Pulmonary Hypertension Due to Left Heart Disease
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.111.085761
ISSN1524-4539
AutoresMarco Guazzi, Barry A. Borlaug,
Tópico(s)Cardiac Valve Diseases and Treatments
ResumoHomeCirculationVol. 126, No. 8Pulmonary Hypertension Due to Left Heart Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBPulmonary Hypertension Due to Left Heart Disease Marco Guazzi, MD, PhD, FACC and Barry A. Borlaug, MD, FACC Marco GuazziMarco Guazzi From the Heart Failure Unit, Cardiology, I.R.C.C.S., Policlinico San Donato, Department of Medical Sciences, University of Milano, San Donato Milanese, Milano, Italy (M.G.); and the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (B.A.B.). and Barry A. BorlaugBarry A. Borlaug From the Heart Failure Unit, Cardiology, I.R.C.C.S., Policlinico San Donato, Department of Medical Sciences, University of Milano, San Donato Milanese, Milano, Italy (M.G.); and the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (B.A.B.). Originally published21 Aug 2012https://doi.org/10.1161/CIRCULATIONAHA.111.085761Circulation. 2012;126:975–990IntroductionPulmonary hypertension (PH) due to left heart disease, classified as group 2 according to the Dana Point 2008 classification, is believed to be the most common cause of PH and is associated with high morbidity and mortality. Epidemiological studies of group 2 PH are less exhaustive than for rarer causes of PH such as isolated pulmonary vasculopathies, but attention for this entity is growing rapidly. Group 2 PH may be caused by passive downstream elevation in left heart pressures or by a combination of the latter with pulmonary arteriolar pathologies. Improved understanding of the perturbations in pulmonary vascular structure and function that cause PH due to left heart disease is essential to reduce heart failure morbidity and mortality. In this review, epidemiology, mechanisms, diagnostic approaches, hemodynamic models, and clinical trials of heart failure complicated by group 2 PH are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.DefinitionsInterest in group 2 PH has historically been confined to mitral valve disease and advanced stages of heart failure (HF), wherein clinical manifestations of right ventricular (RV) failure carry an extremely unfavorable prognosis.1–3 Clinical recognition of group 2 PH has expanded, with recent studies demonstrating that increases in rest and exercise pulmonary arterial pressures may accompany normal aging4,5 and that patients with HF and preserved ejection fraction (HFpEF) frequently also display PH.6Although left heart disease is believed to represent the most common form of PH, epidemiological data are less abundant in this group in comparison with others.7 The most recent European Guidelines define group 1 PH as a chronic elevation of a mean pulmonary arterial pressure ≥25 mm Hg in association with normal pulmonary capillary wedge pressure (PCWP; ≤15 mm Hg; Table).8 This type of PH has historically been referred to as pulmonary arterial hypertension (PAH), because the pathological process resides at the level of the vasculature. In this review, the term PH refers to any elevation in mean pulmonary arterial pressure ≥25 mm Hg, and PAH is referred to as group 1 PH. Previous guidelines had stipulated that an increase in mean pulmonary arterial pressure to ≥30 mm Hg with exercise was also diagnostic of PAH, but a recent meta-analysis showed that normal aging may be associated with significant elevation in pulmonary arterial pressure (PAP) during exercise,9,10 even in the apparent absence of disease. The updated guidelines have removed this exercise criterion for PAH, although recent studies in patients with unexplained dyspnea have shown that PAP elevation during exercise may be an important clue to the presence of underlying HF, suggesting an important role for exercise hemodynamic assessment in the evaluation of possible HFpEF.11,12Table. Hemodynamic Classification of Pulmonary HypertensionPatient GroupMean PAP (mm Hg)PCWP (mm Hg)TPG (mm Hg)PVR (mm Hg/L per min)Normal*14±38±36±20.9±0.4Group 1 PH†≥25≤15>12 to 15‡>2.5 to 3.0‡Group 2 PH, passive†≥25>15≤12 to 15‡ 15>12 to 15‡>2.5 to 3.0‡PH indicates pulmonary hypertension; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; and PVR, pulmonary vascular resistance.*Data taken from Kovacs et al.9,10†Data taken from Galiè et al.8‡Partition values for TPG and PVR used for these definitions have varied between studies and there is no strong evidence to support 1 partition value over the other at this time.The key hemodynamic feature that differentiates group 2 PH from others is PCWP elevation (>15 mm Hg; Table). Group 2 PH patients may present with elevation in PAP and no or only minimal increase in the transpulmonary gradient (TPG: mean PAP-PCWP ≤12–15 mm Hg). In these circumstances (often referred to as passive or postcapillary), PH is merely a reflection of the increase in downstream left heart pressures, and pulmonary vascular resistance (PVR) is normal. Group 2 PH patients may progress to a reactive PH stage, with an increase in TPG and PVR. This form of group 2 PH is often termed precapillary or mixed. For reasons that remain unclear, a number of patients do not progress to develop marked reactive pulmonary vasoconstriction, despite the presence of chronic advanced HF.1 Because TPG is flow dependent (varying directly with cardiac output, CO), some authorities prefer PVR (defined as TPG/CO) as a means of distinguishing passive and reactive. The most recent American College of Cardiology Foundation/American Heart Association PH consensus document did not include a PVR >3 Wood units (WU) in the definition of group 1 PH, although this has been a matter of debate.13 An advantage of using PVR over TPG is that it normalizes for blood flow. A disadvantage is that any error incurred in the determination of CO will affect the derived value of PVR. This can become quite significant in low-output states as often observed in HF.The widespread use of transthoracic echocardiography, which allows estimation of the right ventricular systolic pressure (RVSP) from the velocity of tricuspid regurgitation by adding a given right atrial pressure, has led to increased appreciation of the burden of PH in patients with cardiovascular disease, and in the general population without apparent cardiovascular disease, as well.14 Estimated RVSP is often used interchangeably with pulmonary artery systolic pressure (PASP), an assumption that relies on the absence of pulmonary valve stenosis. PH is considered mild if the echo-estimated PASP is 35 to 45 mm Hg, moderate if it is 46 to 60 mm Hg, and severe when >60 mm Hg. However, it is important to appreciate that correlations between echo and invasive data are modest (r≈0.7),15 and substantial disagreement may be observed with gold standard invasive measures16 Previous studies have shown inaccurate PASP estimation ranging from 48% to 54%, and PASP may be over- or underestimated from the tricuspid regurgitant velocity.17,18Catheterization is essential to make the diagnosis of PH and is particularly critical when clinical decisions and therapeutic interventions are going to be made based on PAP measurements. The diagnosis of HFpEF is often made based on echocardiographic parameters alone,19 although catheterization remains the gold standard to characterize diastolic properties at rest and with stress and is often required in patients in whom the pretest probability of HFpEF is intermediate after review of clinical and noninvasive data.12,20EpidemiologyRecent studies from Olmsted County5,6 have shed new light on the burden of left-sided PH, both in the general community and in HFpEF. Lam et al5 reported data from a prospective study of randomly recruited adults, including 1413 subjects with estimated PASP at Doppler echocardiography. They showed that the median PASP by echocardiography was 26 mm Hg, and 6.6% of the participants had a PASP ≥36 mm Hg. Aging, increased LV filling pressures (estimated by E/e′ ratio), and systemic vascular stiffening (brachial pulse pressure) were each associated with increasing PASP. Importantly, PASP was the strongest predictor of mortality in comparison with established markers, and it similarly stratified outcomes in the general population and in the subgroup of patients free of cardiopulmonary disease (Figure 1A and 1B).Download figureDownload PowerPointFigure 1. Pulmonary artery systolic pressure (PASP) estimates are a risk factor for death. Elevation in PASP as estimated noninvasively by Doppler echocardiography is associated with increased mortality in the general population (A, modified from Lam et al5) and patients without apparent cardiopulmonary disease (B, modified from Lam et al5), in addition to heart failure with preserved (C, modified from Lam et al6) or reduced ejection fraction (D, modified from Abramson et al2). PASP indicates pulmonary artery systolic pressure; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; and TR vel, tricuspid velocity.In another prospective study from this group,6 the prevalence and significance of PH in HFpEF population was examined. Patients with HFpEF (n=224, 96% with hypertension) were compared with hypertensive subjects without HF (n=719). Median PASP was 28 mm Hg in asymptomatic hypertensive subjects and 48 mm Hg in patients with HFpEF (P 35 mm Hg) was detected in 8% of hypertensive subjects and 83% of HFpEF patients. As in the general population, PASP was highly predictive of survival in HFpEF (Figure 1C). These observations emphasize the relevance of elevated PASP as another echocardiographic indicator of abnormal PCWP, and they suggest that its presence should trigger further consideration for the diagnosis of HFpEF.6,11 The recently updated Dana Point guidelines include LV diastolic dysfunction as a predominant cause of group 2 PH.21Epidemiological data regarding PH in HF with reduced ejection fraction (HFrEF) are extensive but limited mostly to populations with advanced (stage D) HF.22 Abramson et al2 found that echocardiography-estimated PH was associated with markedly increased morbidity and mortality in HFrEF (Figure 1D), whereas Ghio et al3 showed that the presence of RV dysfunction has important implications for risk stratification in group 2 PH above and beyond PAP. In a series of 320 HFrEF patients, Butler et al1 found that PVR was normal ( 3.5 WU) in 19%. More recent data suggest that the prevalence of reactive PH is similar in all ejection fraction groups. Indeed, in a recent study, 80% to 90% of patients with HFrEF and HFpEF displayed PVR >1.7 WU, and over half had PVR >3 WU or TPG >15 mm Hg (Figure 2).23 Ghio et al3 reported PH in >60% of their patients with moderate or severe HF. Among 388 HF patients investigated in an echo-based study, the presence of PH (defined as PASP ≥39 mm Hg) was associated with worse survival in both HFrEF and HFpEF, with no between-group difference in the magnitude of the effect.22Download figureDownload PowerPointFigure 2. Distribution of PVR and TPG in a patients with group 2 PH due to HFrEF and HFpEF. Data show a high prevalence of reactive PH, where 80% to 90% of patients with HFrEF and HFpEF displayed PVR >1.7 WU (2 SDs beyond normal), and over half displayed PVR >3 WU or TPG >15 mm Hg. Data adapted from Schwartzenberg et al.23 PVR indicates pulmonary vascular resistance; TPG, transpulmonary gradient; IQR, interquartile range; HFrEF, heart failure with reduced ejection fraction; and HFpEF, heart failure with preserved ejection fraction.PathobiologyPulmonary Capillary Stress Failure and Arterial RemodelingIn contrast to PAH, specific gene mutations conferring increased susceptibility to reactive PH are not well understood. However, candidate genetic determinants of susceptibility would be expected to perturb pulmonary arteriolar structure and function in HF, just they do in group 1 PH. Primary or pathognomonic vascular changes in the arterial wall may be absent in group 2 PH. Capillary and arterial remodeling develop from backward transmission of increased left atrial pressure (LAP), challenging vascular structural integrity and functional properties. Acuity and chronicity of LAP elevation have important effects on the pathobiology of group 2 PH.24 As the lung vasculature transits from acute to sustained pressure-induced injury, abnormalities in the capillary network precede those occurring at the arteriolar and pulmonary artery levels. Acutely, lung capillaries are exposed to stress failure, ie, loss of cellular integrity promoting edema within the interstitial and alveolar compartments. This phenomenon has classically been considered to be most relevant to acute pulmonary edema, although it may function as a trigger for maladaptive cellular processes that have more sustained effects on the pulmonary vasculature.25 Experimental models of pressure and volume capillary overload have defined the molecular bases of this process, while identifying the critical capillary pressures required for edema formation26,27 and gas exchange impairment.28In humans, stress failure of lung capillaries may be more common than is typically considered, occurring in a number of physiological conditions such as strenuous exercise and high-altitude exposure.24 The normal pulmonary–capillary interface exhibits remarkable plasticity, being able to restore its integrity after normalization of LAP.29 With chronic and repeated barotrauma there is true capillary remodeling, with demonstrable changes in the alveolar–capillary membrane interface. In a canine model of pace-induced HF, alveolar–capillary membrane thickness increased in comparison with controls, principally because of a change in basement membrane composition and deposition of type IV collagen.30 These findings are qualitatively similar to those observed in patients with mitral stenosis and chronic pulmonary venous hypertension.31 Local activation of growth stimuli, such as angiotensin II, endothelin-1, and hypoxia, may contribute to this microvascular remodeling.25 In a HF model induced by thoracic aortic banding, alveolar–capillary remodeling was linked to loss of nitric oxide (NO)-induced physiological oscillations in endothelial calcium handling, serving as a trigger for cytoskeleton disorganization.32 The alveolar–capillary interface remodeling induced results in gas exchange abnormalities, including reductions in membrane conductance, that have emerged as strong prognosticators in group 2 PH.33The pathobiology of changes in small and medium arteries has been investigated in patients with advanced HFrEF awaiting heart transplant.34 At this stage, arterial intima and media undergo hypertrophy with peripheral migration of smooth muscle into intra-acinar arterioles, effectively causing muscularization of these vessels. A key step is the induction of an endogenous vascular serine elastase, releasing growth factors and glycoproteins (tenascin-C and fibronectin). Pressure-induced endothelial disruption allows serum proteins into the vessel wall that activate endogenous vascular serine elastase and matrix metalloproteinases, disrupting the elastic lamina, stimulating smooth muscle growth and collagen and elastin synthesis.35 Fibroproliferative changes originate from growth of smooth muscle cells and myofibroblasts derived from the media. As medial hypertrophy becomes prominent, a process of pulmonary venous arterialization may develop. Bronchial veins may become congested and dilated because of increased flow through bronchopulmonary anastomoses. True plexiform lesions, commonly seen in PAH, are not observed in group 2 PH. There is a wide variability in the pulmonary vascular structural changes with elevated venous pressure. In patients with a variety of forms of PH (including group 2 PH due to mitral valve disease), reduced expression of bone-morphogenetic protein receptor has been observed, coupled with increased expression of angiopoietin-1, suggesting a common pathway in disease progression.36 However, the mechanisms dictating these remodeling processes within individual patients remain poorly understood. Regression of pulmonary vascular remodeling after normalization of LAP by cardiac transplantation, mitral valve surgery, or left ventricular assist device (LVAD) may be substantial, although often incomplete.37Impaired Vascular Reactivity and Endothelial DysfunctionPVR may become elevated in left-sided PH as a result of abnormalities in smooth muscle tone, caused by endothelial dysfunction primarily as a consequence of the imbalances between NO and endothelin-1 (ET1) signaling (Figure 3).38,39 A series of classical studies investigating the effects of NO blockade in the pulmonary circulation have shown that endothelium-derived NO mediates basal pulmonary vascular tone and dilation to endothelium-dependent stimuli. In healthy humans, systemic infusion of acetylcholine, an NO synthase agonist, increases local pulmonary blood flow.39 Conversely, infusion of NG-monomethyl-l-arginine, an inhibitor of NO synthase, decreases pulmonary flow velocity,39 promotes vasoconstriction and elevation in PAP,40 aggravates hypoxia-induced pulmonary vasoconstriction,41 and impairs gas diffusion by altering alveolar membrane conductance properties.42 In HF patients with elevated PVR, Cooper and colleagues43 noted that NG-monomethyl-l-arginine infusion caused less vasoconstriction than in patients with normal PVR, suggesting loss of NO-dependent regulation of tone. Wensel and colleagues44 showed that the extent of increase in pulmonary artery flow in response to acetylcholine was correlated with resting PAP and PVR. Porter et al45 found that intrapulmonary infusion of acetylcholine caused vasodilation in subjects with HF and normal PAP, but failed to cause dilation in those with PH, although measures were performed by intravascular ultrasound in larger pulmonary artery (PA) branch vessels that do not contribute to resistance vessel regulation. Endothelial-derived NO also inhibits smooth muscle cell proliferation and hypertrophy in tandem with prostacyclin, preventing platelet aggregation and adhesion.46Download figureDownload PowerPointFigure 3. Endothelial and vascular smooth muscle cell pathways involved in the regulation of pulmonary arterial tone and pharmacological approaches. Vasorelaxation is mediated by increases in cGMP, antagonism of the endothelin A and B receptors (ETra and ETrb), or stimulation of adenylate cyclase by prostaglandins, primarily prostacyclin. Intracellular levels of cGMP can be targeted at different levels by exogenous nitric oxide (inhaled NO), activators/ stimulators of soluble guanylate cyclase (sGC), or by inhibiting the catabolism of cGMP by phosphodiesterase 5 inhibitors. PDE indicates phosphodiesterase; e-NOS, endothelial nitric oxide synthase.ET1, a 21-amino-acid vasoactive peptide with potent vasoconstrictor and platelet-aggregating properties, is widely distributed in the pulmonary endothelium.47 In mammals, 2 ET receptors have been described: ETA, through which vasoconstriction and cellular growth are elicited, and ETB, which can mediate either vasoconstriction by its effects on smooth muscle or vasodilatation through an action on endothelial cells.47 ETB receptors also play an important role in ET1 clearance.48 The ratio of ETA to ETB receptors on human resistance and conduit pulmonary arteries is ≈9:1, and the net effect of ET1 in pulmonary arteries is constriction.49 ET1 may also contribute to pathological pulmonary vascular remodeling by causing proliferation and hypertrophy of vascular smooth muscle cells and increasing collagen synthesis. ET1 immunoreactivity is abundant in pulmonary vascular endothelial cells from patients with left-sided PH,50 and augmented plasma ET1 levels have been repeatedly reported in both experimental51 and clinical HF.52 The extent of ET1 increase predicts mortality in HFrEF.53Hemodynamic DerangementsPulmonary Arterial Loading in PHThe pulmonary and systemic circulations have important hemodynamic and anatomic differences. Vascular resistance is 10-fold lower in the lung than in the systemic vasculature, related to the fact that there are ≈10-fold more vessels in the pulmonary bed. This distributes arterial compliance evenly across the lungs, in contrast to the systemic circuit where ≈80% of compliance is located in the aorta. As a result, PA systolic, mean, and diastolic pressures all show a fairly linear relationship with one another, and the product of PVR and compliance is a constant (at a given downstream LAP).54 A plot of PVR versus compliance forms a hyperbola (Figure 4A) that is remarkably consistent across patients of variable age, sex, or underlying disease process.55 In early stage PH, relatively small increases in PVR are associated with more dramatic reductions in compliance (Figure 4B).56,57 This may explain why compliance is a more sensitive marker of outcome than PVR in patients with group 1 PH (Figure 4C).58 Tedford et al55 have recently shown that acute or chronic increases in LAP shift the resistance/compliance relationship leftward, such that compliance is lower at any given PVR. This effectively enhances the pulsatile (oscillatory) component of afterload relative to resistive load on the right heart. The implication is that RV hydraulic efficiency is compromised in group 2 PH, because oscillatory work does not contribute to net transport of blood.54Download figureDownload PowerPointFigure 4. Relationships between pulmonary arterial compliance and resistance. A, invasive data from 257 patients with HFpEF and HFrEF undergoing sodium nitroprusside (SNP) infusion (data plotted from Tedford et al55), illustrating the inverse relationship between pulmonary artery (PA) compliance and resistance. Because of the hyperbolic inverse relationship between resistance and compliance, small increases in PVR that develop early in disease progression are associated with dramatic reductions in PA compliance (B, plot modified from Saouti et al54). Reduced PA compliance or capacitance is a potent predictor of outcome in patients with group 1 PH (C, modified from Mahapatra et al58). HFrEF indicates heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; and PVR, pulmonary vascular resistance.Although it is an oversimplification, RV afterload is usually conceptualized in terms of mean PAP and PVR. However, it is important to appreciate that arterial pressure is produced by the integration of flow and vascular impedance, summed with downstream pressure. In the systemic circulation, downstream hydraulic pressure (in the right atrium) contributes little (<5%) to systemic arterial pressure.59 In the lung, downstream pressure (ie, LAP) is a much more important contributor to mean PAP (≈50%), and this proportion can become even greater in HF. Indeed, in the early stages of group 2 PH, PAP elevation may be associated with purely passive increases in LAP, with normal TPG (Figure 5A) and normal PVR. This stage appears to be completely reversible if LAP elevation can be treated.Download figureDownload PowerPointFigure 5. Diagram showing the various hemodynamic stages observed in group 2 PH. A, Passive. The increase in pulmonary artery pressure (PAP) is thought to be exclusively due to downstream left atrial pressure (LAP) elevation and no component of the PH seems to result from abnormalities intrinsic to the arterial wall. B, Reactive. The increase in PAP is due to intrinsic vascular changes in addition to elevated LAP. The TPG is increased and may or may not reverse under pharmacological challenge. C, Out of proportion increase in PH. This condition refers to some cases of TPG increase occurring in the presence of mild or no increase in PCWP. The pathobiological arterial changes of this condition are not well defined, even though some evolving reactive precapillary component is thought to take place earlier in the expected course of the disease. PH indicates pulmonary hypertension; TPG, transpulmonary gradient; PCWP, pulmonary capillary wedge pressure; RV, right ventricle; and LA, left atrium.Subsequent stages of PH are defined as reactive when structural and functional abnormalities intrinsic to the pulmonary vasculature cause elevation in PVR and TPG (Figure 5B). This may be either reversible or fixed. In the former case, vasodilating challenge may normalize the TPG, suggesting a predominance of functional over structural abnormalities. Conversely, when PAP does not normalize after alleviation of the high downstream pressure, the vasculature behaves similar to what is seen in precapillary forms of PH, such as PAH. According to the European Society of Cardiology Guidelines,8 a condition that may be representative of an early evolution to mixed PH is the so-called out-of-proportion group 2 PH, a qualitative definition that is characterized by an increase in PAP that appears excessive for the mild degree of increase in PCWP (Figure 5C). This hemodynamic status seems to reflect an early development of precapillary vascular changes resembling the transition from passive to reactive PH. Although this condition may play a relevant pathophysiological role, additional information regarding its usefulness as a term and a precise hemodynamic definition are needed.The chronicity of the transition from passive to reactive PH is highly variable from patient to patient and does not appear to be consistently related to severity of LAP elevation. Lam et al,5 found that, although pulmonary artery systolic pressure increases as a function of estimated LAP (E/e′ ratio), it was persistently higher in HFpEF patients than in controls, suggesting elevation in PVR and a component of reactive PH.Right Ventricular–Pulmonary Artery CouplingThe RV is the ultimate victim of these vascular processes, and a common phenotype of end-stage HFrEF and HFpEF is that of predominant RV failure, with systemic venous congestion, renal dysfunction, and ascites. Under normal conditions, the RV operates against a low-impedance, high-capacitance, low-pressure system, with a short isovolumic contraction period and a prolonged systolic ejection time. Peculiar ontological and morphological differences in the RV in comparison with LV have been described, such as a differential distribution of RV myofibers in series and differences in sarcomere shortening and excitation–contraction coupling.60 Accordingly, although the RV is well suited to accommodate an increase in volume load, it is exquisitely afterload sensitive (similar to the LV in HFrEF). The implication of this enhanced afterload sensitivity is that an acute pressure overload causes much greater reduction in stroke volume of the RV than of the LV (Figure 6).61,62 In a model of pace-induced HF, early development of even mild PH led to a profound RV-PA uncoupling, characterized by an inability of the RV to adapt to the combined effects of increased pulmonary arterial resistance and elastance.63 Exposure of a normal RV to acute afterload mismatch can be catastrophic. This explains the common observation of massive circulatory insufficiency and death despite minimal PAP elevation in states such as acute pulmonary embolism. The circulation fails in these instances because the RV cannot generate sufficient pressure to overcome the acute increase in arterial afterload.Download figureDownload PowerPointFigure 6. Enhanced afterload sensitivity of the right ventricle compared with the left. Right ventricular stroke volume is impaired to a much greater extent in comparison with the left ventricle with comparable acute increases in arterial pressure. Adapted from Abel and Waldhausen.61Chronically, the RV may adapt to elevated afterload with hypertrophy. This may allow ejection against tremendous afterload for sustained periods of time. Although this pattern of remodeling is often tolerated for many years, it may ultimately progress to chamber dilatation, functional tricuspid incompetence, and frank RV failure.64 RV hypertrophy may decrease RV subendocardial perfusion, whereas dilatation results in increased wall stress, both enhancing myocardial oxygen demand and provoking ischemia and symptoms of effort angina. Further study is needed to better understand mechanistic differences between the RV and LV.The RV and LV are connected in series, and reductions in RV output in advanced HF may lead to underfilling of the LV. This was evidenced by a paradoxical decrease in PCWP during exercise noted in HFrEF patients with severe PH in an early report by Butler and colleagues.1 In addition to series effects, the right and left heart share a common space in the pericardial sac, so that changes in right heart pressure and volume may affect the left heart in parallel.65 This cross talk or coupling between the right and left sides, referred to as diastolic ventricular interaction, is evidenced by an equalization in right and left heart pressures during cardiac catheterization (Figure 7A). Transmural LV filling pressure may be estimated by the difference between intracavitary pressure (ie, PCWP) and pericardial pressure. The latter can be estimated by right atrial pressure (Figure 7B),66 and therefore when right atrial pressure is elevated to a similar extent as PCWP, right-sided chambers may effectively outcompete those on the left for limited pericardial space, constraining and compromising LV filling as the interventricular septum bows from right to left (Figure 7C). Acut
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