardiography and lung ultrasound in a prospective study. Results As compared with controls and HFpEF-no-AF, subjects with HFpEF-AF displayed poorer left ventricular (LV) longitudinal strain, lower LA reservoir strain with greater LA volume at rest. With exercise, subjects with HFpEF-AF displayed more severe exercise-induced pulmonary hypertension, higher right atrial pressure (RAP) and more pronounced right ventricular-pulmonary vascular uncoupling. Peak oxygen consumption was lowest in patients with HFpEF-AF, coupled with greater limitations in cardiac output reserve and more severe increases in lung congestion and pulmonary vascular resistance (Figure 1). Dynamic ventricular interaction was greatest in HFpEF-AF, evidenced by greater increases in LV eccentricity index and RAP/PCWP (Figure 2) and less increase in LV transmural pressure compared with HFpEF-no-AF. In a sensitivity analysis, patients with HFpEF-AF displayed more severe pulmonary hypertension and pulmonary vascular disease compared to HFpEF-no-AF even after matching for the severity of LA remodeling and dysfunction. Conclusions Patients with AF and HFpEF display more severe abnormalities in pulmonary vascular reserve with exercise leading to greater lung congestion and enhanced exertional ventricular interdependence compared to patients with HFpEF-no-AF. While many of these differences appear attributable to LA dysfunction, the presence of AF is associated with more severe pulmonary vascular disease independent of LA myopathy, suggesting potential benefit from restoration of sinus rhythm even in the setting of LA myopathy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): R01 HL128526

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.