Koepp, Katlyn E.

Abstract Background In patients with heart failure with preserved ejection fraction (HFpEF), studies have described different HFpEF phenogroups based on medical comorbidities and variable echocardiographic, invasive hemodynamic, and biomarker data. We hypothesized that myocardial histopathologic findings may define phenogroups with differing clinical features and outcomes in patients with HFpEF. Methods We analyzed consecutive patients with left HF and EF ≥50% who underwent right ventricular septal endomyocardial biopsy (EMB) at our institution between 2001 and 2022 to investigate HF etiology. Patients with infiltrative or hypertrophic cardiomyopathy, sarcoidosis, myocarditis, primary valvular heart disease, constrictive pericarditis, isolated right HF, or insufficient EMB samples were excluded. Clinical, echocardiographic, and invasive hemodynamic data were collected. The severity of hypertrophy and fibrosis on EMB specimens was characterized (semiquantitative grading) by experienced cardiac pathologists based on standard histologic stains. Patients were stratified into four phenogroups based on EMB findings: "mild" (none/mild hypertrophy and fibrosis), "hypertrophy" (moderate/marked hypertrophy, minimal/mild fibrosis), "fibrosis" (moderate/marked fibrosis, none/mild hypertrophy), and "severe" (moderate/marked hypertrophy and fibrosis). Results Among the 121 patients analyzed, the median age was 67 years, 50% were female and cardiovascular conditions were common (Table 1). Fibrosis was graded as minimal in 21% (n=25), mild in 64% (n=77), moderate in 12% (n=15), and marked in 3% (n=4). Hypertrophy was graded as none in 4% (n=5), mild in 41% (n=50), moderate in 40% (n=48), and marked in 15% (n=18). Only one patient had the isolated "fibrosis" phenogroup and was excluded from further analysis, while 54 had the "mild", 48 had the "hypertrophy", and 18 had the "severe" phenogroup (Table 1). The "hypertrophy" phenogroup exhibited significantly higher rates of hypertension, diabetes, RV dilation, and higher pulmonary artery pressures. Over a median follow-up of 7.9 years (3.1–13.8), mortality rate varied according to the histopathologic phenogroups (Figure 1, p=0.034) with "severe" having the worst and "mild" having the best outcomes. Survival analyses based on fibrosis grades alone, hypertrophy grades alone, or echocardiographic hypertrophy did not reveal significant differences (all p = NS). Differences in survival remained significant adjusting for age (HR 3.39, 95% CI 1.20-9.58). Conclusions The integrated severity of histopathologic hypertrophic and fibrotic remodeling defined HFpEF phenogroups with variable prognosis. Clinical features did not reliably identify histopathologic phenogroups. These data suggest that advanced myocardial phenotyping (e.g., gene, protein, metabolism) may reveal unique HFpEF myocardial subtypes in need of specific therapies.Figure 1

Background: Pulmonary vascular resistance (PVR) is commonly considered to reflect opposition to lung blood flow caused by the arteries (PVRa), but downstream venous resistance (PVRv) may also contribute to pulmonary hypertension (PH) associated with left heart diseases (PH-LHD). In patients referred for right heart catheterization, we investigated PVR distribution and its pathophysiologic implications in PH-LHD and other forms of PH. Methods: Patients with PH-LHD (n=292), pulmonary veno-occlusive disease (PVOD, n=10), chronic thromboembolic PH (CTEPH, n=36) and controls without PH (Ctrl, n=28) were included. Pulmonary capillary pressure (Pc) was calculated using the pulmonary artery occlusion technique. PVR was partitioned into PVRa ((mPAP-Pc)/CO) and PVRv ((Pc-PAWP)/CO) with each expressed as % of PVR. PH-LHD was divided into isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). Further, PH-LHD was categorized as heart failure with preserved (HFpEF, EF≥50%) or reduced (HFrEF, EF<50%) ejection fraction or left valvular heart disease (L-VHD). In subsets, functional tests (n=71-81) and histological pulmonary venous (PV) remodeling (autopsy, n=15) were performed to investigate correlations with PVR distribution. Results: PVR distribution showed an arterial predominance in Ctrl and CTEPH, and increasing venous contribution in PH-LHD (both IpcPH and CpcPH) and PVOD (Figure A-F). In PH-LHD, patients with HFpEF had proportionately greater venous contribution to PVR than HFrEF and L-VHD (Figure G-I), though not to the extent observed in PVOD. In subsets, PVRv was more strongly correlated with E/e’, extravascular lung water estimated by sonographic B-lines, arterial PO 2 , pulmonary dead space fraction (VD/VT), DLCO, and, among the autopsy series, PV intimal thickness as compared to PVRa (Figure J-O). Conclusions: Pulmonary venous contributions to PVR are amplified in patients with PH-LHD, which is correlated with greater lung congestion, ventilatory and gas exchange abnormalities, and histological venous remodeling. Further study is required to determine the molecular mechanism and novel therapeutics of pulmonary venous disease in PH-LHD.

Importance Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial. Objective To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique. Interventions A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks. Main Outcomes and Measures The primary end point was oxygen consumption (V̇ o 2 ) at anaerobic threshold (V̇ o 2,AT ); secondary end points were peak V̇ o 2 , ventilatory efficiency (V̇ e /V̇ co 2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Results Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇ o 2 and V̇ o 2 at anaerobic threshold (V̇ o 2,AT ) were both correlated with peak exercise heart rate ( r = 0.46-0.51, P &amp;lt; .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P &amp;lt; .001; 14/min [95% CI, 7 to 21], P &amp;lt; .001), but there was no significant change in V̇ o 2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, −0.5 to 1.0] mL/kg/min; P = .46), peak V̇ o 2 , minute ventilation (V̇ e) /carbon dioxide production (V̇ co 2 ) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (−24 mL [95% CI, −43 to −5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%). Conclusions and Relevance In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events. Trial Registration ClinicalTrials.gov Identifier: NCT02145351

Introduction: Obesity is common in heart failure with preserved ejection fraction (HFpEF) and is directly linked with lower levels of physical activity (PA). Visceral adiposity (VAT) is more common in HFpEF than controls and may play a role in its pathogenesis, characterized by impaired exercise capacity (peak VO 2 ). The direct relationship between VAT and PA in HFpEF is unknown. Hypothesis: Compared to controls, HFpEF patients will have excess regional adiposity (VAT, subcutaneous (SAT), and intramuscular (IMAT)), and these fat depots will be associated with lower levels of chronic physical activity. Methods: HFpEF patients (n=51; age 70±9) and non-HFpEF controls (n=49; age 65±5) prospectively underwent body composition measurement by dual-energy x-ray absorptiometry and magnetic resonance imaging. Peak VO 2 was measured by standard cardiopulmonary exercise testing. PA was monitored continuously via accelerometry over two weeks. Data were binned in arbitrary accelerometry units, averaged and stored in 30-second epochs (counts per epoch, CPE). Models were adjusted for age, sex, and ideal body weight. Results: HFpEF were less active overall (3.15±0.80 vs 3.59±0.73 CPE), had less moderate intensity PA (10.13±0.04 vs 10.15±0.03 CPE), and less morning (3.83±1.15 vs 4.24±1.09 CPE) and afternoon (3.84± 1.20 vs 4.53± 0.97 CPE) (p<0.05 for all) PA. Patients with HFpEF spent a greater proportion of time sedentary (0.71±0.08 vs 0.67±0.08 CPE) and less time in moderate (0.04±0.03 vs 0.06±0.03 CPE) and vigorous (0.02±0.01 vs 0.03±0.03 CPE) PA (p<0.01 for all). Chronic PA was significantly associated with regional fat depots (VAT β= -0.003, 95% CI: -0.004-0.001; SAT β= -0.003, 95%CI: -0.004-0.001; IMAT β=-0.02, 95% CI: -0.04—0.01) as a combined cohort (p<0.01 for all). Muscle quality (β=0.28, 95%CI: 0.15-0.40), peak VO 2 (β=0.08, 95% CI: 0.03-0.13), and peak watts (β=0.01, 95% CI: -0.004-0.02) were associated with PA in HFpEF only (p≤0.01 for all). Conclusions: The amount and pattern of PA differs between HFpEF and controls, as do relationships between regional fat depots and PA, and the relationship of PA and peak VO 2 . Further investigation is needed to better understand the temporality and mechanisms related to the pathophysiology and severity of HFpEF.

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: Peripheral factors contribute to exercise limitations in heart failure (HF) with preserved ejection fraction (HFpEF) and may be related to excess regional adiposity. Slowed oxygen uptake (VO 2 ) kinetics are common in HF with reduced ejection fraction (HFrEF) and reflect peripheral O 2 transport impairments and abnormal muscle metabolic control. Differences in VO 2 kinetics between HFpEF and HFrEF may reveal phenotype-specific impairments in peripheral O 2 transport but remain unknown. Hypothesis: We hypothesized that VO 2 kinetics are slower in HFpEF (compared to HFrEF) and associated with greater leg adiposity. Methods: Patients with HFpEF (n=12; 3 women; 66±6 yrs; 29±3 kg/m 2 ; ejection fraction: 59±5%), HFrEF (n=12; 3 women; 62±9 yrs; 28±4 kg/m 2 ; ejection fraction: 37±8%), and controls (n=12; 3 women; 65±5 yrs; 28±3 kg/m 2 ) cycled at 20 W for 5 minutes prior to a maximal exercise test to determine VO 2peak . Age, sex, and BMI were matched by design and were not different among groups (p>0.05). A monoexponential function with a time delay was used to describe the VO 2 transition from rest to 20 W and calculate the O 2 deficit. Leg fat mass was measured via dual energy X-ray absorptiometry. Results: VO 2peak was lower in HFpEF (18.6±6.2 mL/kg/min) and HFrEF (19.0±3.7 mL/kg/min) compared to controls (26.0±3.1; both p<0.05). Amplitude (HFpEF: 507±97 mL/min; HFrEF: 443±91 mL/min; controls: 477±117 mL/min) and time delay (HFpEF: 16±9 s; HFrEF: 11±7 s; controls: 11±6 s) were not different among groups (p>0.05). The time constant was slower in HFrEF compared to controls (45±9 s vs. 32±6 s; p=0.03) and further slowed in HFpEF (66±18 s; p<0.001). The O 2 deficit was significantly greater in HFpEF (895±201 mL) and HFrEF (649±131 mL) compared to controls (590±125 mL; both p<0.05). There were no differences in percent leg fat mass among groups (HFpEF: 33±8%; HFrEF: 31±6%; controls: 34±9%) and no associations were detected between percent leg fat mass and any VO 2 parameters (all p>0.05). Conclusions: Patients with HFpEF exhibited slower VO 2 kinetics compared to HFrEF with no association to leg adiposity. These data suggest differences in peripheral O 2 transport and intramuscular metabolic control abnormalities between HF phenotypes.

Background: Destination therapy left ventricular assist devices (DT-LVADs) have become a treatment option for carefully selected patients with end-stage heart failure. Death is inevitable despite DT-LVAD, with 1-year mortality approximately 20% and median survival 5 years. However, end-of-life processes for LVAD patients vary significantly by institution, provider, and patient preference. Palliative care has played an increasing role in the care of this patient population, yet there remains little data on the most effective way to integrate palliative care and hospice in the DT-LVAD population. Therefore, we aimed to understand the end-of-life perspectives regarding LVADs among both cardiology and palliative care/hospice providers. Methods: Using internet-based, secure methods, we administered a 41-item survey via electronic mail to members of the American Academy of Hospice and Palliative Medicine, European Society of Cardiology-Heart Failure Association, the International Society for Heart and Lung Transplantation, and the Heart Failure Society of America to assess their perspectives on end-of-life care in patients with LVADs. Descriptive statistics were used to analyze data. Fisher’s exact test was used to compare categorical data. Results: From October to November 2011, there were a total of 440 respondents (palliative care/hospice=137; cardiology=303). Most were physicians (80%; n=320) and male (59%; n=232). The majority of providers in both groups viewed an LVAD as a life-sustaining treatment. The groups differed in their attitudes, beliefs, and comfort with end-of-life care in patients with an LVAD. Few palliative care/hospice providers believed a patient needed to be imminently dying to turn off an LVAD; whereas most cardiology providers noted patients should be imminently dying in order to consider LVAD deactivation (2% vs 60%; p=<0.001). Most palliative care/hospice providers believed requests for turning off an LVAD in a patient who is not nearing death should be honored. In contrast, just over half of cardiology providers contended the request should be honored (88% vs 57%; p=<0.001). The provider groups also disagreed on requiring ethics consultation, with most cardiology providers stating it was necessary prior to turning off an LVAD near the end of life (67% vs 24%; p=<0.001). Conclusion: Cardiology providers and palliative care/hospice providers collectively have different perceptions on management of end of life in patients with an LVAD. Bridging the gaps between these two disciplines is a critical first step in creating a more cohesive approach to end-of-life care for these patients—one that honors autonomy but respects individual provider comfort levels.

Abstract Aims To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O 2 ) transport during exercise in heart failure with preserved ejection fraction (HFpEF). Methods and results Data from two invasive, randomized, double‐blind, placebo‐controlled trials with matched workload exercise of inhaled and intravenous sodium nitrite were pooled for this analysis ( n = 51). Directly measured O 2 consumption (VO 2 ) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O 2 conductance (Dm), VO 2 kinetics, alveolar capillary membrane O 2 conductance (D L ), and O 2 utilization during submaximal exercise. As compared to placebo, treatment with nitrite resulted in an improvement in Dm (+4.9 ± 6.5 vs. −0.9 ± 4.3 mL/mmHg*min, P = 0.0008) as well as VO 2 kinetics measured by mean response time (−5.0 ± 6.9 vs. −0.6 ± 6.0 s, P = 0.03), with preserved O 2 utilization despite increased convective O 2 delivery through cardiac output (+0.4 ± 0.7 vs. −0.3 ± 0.9 L/min, P = 0.02). Nitrite improved D L (+2.5 ± 6.3 vs. −2.0 ± 9.0 mL/mmHg*min, P = 0.05) with exercise, which was associated with lower pulmonary capillary pressures (r = −0.34, P = 0.02), and reduced pulmonary dead space ventilation fraction (−0.01 ± 0.05 vs. +0.02 ± 0.05, P = 0.02). Conclusion Sodium nitrite enhances skeletal muscle Dm during exercise as well as pulmonary O 2 diffusion, optimizing O 2 kinetics in tandem with increased convective O 2 delivery through cardiac output augmentation. The favourable combined pulmonary, cardiac and peripheral effects of nitrite may improve exercise tolerance in people with HFpEF and requires further investigation. Clinical Trial Registration: ClinicalTrials.gov ID NCT01932606 and NCT02262078.