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Pulmonary Hypertension Is Related to Peripheral Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction
Study Questions:
Peripheral endothelial dysfunction (PED) has been described in heart failure (HF) and in pulmonary arterial hypertension (PAH). Is PAH associated with PED and impaired collagen metabolism in patients with HF with preserved ejection fraction (HFpEF)?
Methods:
Flow-mediated dilation (FMD) of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization.
Results:
Mean age was approximately 70 years. The HFpEF group had a much higher prevalence of atrial fibrillation (81% vs. 2%), and use of beta-blockers, diuretics, insulin, digoxin, and nitrates. Patients with HFpEF had more severe PED than controls: FMD 1.95% (−0.81 to 4.92) versus 5.02% (3.90 to 10.12), p = 0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure (mPA) 38 (27–52) mm Hg, wedge capillary pressure 18 (16–22) mm Hg, pulmonary vascular resistance (PVR) 362 (235–603) dyn s cm-5. There was a significant inverse correlation between FMD and PVR in patients with HFpEF and PH (r = −0.679; p = 0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mPA (r = 0.553; p = 0.014), transpulmonary gradient (r = 0.560; p = 0.013), and PVR (r = 0.626; p = 0.004).
Conclusions:
In patients with HFpEF, there is a significant correlation between PED and PVR. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.
Perspective:
The study was strengthened considerably by using patients with hypertension as controls. Cor pulmonale and right heart dysfunction are indicators of a poor outcome in HFpEF. PH is easily explained by pulmonary venous hypertension, but patients with HFpEF often have ‘out of proportion’ pre-capillary pulmonary hypertension or PAH, which might be a therapeutic target for PAH-specific drugs. Further, the association with extracellular protein matrix levels may provide a novel therapeutic target.
Keywords: Insulin, Pulmonary Wedge Pressure, Brachial Artery, Digoxin, Cardiac Catheterization, Diuretics, Tissue Inhibitor of Metalloproteinase-1, Collagen Type I, Nitrates, Heart Failure, Hypertension, Pulmonary, Atrial Fibrillation, Vascular Resistance, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Pulmonary Heart Disease
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