Diffusion Capacity in Patients with PH-HFpEF
Heart failure with preserved ejection fraction (HFpEF) has emerged as one of the most common cardiac diseases among the elderly.1-3 During the course of the disease, the majority of these patients develop pulmonary hypertension (PH),4 which can present either as isolated post-capillary PH or as post-capillary PH with a pre-capillary component.5 The development of PH in patients with HFpEF is associated with an increased mortality risk, in particular when there is a pre-capillary component.4, 6, 7
The mechanisms leading to PH in patients with HFpEF are incompletely understood and the same is true for causes of and contributors to the increased mortality risk in these patients. In a study of 339 patients with PH-HFpEF, Agarwal, et al identified several factors that were independently associated with mortality, including low blood pressure, low pulmonary arterial oxygen saturation, right ventricular hypertrophy, impaired kidney function, interstitial lung disease and low diffusion capacity for carbon monoxide (DLCO).8
A recent study from Hannover Medical School, Hannover, Germany further investigated the role of a low DLCO (defined as <45% of the predicted value) in 108 patients with PH-HFpEF, all but one suffering from post-capillary PH with a pre-capillary component as defined by a diastolic pressure gradient >7 mmHg and a pulmonary vascular resistance >240 dyn·s·cm-5.9 The average age was 72±7 years, 57% of the patients were female, mean pulmonary artery wedge pressure was 19 ± 3 mmHg, mean pulmonary artery pressure 45 ± 10 mmHg, and mean pulmonary vascular resistance 537 ± 216 dyn·s·cm-5. Almost half of these patients (n=52; 48%) presented with a low DLCO. Risk factors for a low DLCO were male sex (odds ratio 2.71; 95% confidence interval (CI), 1.05 to 6.99; p=0.039) and smoking history (odds ratio 5.01; 95% CI, 1.91 to 13.10; p<0.001). Pulmonary function was otherwise normal or near-normal. Where available, chest computed tomography showed mostly normal findings or mild abnormalities, thereby excluding the presence of emphysema or interstitial lung disease in the majority of patients.
Compared to patients with DLCO≥45%, patients with DLCO<45% had a significantly worse survival. The 3-year survival rate was 36.5% in patients with a low DLCO versus 87.8% in patients with DLCO≥45% (p<0.001 by log rank analysis). Cox proportional hazard analysis identified a low DLCO as an independent predictor of death (hazard ratio 7.0; 95% confidence interval 2.8 to 17.6; p<0.001). Each 10% decline in the DLCO was associated with a hazard ratio of 1.6 (95% confidence interval 1.2 to 2.0; p<0.001). The only other independent predictor of mortality was male sex. Hemodynamics were not predictive of death. The authors concluded that a low DLCO was strongly associated with mortality in patients with PH-HFpEF.
The data from Hannover confirm previous findings by Agarwal, et al showing that a low DLCO is an independent predictor of mortality in patients with PH-HFpEF. In the Hannover series, virtually all patients had post-capillary pulmonary hypertension with a pre-capillary component. The authors raised the hypothesis that a low DLCO may reflect the presence of a small-vessel vasculopathy that affects the pulmonary capillaries and the post-capillary venules. Autopsy or biopsy data were not available from this study, but there are a few reports in the medical literature showing pulmonary capillary hemangiomatosis-like lesions in patients who died from congestive heart failure.10, 11 Such lesions would well explain an impaired diffusion capacity. Another potential explanation for a low DLCO could be a smoking-induced loss of pulmonary microvessels as it has been demonstrated in animal models.12 Still, although a low DLCO was strongly associated with a history of smoking, about one third of the patients in the low DLCO group from the Hannover cohort never smoked. More detailed histomorphological studies are required to understand the mechanisms causing a low DLCO in patients with heart failure.
For now, there are no clear therapeutic implications that could be derived from detecting a low DLCO in patients with PH-HFpEF. Still, given its strong predictive power, DLCO should be measured in these patients as it should be part of the diagnostic work-up of any patient with severe PH.5 Understanding the mechanisms resulting in a low DLCO may help to develop treatment strategies for this group of patients for whom effective treatments are not yet available. Additionally, sponsors of future clinical trials in patients with PH-HFpEF should consider stratifying their cohorts according to baseline DLCO given the strong impact on survival.
- Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL,Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251-9.
- Redfield MM, Jacobsen SJ, Burnett JC, Jr., Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003;289:194-202.
- Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respir Med 2016. [Epub ahead of print].
- Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009;53:1119-26.
- Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2015;46:903-75.
- Gerges C, Gerges M, Lang MB, et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in "out-of-proportion" pulmonary hypertension. Chest 2013;143:758-66.
- Gerges M, Gerges C, Pistritto AM, et al. Pulmonary Hypertension in Heart Failure. Epidemiology, Right Ventricular Function, and Survival. Am J Respir Crit Care Med 2015;192:1234-46.
- Agarwal R, Shah SJ, Foreman AJ, et al. Risk assessment in pulmonary hypertension associated with heart failure and preserved ejection fraction. J Heart Lung Transplant 2012;31:467-77.
- Hoeper MM, Meyer K, Rademacher J, Fuge J, Welte T, Olsson KM. Diffusion Capacity and Mortality in Patients With Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction. JACC: Heart Failure 2016. [Epub ahead of print].
- Jing X, Yokoi T, Nakamura Y, et al. Pulmonary capillary hemangiomatosis: a unique feature of congestive vasculopathy associated with hypertrophic cardiomyopathy. Arch Pathol Lab Med 1998;122:94-6.
- Wang KY, Tanimoto A, Inenaga T, et al. Pulmonary capillary hemangiomatosis in chronic cardiac failure due to aortic stenosis. J UOEH. 2009;31:339-44.
- Seimetz M, Parajuli N, Pichl A, et al. Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 2011;147:293-305.
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