Left ventricular heart failure and pulmonary hypertension†

Pathobiology of pulmonary hypertension related to left heart disease

The pathobiology of PH in left HF is complex and highly heterogeneous, and remains incompletely understood. Pulmonary hypertension primarily results from the passive backward transmission of elevated left-sided filling pressures, which occur as a consequence of systolic or diastolic LV dysfunction (Figure 1).11 Furthermore, functional mitral regurgitation (MR) will result in elevations of LAP and PAP, which usually worsen during exercise. In addition to LV remodelling and dysfunction, an increase in LA size (which is relatively load-independent and serves as a marker of morbidity and mortality in HF), interstitial fibrosis causing LA stiffness, and reduced LA compliance, as well as impaired LA contractility, contribute to pathogenic alterations in the pulmonary circuit and right heart (Figure 2). These alterations of LA diastolic and systolic properties affect cardiac filling and output, and the backward transmission of elevated left-sided filling pressures leads to an increase of pulmonary pressures, particularly during exercise.25,26 Consistently, LA dysfunction relates to symptom onset in patients with HFpEF.27 In addition to its pathophysiological significance, LA dysfunction may also determine treatment responses to targeted PH therapies in patients with LHD, since lowering of PVR and increased pulmonary blood flow may lead to increased PAWP and pulmonary oedema in patients with reduced LA compliance.

In the pulmonary circulation, sudden increases of LAP may cause ‘alveolar-capillary stress failure’, a reversible barotrauma altering endothelial permeability and allowing leakage of erythrocytes, proteins, and fluid into the alveolar lumen, thus causing interstitial and alveolar oedema. Sustained elevation of left-sided filling pressure and pulmonary venous pressure may be accompanied by superimposed components in the pulmonary circuit, which include decreased NO availability, increased expression of endothelin-1, desensitization to natriuretic peptide-induced vasodilatation, infiltration of inflammatory cells, and neurogenic or metabolic factors.11 Furthermore, hypoxia promotes vasoconstriction and growth responses in the pulmonary circuit,28 and tachyarrhythmias, particularly atrial fibrillation, may precipitate PH in patients with LV HF. These additional components may trigger pulmonary arterial vasoconstriction, and—over time—structural remodelling of small pulmonary resistance arteries, indicative of a pre-capillary component of PH where PAP further increases in excess of PAWP elevation (Figure 1). Indeed, pulmonary arteriolar remodelling similar to PAH has been described in severe PH-LHD, particularly in patients with Cpc-PH (DPG ≥7 mmHg).10 Histopathological changes include thickening of the alveolar-capillary membrane, medial hypertrophy, intimal and adventitial fibrosis, and luminal occlusion in small pulmonary arterioles, whereas ‘plexiform lesions’ pathognomonic of PAH are not usually found.10,29,30 The fact that unloading of the LV by implantation of a LV assist device (LVAD) in patients with HFrEF and severe ‘fixed’ PH may substantially lower or even normalize PAP over time indicates that the alterations in the pulmonary circulation are partly reversible at least in some patients.31,32 In contrast to the systemic circulation, where vascular compliance is mainly determined by the aorta, arterial compliance in the lung is distributed over the entire pulmonary vascular bed, so that resistance (R) and compliance (C) are predominantly determined by the small resistance vessels. Hence, pulmonary arteriolar remodelling mainly contributes to the increase in PVR and reduced PA compliance in Cpc-PH.

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Of interest, there is an inverse relation between R and C in the pulmonary circulation, and this holds true in PH-LHD.22,33 The product of R and C (RC time) determines the drop in PAP after pulmonary valve closure. It was found that in left HF with increased PAWP, the RC time under the influence of the increased PAWP is slightly decreased in comparison with PAH (Figure 3). Whether this is due to abnormal pulmonary venous remodelling, increased pulmonary vascular tone in left HF or just the consequence of the increased wedge pressure on the RC time calculations remains unknown. It has been suggested that the pressure gradient between the diastolic PAP and PAWP (DPG) is less dependent on volume load and stroke volume than the TPG, and that an elevated DPG may therefore be a better indicator of a pre-capillary component of PH.9 However, the DPG may not be an ideal parameter, as it is subject to inaccuracies related to heart rate, hypoxia, catheter whip, utilizing computer-generated measurements, and the presence of negative values or elevated DGP without PH. While in two retrospective studies, the DPG was shown to be a predictor of survival in PH-LHD,10,22 two other studies failed to demonstrate a prognostic impact of the DPG in patients with cardiomyopathy or heart transplantation and PH.14,24 Thus, its role for prognostication of survival and/or response to PH therapies must be further explored. Another implication of the constant RC is that based on the inverse relationship between compliance and resistance, PA compliance is a more sensitive marker for early disease than PVR. Indeed, a reduced PA compliance and abnormal RV/PA coupling are found even in early stages of HFpEF, and PA compliance appears to be prognostically relevant even with normal PVR.21–23,34,35

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The elevations of pulmonary pressures and PVR represent an increase of both resistive and pulsatile RV afterload, which results in dilatation and maladaptive remodelling of right heart chambers, functional tricuspid regurgitation, and ultimately RV dysfunction and failure. Pathological changes of the RV include hypertrophy, fibrosis, dilatation, and a change in RV shape from a crescent to a more spherical shape, which is associated with functional tricuspid regurgitation and elevated right atrial pressure (RAP). Right ventricular dysfunction resulting in low cardiac output is a key determinant of outcome in PH-LHD. In fact, the prognostic significance of an elevated PAP in HF increases with the degree of RV dysfunction irrespective of LVEF.13,19 However, the relationship between the severity of PH and RV dysfunction is not ‘linear’, as some patients with severe PH display normal RV function. In summary, a dysfunctional RV and clinical signs of right HF in patients with LHD occur as a consequence of pathological changes at the level of the ventricles, atrioventricular valves, and atria in both the left and right heart, and complex pathomechanisms of cardiopulmonary interaction affecting PVR and PA compliance determine the impact of LHD on the right heart (Figure 3).

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About the Author: Tung Chi