Heart-Lung Interaction and Its Prognostic Significance in Heart Failure Patients With Preserved Ejection Fraction
Article ID: CJ-21-0358
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Article ID: CJ-21-0358
Heart failure (HF) patients often develop changes in pulmonary function, ranging from minimal restriction to a mixed restrictive/obstructive pattern.1,2 In acute decompensated HF (ADHF), as left ventricular (LV) filling pressure increases, interstitial lung edema develops. Lung edema causes reductions of forced vital capacity (FVC) and lung diffusing capacity.3 Because the lungs and heart reside in an enclosed thorax, cardiac enlargement contribute to the changes in intrathoracic pressure and pulmonary function, which result in restrictive pattern manifested as reductions in FVC.2 Furthermore, neurohumoral changes, lung fluid imbalance, chronic pulmonary hypertension (PH), respiratory muscle weakness, and inflammation have been reported to contribute to abnormal pulmonary function in HF.4 Therefore, it is conceivable that a pulmonary function test (PFT) reflects the disease severity of HF. In fact, earlier reports demonstrated that spirometry provides prognostic information for all-cause mortality in hospitalized ADHF,5 and compensated HF patients.6
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In this issue of the Journal, Kawakami et al7 report a retrospective cohort study of the prevalence and prognostic significance of abnormal PFT in hospitalized ADHF patients before discharge. They show the high prevalence (63.0%) of abnormal PFT and a particularly restrictive pattern was detected in the majority (36.7%) of patients. In their study population, the prevalence of a restrictive pattern in HF with preserved ejection fraction (HFpEF) was significantly higher than in HF with reduced ejection fraction (HFrEF) (43.3% vs. 30.0%). They also show that the cardiothoracic ratio (CTR) and atrial fibrillation were significant independent predictors of an abnormal PFT. The relationship between CTR and an abnormal PFT suggests that cardiac enlargement contributes to restrictive lung changes and it has prognostic significance in ADHF. As mentioned above and discussed by the authors,7 mechanical compression caused by an enlarged heart, but also HF itself, can cause PFT abnormalities by multiple causes such as congestion, inflammation and alveolar-capillary remodeling. Indeed, as spirometry is a non-invasive assessment of pulmonary function, clinicians could obtain useful information of prognosis in daily practice. Furthermore, most intriguingly, Kawakami et al7 show that restrictive and mixed pulmonary dysfunction were independent predictors of cardiovascular events in patients with HFpEF, but not in those with HFrEF, after multivariate analyses. Although underlying mechanisms were undetermined, it was reported that heart-lung interaction plays a crucial role in the pathophysiology of HFpEF.8 Hemodynamically, HFpEF is characterized by increased LV filling pressure secondary to diastolic dysfunction; this pressure elevation could be observed at rest or is exacerbated by exercise and causes postcapillary PH.4,8 Postcapillary PH causes elevated hydrostatic pressure, injury of the alveolar-capillary membrane, and fluid retention in the interstitium. Then, activation of inflammatory mediators promotes alveolar-capillary and microvascular remodeling, which impairs alveolar-capillary gas transfer, as reflected by an abnormal PFT (Figure).9 In the study by Kawakami et al,7 however, markers of congestion including tricuspid regurgitation peak velocity and brain natriuretic peptide levels were comparable in normal and abnormal PFTs in HFpEF patients. This discordance might be attributed to the severity of chronic alveolar-capillary interface remodeling, independent of congestion. Their study had a limitation in generalizability because the study sample displayed only ADHF patients before discharge. Thus, the prevalence and prognostic significance of an abnormal PFT in a larger, unbiased HFpEF population remains unclear. Large-scale studies will be needed to better understand the heart-lung interaction in HF. Nevertheless, the authors are to be commended on this important contribution that establishes the importance of PFTs in risk stratification for cardiovascular events in terms of HFpEF.
Possible mechanisms by which hemodynamic abnormalities alter pulmonary function in HFpEF patients. Diastolic dysfunction is the cause of increased LV filling pressure and LA pressure, followed by postcapillary PH. The increased pressure promotes hypertrophy and fibrotic changes in the pulmonary arteries and veins (pulmonary vascular remodeling). Chronically elevated hydrostatic pressure injures the alveolar-capillary membrane, resulting in leakage of protein, activated extracellular matrix and collagen deposition, then leads to impairment of gas diffusion (alveolar-capillary stress failure). HFpEF, heart failure with preserved ejection fraction; LA, left atrium; LV, left ventricle; MR, mitral regurgitation; PH, pulmonary hypertension.
Considering that the lungs are damaged and contribute to adverse outcomes in terms of HFpEF, heart-lung interactions can be a therapeutic target. Of note, in the CHAMPION trial, pulmonary artery pressure-guided diuretic therapy using an implantable monitoring device substantially reduced HF hospitalizations in a HFpEF population.10 Furthermore, Yoshihisa et al11 reported that adaptive servo-ventilation improved the prognosis of HFpEF patients with sleep-disordered breathing. In contrast, well-established efficacious medical therapies for HFrEF, including β-blockers, renin-angiotensin-aldosterone antagonists and sacubitril-valsartan, have failed to demonstrate a benefit for HFpEF.12 Recent randomized trials for HFpEF, which targeted cyclic guanosine monophosphate13,14 or the nitric oxide signaling,15 also failed to improve outcomes. These studies showed the difficulties of therapeutic development in patients with HFpEF, many of whom have multiple comorbidities. As the pathophysiology of HFpEF is heterogeneous,4 therapeutic attempts with a single agent that stimulates or inhibits a particular signaling seem insufficient for better outcomes. Despite the multiple confounding factors in initiation and progression, they seem to converge at the common clinical phenotypes of HFpEF, characterized by high left-sided filling pressures and PH secondary to diastolic dysfunction, complicated by remodeling of pulmonary vasculature and the alveolar-capillary interface, leading to abnormal PFTs (Figure). In this issue of the Journal, Kawakami et al7 provide a new important message that abnormal PFTs not only acted as a marker of disease severity, but also significantly elevated a risk for cardiovascular events independently in HFpEF patients. Novel therapies targeting heart-lung interaction have emerged as an initial step towards achieving the goals of improved HFpEF prognosis.
N.S. is a member of Circulation Journal’s Editorial Team.
