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European Journal of Heart Failure 2005 7(6):1011-1016; doi:10.1016/j.ejheart.2004.10.021
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© 2005 European Society of Cardiology

Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure

Juan F. Delgadoa,*, Esther Condeb, Violeta Sáncheza, Fernando López-Ríosb, Miguel A. Gómez-Sáncheza, Pilar Escribanoa, Teresa Soteloa, Agustín Gómez de la Cámarac, José Cortinad and Carlos S. de la Calzadaa

a Heart Failure and Transplant Unit, Hospital "Doce de Octubre" Avenida de Córdoba sn, Km 5,400. 28041 Madrid, Spain
b Pathology Department, Hospital "Doce de Octubre" Madrid, Spain
c Clinical Epidemiology Unit, Hospital "Doce de Octubre" Madrid, Spain
d Cardiac Surgery Service, Hospital "Doce de Octubre" Madrid, Spain

* Corresponding author. Tel./fax: +34 91 3908669. E-mail address: jdelgado.hdoc{at}salud.madrid.org


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Pulmonary hypertension (PHT) associated with chronic heart failure (CHF) is a risk factor of right ventricular failure after heart transplantation (HT). Our aim was to study pulmonary vascular changes in patients with CHF and to assess any correlation with haemodynamic data.

Methods: We studied 17 HT recipients with preoperative CHF who died shortly after HT. Preoperative haemodynamic information was obtained immediately before HT. Vascular lesions in muscular arteries were assessed by linear morphometry. Haemodynamic data were correlated with the morphologic changes.

Results: Mean transpulmonary gradient (TPG) was 8.9±4.5 mm Hg and pulmonary vascular resistance (PVR) was 2.25±1.34 Wu. According to the threshold for at-risk PHT (TPG>12 mm Hg or PVR>2.5 Wu), six patients had at-risk PHT. Medial thickness was 23.82±7.23% in patients with at-risk PHT and 17.16±3.24% in patients without at-risk PHT (p=0.018).

Conclusions: Medial hypertrophy of muscular pulmonary arteries is more common and severe than expected in patients with CHF, even in patients without at-risk PHT. This structural change could explain why PHT, even in range of values not excluding HT, is a risk factor for right ventricular failure after HT and influences post-HT haemodynamic behaviour.

Key Words: Pulmonary hypertension • Heart failure • Pulmonary vasculopathy

Received May 23, 2004; Revised July 15, 2004; Accepted October 20, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Pulmonary hypertension (PHT), secondary to chronic heart failure (CHF), represents a major risk factor for morbidity and mortality following heart transplantation (HT) [1–13]. In fact, preoperative pulmonary vascular resistance (PVR) has a linear impact on mortality in heart transplant recipients [14].

Classically, PHT due to heart failure has been regarded as the passive consequence of high preloading of the left ventricle [15]. However, the pulmonary pressure values at rest remain high after HT and tend to decrease gradually; this has been confirmed by some longitudinal studies. Patients with higher levels of preoperative pulmonary pressure still maintain a residual PHT even 3 years after transplantation [13,16–20], suggesting the presence of structural changes in the pulmonary vasculature apart from high preload.

Indeed, the term "congestive vasculopathy" has been used for the morphological changes in pulmonary vasculature caused by congestion, most commonly found in rheumatic mitral stenosis [21]. However, in patients with cardiomyopathy and CHF this anatomic pattern has been less studied.

This study was performed in a retrospective manner to examine the structural changes in the pulmonary vasculature associated with CHF, and the relationship between the anatomic and the haemodynamic features.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
Between January 1991 and January 2002, 290 adult patients underwent heart transplantation at our hospital; 79 recipient deaths were recorded over the same period. We studied 17 patients (mean age 51.8 S.D. 7.7 years, 14 males and 3 females) who had a fatal outcome early after HT and who underwent an autopsy study. The aetiology in these patients was: ischemic heart disease (n=9, 52.9%), idiopathic dilated cardiomyopathy (n=4, 23.5%), valvular heart disease (n=3, 17.6%) and constrictive pericarditis (n=1, 5.9%). The mean time of the disease evolution (first ischemic episode or initial diagnosis of the disease) was 117±100 months.

Before HT, nine patients (53%) with cardiogenic shock were treated with intravenous inotropes and/or vasodilators (six dopamine and dobutamine, one dobutamine and prostacyclin, one dobutamine and one dopamine). Additionally, one patient was on mechanical ventilation, four had intraaortic balloon pumps and one had a biventricular assist device (Abiomed BVS 5000).

The remaining eight patients (47%) received only oral medical treatment (64% angiotensin-converting enzyme inhibitors, 17% carvedilol, 100% diuretics and 70% digitalis). The mean time between heart transplantation and death was 2.01±2.3 months. The causes of death were: seven infections (five Aspergillus, one cytomegalovirus and one tuberculosis), four early graft failures, three acute rejections, one stroke, one accelerated graft vascular disease and one constrictive pericarditis.

2.2. Haemodynamic evaluation before HT
Right heart catheterization was carried out routinely every 6 months in all patients on the waiting list for HT. Data from the last preoperative catheterization before HT was used for this study. The mean time between haemodynamic evaluation and HT was 1.8±2.2 months.

The baseline right atrial pressure (RAP), pulmonary arterial pressure (PAP) and pulmonary capillary wedge pressure (PCWP) were obtained. Cardiac output (CO) was calculated by the thermodilution method. Transpulmonary gradient (TPG), measured in mm Hg, was defined as the difference between the mean PAP and the mean PCWP. Pulmonary vascular resistance (PVR), measured in Wood units (Wu), was calculated as TPG/CO and PVR index (PVRI), measured in Wu/m2, express PVR corrected for body surface area.

According to the preoperative baseline catheterization data and accepted threshold for at-risk PHT, the population was divided into two groups: group A, six patients with at-risk PHT (TPG>12 mm Hg and/or PVR>2.5 Wu) and group B, 11 patients without at-risk PHT (TPG≤12 mm Hg and PVR≤2.5 Wu).

2.3. Morphologic studies
Morphologic studies were performed in all patients. Lung specimens were fixed immediately in 10% formalin, and processed routinely. Tissue samples were stained with haematoxylin and eosin, PAS, Masson, orcein, and elastic van Gieson. Muscular artery (100–1000 µm in diameter) vascular lesions were assessed by a linear morphometric method, using ocular micrometry. We examined 19±3 pulmonary artery segments using the method described by Wagenvoort et al. [22] and Rabinowitz et al. [23].

Thickness of the medial layer of the artery was assessed using the following formula: percent medial layer thickness=(2xmedial layer thickness/external diameter)x100; normal values less than 7% [24] (Fig. 1). In addition, the intimal fibrosis of the pulmonary arteries was studied. One observer performed all of the histological measurements (EC).


Figure 1
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  		Fig. 1 Muscular pulmonary arteries showing medial hypertrophy (van Gieson stainsx100). Thickness of the medial layer (MT) of the artery was studied by the included formula. Left: severe medial thickness. Arrow a measures medial layer and arrow b external diameter of artery. Right: mild medial thickness.

 
2.4. Data analysis
Data measurements are presented as the mean±standard deviation (S.D.) from the mean. We correlated all haemodynamic variables with the percentage medial thickness of the muscular arteries using simple linear regression analysis. Comparison of the mean values between groups was done using Student's t-test. Statistical significance was defined as a p-value lower than 0.05. Version 6.09 of the SAS computer programme (SAS Institute, SAS Campus Drive, Cary, NC 27513, USA) was used in the analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
According to the definition of PHT (pulmonary artery systolic pressure >30 mm Hg or mean pulmonary artery pressure ≥19 mm Hg) all patients, except one, had PHT before HT. The mean haemodynamic values in these patients were: RAP 11±7 mm Hg, mean PAP 28±9 mm Hg, PCWP 20±7 mm Hg and CO 4.2±1 l/min.

We examined muscular arteries with a diameter of 450.8±218.5 µm (range 170.6–883.4). Histologic studies showed an increase in the medial thickness of the muscular arteries in all patients. The percentage medial thickness was 19.5±5.8% (range 12.7–36.05). No significant intimal fibrosis of the pulmonary arteries was found.

There was a poor correlation between the haemodynamic variables and the percentage medial thickness (mPAP, β coefficient 0.348, p=0.17; TPG, β coefficient 0.321, p=0.21, PVR, β coefficient 0.296, p=0.24 and PVRI, β coefficient 0.200, p=0.43; Table 1 and Fig. 2).


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  		Table 1 Clinical, haemodynamic and anatomic characteristics of the study group

 


Figure 2
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  		Fig. 2 Linear correlation between the haemodynamic variables and the percentage medial thickness: (A) transpulmonary gradient and percentage medial thickness; (B) pulmonary vascular resistance and percentage medial thickness.

 
However, according to the preoperative baseline catheterization data and accepted threshold for at-risk PHT, the percentage medial thickness was 23.82±7.23 in group A (patients with at-risk PHT) and 17.16±3.24 in group B (patients without at-risk PHT) (p=0.018).

There was no correlation between the percentage medial thickness and either the native heart disease or the time of the disease evolution.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
4.1. Pathophysiology of pulmonary hypertension in CHF
In patients with CHF an elevation in the left ventricular filling pressure results in a "passive" increase in pulmonary venous pressure. It should be taken into account that pulmonary venous congestion is frequently associated with a "reactive" increase in the PVR, which results in an increased TPG that is superimposed on the pulmonary venous pressure. Initially, this reactive increase in PHT is secondary to pulmonary vasoconstriction and readily reversed by vasodilators.

However, secondary PHT or pulmonary venous hypertension may reflect "remodeling" of the arterial wall due to abnormalities of the elastic fibers, intimal fibrosis and medial hypertrophy. These changes eventually lead to reduced vasodilator responsiveness. Although possibly reversible over the time, the PHT attributable to structural remodeling is generally referred as "fixed" because it is not rapidly responsive to reversal with pharmacological treatments [25].

It is worth noting that the pathophysiology and pathoanatomy of the pulmonary vasculature in pulmonary venous hypertension have so far been described mainly in patients with rheumatic mitral stenosis [26].

To our knowledge, our study is the first to examine the structural changes in the pulmonary vasculature in a group of patients with CHF and their relationship with the haemodynamic features; however, Hasleton and Brooks [27] described changes in the pulmonary arteries and veins of two patients who died from right heart failure after heart transplant.

4.2. Congestive vasculopathy
Medial hypertrophy of muscular pulmonary arteries is the main pathologic finding in patients with congestive vasculopathy. This was present in all our patients and was often severe [24]. This increase in medial thickness was greater than the one observed in patients with idiopathic pulmonary hypertension with a comparable elevation of pressure [28], a finding previously reported by other authors [21]. This apparent discrepancy could be partly explained from the different aetiology of the pulmonary hypertension.

In adult patients with mitral valve disease, there is a poor correlation between the medial thickness and the associated pulmonary hypertension [21,26]. Also, in our patients there was a poor overall correlation of the severity of medial thickness with the results of right heart catheterization for a number of reasons: the variable time between catheterization and death, some of the deaths were due to failure of the donor heart which might itself have further modified the vascular changes, the inaccuracy of measurement of cardiac output by thermodilution and the poor concordance between the two methods of assessing pulmonary resistance (TPG and PVR) despite their physiological relationship.

However, in our patients with CHF those with higher pulmonary pressure had greater medial hypertrophy. One possible explanation of this novel finding is the different aetiology of the pulmonary venous hypertension. Another explanation is the different methods used for the morphologic studies. Goodale et al. [26] studied the correlation of pulmonary arteriolar resistance with pulmonary vascular changes in patients with mitral stenosis through a lung biopsy obtained at valvulotomy operation.

In our patient group, vascular lesions were assessed in 19±3 pulmonary artery segments per patient, obtained from different zones of each pulmonary lobule.

The high frequency and severity of medial hypertrophy in this setting may explain, at least in part, why PHT in patients with CHF, even in range of values not excluding HT, is a risk factor for right ventricular failure after HT and influences post-HT haemodynamic behaviour [13].

The second pathological change that we studied was the intimal fibrosis of the pulmonary arteries. A significant intimal fibrosis was not found in our patients. In congestive vasculopathy, intimal fibrosis of the pulmonary arteries is very common, and often extensive and severe [21]. The pathogenesis of arterial intimal fibrosis in pulmonary venous hypertension has not been established. However, it may be the result of intimal oedema as part of the general interstitial oedema caused by venous hypertension [21]. The disappearance of the interstitial oedema after HT may explain the absence of a significant intimal fibrosis in our patients.

The pulmonary veins and venules in congestive vasculopathy are affected in various ways: medial hypertrophy of the veins parallels that of the arteries and intimal fibrosis [21]. Hasleton and Brooks described advanced changes in the pulmonary arteries and veins of two patients who died from right heart failure after HT. Histological examination of the lungs showed occlusion of the pulmonary veins [27]. This is an exceptional change because intimal fibrosis is common in pulmonary veins and venules but usually not severe and obliterative [21]. A significant medial hypertrophy or intimal fibrosis of the veins was not found in our patients, presumably because of the relatively mild pulmonary hypertension in several cases.

In conclusion, we have shown that medial hypertrophy of muscular pulmonary arteries is more common and severe than expected in patients with advanced CHF, even in patients without at-risk PHT. This structural change could explain why PHT, even in range of values not excluding HT, is a risk factor for postoperative right ventricular failure after HT and influences post-HT pulmonary haemodynamic behaviour.

4.3. Study limitations
The validity of the present findings may be questioned because of the small number of patients. However, the difficulty in obtaining tissue samples in patients shortly after their haemodynamic evaluation cannot be overemphasised.

In addition, the heart transplantation procedure initiated the regression of morphologic changes, by normalising the elevation of left ventricular filling pressure. However, it must be considered that the mean time between heart transplant and autopsy was only 2.01±2.3 months, which is a relatively short period of time considering the above-mentioned limitation. Besides, this short period of time could not have had a major effect on pulmonary vascular remodeling [13]. However, it would be interesting to examine the pulmonary vascular bed of patients who died on the HT waiting list. This would help to clarify the issue of how much pulmonary vascular remodeling may occur after HT.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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