Obokata, Masaru

Abstract 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.

Abstract Aims Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. Methods and results Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = −0.52 and −0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s′ and e′ tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e′, r = −0.59 and −0.67, both P < 0.001), reduced cardiac output responses to exercise (r = −0.59 and −0.61, both P < 0.0001), and more severely impaired peak VO2 (r = −0.60 and −0.67, both P < 0.0001). Conclusion Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. Clinical trial registration NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search

Abstract Aims Left atrial (LA) function is impaired in heart failure with preserved ejection fraction (HFpEF) and predicts disease severity and risk of adverse outcome. We sought to evaluate whether LA strain could enhance diagnosis of HFpEF. Methods and results Consecutive patients with unexplained exertional dyspnoea and image quality suitable for measuring LA strain underwent invasive cardiopulmonary exercise testing to ascertain the presence of HFpEF or non-cardiac causes of dyspnoea (NCD). LA reservoir strain was measured in all patients, while LA conduit and booster strain were measured in patients with sinus rhythm. LA strain was measurable in 363 of 378 examinations (96.5%; HFpEF: 238, NCD: 125). LA reservoir strain (29 ± 16% vs. 40 ± 13%, P < 0.0001) and conduit strain (18 ± 10% vs. 22 ± 10%, P = 0.0001) were significantly impaired in HFpEF compared to NCD. Of all echocardiographic indices, LA reservoir strain best discriminated HFpEF from NCD [area under the curve (AUC) 0.719, P < 0.0001], outperforming E/e' (AUC difference +0.117, P < 0.0001), LA enlargement (+0.090, P = 0.001), tricuspid regurgitation velocity > 2.8 m/s (+0.082, P = 0.0085), left ventricular hypertrophy (+0.0159, P < 0.0001) and left ventricular global longitudinal strain (+0.0198, P < 0.0001). Indexing LA reservoir strain to estimated LA pressure (E/e') as a surrogate for LA compliance further improved diagnostic performance (AUC 0.772, P < 0.0001; +0.053 compared to LA reservoir strain alone, P = 0.003). Conclusion Left atrial reservoir strain may provide enhanced diagnostic accuracy beyond conventional echocardiographic measures to discriminate HFpEF from NCD. Further study is required to verify the diagnostic utility of LA strain.

Rationale: Pulmonary vascular resistance fails to decrease appropriately during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Interventions that enhance pulmonary vasodilation might be beneficial in this cohort but could also worsen left atrial hypertension, exacerbating lung congestion. Intravenous β-agonists reduce pulmonary vascular resistance but are not suitable for chronic use. Objective: We hypothesized that the inhaled β-adrenergic agonist albuterol would improve pulmonary vasodilation during exercise in patients with HFpEF, without increasing left heart filling pressures. Methods and Results: We performed a randomized, double-blind, placebo-controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in subjects with HFpEF using high-fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance during exercise. Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo. Rest and exercise hemodynamic testing was then repeated. Albuterol improved the primary end point of exercise pulmonary vascular resistance as compared with placebo (−0.6±0.5 versus +0.1±0.7 WU; P =0.003). Albuterol enhanced cardiac output reserve and right ventricular pulmonary artery coupling, reduced right atrial and pulmonary artery pressures, improved pulmonary artery compliance, and enhanced left ventricular transmural distending pressure (all P <0.01), with no increase in pulmonary capillary hydrostatic pressures. Conclusions: Albuterol improves pulmonary vascular reserve in patients with HFpEF without worsening left heart congestion. Further study is warranted to evaluate the chronic efficacy of β-agonists in HFpEF and other forms of pulmonary hypertension. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02885636.

Abstract Aims Prevalent right ventricular (RV) dysfunction (RVD) is associated with increased mortality in patients with heart failure with preserved ejection fraction (HFpEF), but no study has characterized long-term changes in RV structure and function within the same patient. Methods and results Patients with unequivocal HFpEF defined by either invasive haemodynamics or hospitalization for pulmonary oedema (n = 271) underwent serial echocardiographic evaluations &gt;6 months apart. Clinical, structural, functional, and haemodynamic characteristics were examined. Over a median of 4.0 years (interquartile range 2.1–6.1), there was a 10% decline in RV fractional area change and 21% increase in RV diastolic area (both P &lt; 0.0001). These changes greatly exceeded corresponding changes in the left ventricle. The prevalence of tricuspid regurgitation increased by 45%. Of 238 patients with normal RV function at Exam 1, 55 (23%) developed RVD during follow-up. Development of RVD was associated with both prevalent and incident atrial fibrillation (AF), higher body weight, coronary disease, higher pulmonary artery and left ventricular filling pressures, and RV dilation. Patients with HFpEF developing incident RVD had nearly two-fold increased risk of death (adjusted hazard ratio 1.89, 95% confidence interval 1.01–3.44; P = 0.04). Conclusion While previous attention has centred on the left ventricle in HFpEF, these data show that right ventricular structure and function deteriorate to greater extent over time when compared with changes in the left ventricle. Further study is required to evaluate whether interventions targeting modifiable risk factors identified for incident RVD, including abnormal haemodynamics, AF, coronary disease, and obesity, can prevent RVD and thus improve outcomes.

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging in euvolemic patients with dyspnea, and no evidence-based criteria are available. We sought to develop and then validate noninvasive diagnostic criteria that could be used to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea to guide further testing. Methods: Consecutive patients with unexplained dyspnea referred for invasive hemodynamic exercise testing were retrospectively evaluated. Diagnosis of HFpEF (case) or noncardiac dyspnea (control) was ascertained by invasive hemodynamic exercise testing. Logistic regression was performed to evaluate the ability of clinical findings to discriminate cases from controls. A scoring system was developed and then validated in a separate test cohort. Results: The derivation cohort included 414 consecutive patients (267 cases with HFpEF and 147 controls; HFpEF prevalence, 64%). The test cohort included 100 consecutive patients (61 with HFpEF; prevalence, 61%). Obesity, atrial fibrillation, age >60 years, treatment with ≥2 antihypertensives, echocardiographic E/e’ ratio >9, and echocardiographic pulmonary artery systolic pressure >35 mm Hg were selected as the final set of predictive variables. A weighted score based on these 6 variables was used to create a composite score (H 2 FPEF score) ranging from 0 to 9. The odds of HFpEF doubled for each 1-unit score increase (odds ratio, 1.98; 95% CI, 1.74–2.30; P <0.0001), with an area under the curve of 0.841 ( P <0.0001). The H 2 FPEF score was superior to a currently used algorithm based on expert consensus (increase in area under the curve of 0.169; 95% CI, 0.120–0.217; P <0.0001). Performance in the independent test cohort was maintained (area under the curve, 0.886; P <0.0001). Conclusions: The H 2 FPEF score, which relies on simple clinical characteristics and echocardiography, enables discrimination of HFpEF from noncardiac causes of dyspnea and can assist in determination of the need for further diagnostic testing in the evaluation of patients with unexplained exertional dyspnea.