Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction

Abstract

Background: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF.

Methods: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter.

Results: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs.

Conclusions: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Keywords: diffusing capacity of the lungs for carbon monoxide; heart failure; heart failure with preserved ejection fraction; pulmonary function; pulmonary hypertension; right ventricle.

Figure 1. Variable pulmonary vascular remodeling in study groups

For each patient with Heart Failure and Pulmonary Hypertension (with preserved (HFpEF) or reduced (HFrEF) ejection fraction), the median (center dot) and interquartile range (vertical line) for the percent medial thickness (% MT, arteries) and % intimal thickness (%IT, arteries, veins and indeterminate vessels (IV)) in all vessels analyzed in each patient are shown. Similar data are shown in comparator groups (Controls and Pulmonary Veno-occlusive Disease, PVOD).

Figure 2. Pulmonary arteries, veins and indeterminate vessels in study groups

Representative vessels with remodeling approximating the median values for medial and intimal thickening of arteries, veins and indeterminate vessels (IV) in each study group are shown. Rows represent cohort groups (from top; Controls, HFrEF, HFpEF and PVOD). Columns represent vessel type (from left; arteries, veins and indeterminate vessels). In Controls; A (artery:ED152 μm), B (vein: ED 247 μm) and C (IV: ED 121 μm). In HFrEF; D (artery: ED 173 μm), E (vein: ED 181 μm) and F (IV: ED 193 μm). In HFpEF; G (artery: ED 176 μm), H (vein: ED113 μm) and I (IV: ED 175 μm). In PVOD; J (artery: ED 148 μm), K (vein: ED 60 μm) and L (IV; ED135 μm). Abbreviations: ED, external diameter; HF, Heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; %IT, percent intimal thickness; %MT, percent medial thickness; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease.

Figure 3. Character of pulmonary venous intimal remodeling in study groups

Rows represent cohort groups (from top; controls, HFrEF, HFpEF and PVOD). Columns represent nature of venous intimal remodeling (from left; dense fibrosis, loose fibrosis and intimal hyalinosis). In Controls: A (ED 152 μm), B (ED 183 μm) and C (ED 119 μm). In HFrEF: D (ED 275 μm), E (ED 98μm) and F (ED 162 μm). In HFpEF: G (ED 347 μm), H (ED 118 μm) and I (ED 125 μm). In PVOD: J (ED 206 μm), K (ED 60 μm) and L (ED 93 μm).

Figure 4. Relationship between pulmonary vascular remodeling and severity of pulmonary hypertension

The relationship between medial (A) and intimal (B) thickening of arteries and intimal thickening of veins (C) and IVs (D) and the severity of pulmonary hypertension as assessed by Doppler echocardiographic estimation of pulmonary artery systolic pressure (PASP) in HF-PH (HFpEF and HFrEF) and pulmonary veno-occlusive disease (PVOD). The solid line represents the estimated PASP via linear regression based on medial/intimal thickening, and the dotted lines represent the 95% confidence interval. Abbreviations: % MT, percent medial thickening; % IT, percent intimal thickening Note, one outlier (HFpEF patient with a PASP of 153 mmHg) is not shown on this scale.

Figure 5. Pulmonary vascular structure in HF-PH and PVOD patients with elevated transpulmonary gradient

Examples representative of the mean histomorphometry values for all vessels within the patient in three patients with approximately similar degrees of elevation in the transpulmonary gradient (TPG) are shown. Rows indicate cohort group; from top, HFrEF, HFpEF and PVOD). Columns represent vessel type (from left; arteries, veins and indeterminate vessels [IV]). Top row, HFrEF: A (artery, ED 219 μm), B (vein, ED122 μm) and C (IV, ED 60 μm). Middle row, HFpEF: D (artery, ED 220 μm), E (vein, ED 86 μm) and F (IV, ED 69 μm). Bottom row, PVOD: G (artery, ED 151 μm), H (vein, ED 48 μm) and I (IV, ED 86 μm).

Figure 6. Relationship between pulmonary vascular remodeling and invasively measured transpulmonary gradient

The relationship between medial (A) and intimal (B) thickening of arteries and intimal thickening of veins (C) and IVs (D) and the severity of pulmonary hypertension as assessed by the transpulmonary gradient measured at right heart catheterization in HF-PH (HFpEF and HFrEF) and pulmonary veno-occlusive disease (PVOD). The solid line represents the estimated TPG via linear regression based on medial/intimal thickening, and the dotted lines represent the 95% confidence interval. Abbreviations: % MT, percent medial thickening; % IT, percent intimal thickening