BACKGROUND Aortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). OBJECTIVES We assessed indices of arterial stiffness at rest and during exercise in subjects with HFpEF and hypertensive controls, to examine their relationship to cardiac hemodynamics and determine whether exertional arterial stiffening can be mitigated by inorganic nitrite. METHODS Twenty-two hypertensive controls and 98 HFpEF subjects underwent hemodynamic exercise testing with simultaneous expired gas analysis. Invasively measured radial artery pressure waveforms were converted to central aortic waveforms by transfer function to assess integrated measures of pulsatile aortic load, including arterial compliance, resistance, elastance, and wave reflection. RESULTS Arterial load and wave reflections were similar in HFpEF and controls at rest. During submaximal exercise, HFpEF subjects displayed reduced total arterial compliance and higher effective arterial elastance despite similar mean arterial pressures to controls. This was directly correlated with higher ventricular filling pressures and depressed cardiac output reserve (both p <0.0001). With peak exercise, increased wave reflections impaired compliance, resistance and elastance were observed. A subset of HFpEF subjects (n = 52) received sodium nitrite or placebo in a 1:1 double blind, randomized fashion. Compared to placebo, nitrite decreased aortic wave reflections at rest and improved arterial compliance, elastance, and improved central hemodynamics during exercise. CONCLUSION Abnormal pulsatile aortic loading during exercise occurs in HFpEF independent of hypertension, and is correlated with classical hemodynamic derangements that develop with stress. Inorganic nitrite mitigates arterial stiffening with exercise and improves hemodynamics, indicating that arterial stiffening with exercise is at least partially reversible. Further study is required to test effects of agents that target the NO pathway in reducing arterial stiffness in HFpEF.

Acute sodium nitrite infusion favorably attenuates hemodynamic derangements of cardiac failure that develop during exercise in individuals with HFpEF. Prospective trials testing long-term nitrite therapy in this population are warranted. (Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606).

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Aims Increases in extravascular lung water (EVLW) during exercise contribute to symptoms, morbidity, and mortality in patients with heart failure and preserved ejection fraction (HFpEF), but the mechanisms leading to pulmonary congestion during exercise are not well-understood. Methods and results Compensated, ambulatory patients with HFpEF (n = 61) underwent invasive haemodynamic exercise testing using high-fidelity micromanometers with simultaneous lung ultrasound, echocardiography, and expired gas analysis at rest and during submaximal exercise. The presence or absence of EVLW was determined by lung ultrasound to evaluate for sonographic B-line artefacts. An increase in EVLW during exercise was observed in 33 patients (HFpEFLW+, 54%), while 28 (46%) did not develop EVLW (HFpEFLW−). Resting left ventricular function was similar in the groups, but right ventricular (RV) dysfunction was two-fold more common in HFpEFLW+ (64 vs. 31%), with lower RV systolic velocity and RV fractional area change. As compared to HFpEFLW−, the HFpEFLW+ group displayed higher pulmonary capillary wedge pressure (PCWP), higher pulmonary artery (PA) pressures, worse RV-PA coupling, and higher right atrial (RA) pressures during exercise, with increased haemoconcentration indicating greater loss of water from the vascular space. The development of lung congestion during exercise was significantly associated with elevations in PCWP and RA pressure as well as impairments in RV-PA coupling (area under the curve values 0.76–0.84). Conclusion Over half of stable outpatients with HFpEF develop increases in interstitial lung water, even during submaximal exercise. The acute development of lung congestion is correlated with increases in pulmonary capillary hydrostatic pressure that favours fluid filtration, and systemic venous hypertension due to altered RV-PA coupling, which may interfere with fluid clearance. Clinical trial registration NCT02885636.

Rationale Abnormalities in nitric oxide (NO) signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to NO in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use. Objective Determine whether inhaled nitrite improves hemodynamics in HFpEF. Methods and Results In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise, prior to and following treatment with inhaled sodium nitrite (90 mg) or placebo. The primary endpoint was the pulmonary capillary wedge pressure (PCWP) during exercise. Prior to study drug, HFpEF subjects displayed an increase in PCWP with exercise from 20±6 to 34±7 mmHg (p<0.0001). Following study drug administration exercise PCWP was substantially improved by nitrite as compared to placebo (baseline-adjusted mean 25±5 vs 31±6 mmHg, ANCOVA p=0.022). Inhaled nitrite reduced resting PCWP (−4±3 vs −1±2 mmHg, p=0.002), improved pulmonary artery compliance (+1.5±1.1 vs +0.6±0.9 ml/mmHg) and decreased mean pulmonary artery pressures at rest (−7±4 vs −3±4 mmHg, p=0.007) and with exercise (−10±6 vs −5±6 mmHg, p=0.05). Nitrite reduced right atrial pressures with no effect on cardiac output or stroke volume. Conclusions Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF. Clinical Trial Registration This single center randomized clinical trial is registered at clinicaltrials.gov (NCT02262078).

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.

In this review, we highlight the underlying mechanisms responsible for the sex differences in the exercise pressor reflex, and, importantly, the impact of sex hormones and menopausal status. The exercise pressor reflex is attenuated in pre-menopausal women compared to age-matched men. Specifically, activation of the metaboreflex (a component of the exercise pressor reflex) results in attenuated increases in blood pressure and sympathetic vasomotor outflow compared to agematched men. In addition, pre-menopausal women exhibit less transduction of sympathetic outflow to the peripheral vasculature than men. In stark contrast, post-menopausal women exhibit an augmented exercise pressor reflex arising from exaggerated metaboreflex-induced autonomic and cardiovascular reflexes. We propose that metaboreflex-induced autonomic and cardiovascular changes associated with menopause majorly contribute to the elevated blood pressure response during dynamic exercise in post-menopausal women. In addition, we discuss the potential mechanisms by which sex hormones in pre-menopausal women may impact the exercise pressor reflex as well as metaboreflex.

ImportanceReduced 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.ObjectiveTo 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 ParticipantsSingle-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.InterventionsA 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 MeasuresThe primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 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.ResultsOf the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,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 V̇o2,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 V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT02145351