Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure
Abstract
Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.
Pulmonary hypertension (PH) in its various forms affects ≈1% of the global population, and up to 10% of individuals >65 years of age.1 PH is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest, although a lower threshold (>20 mm Hg) was recently proposed during the 6th World Symposium on PH.2 Based on left-sided filling pressure, measured as pulmonary arterial wedge pressure (PAWP) or left ventricular end-diastolic pressure, PH is subclassified into pre- (pulmonary arterial wedge pressure/left ventricular end-diastolic pressure ≤15 mm Hg) and postcapillary PH (pulmonary arterial wedge pressure/left ventricular end-diastolic pressure >15 mm Hg).2,3 PH occurs as a common consequence of multiple underlying diseases including pulmonary vascular disease and thromboembolic disease, but is most commonly associated with left-sided heart disease and chronic lung disease, particularly in elderly individuals.1–3 The clinical classification of PH distinguishes 5 groups: (1) Pulmonary arterial hypertension (PAH); (2) PH caused by left heart disease (LHD); (3) PH caused by lung disease or hypoxia; (4) Chronic thromboembolic PH (CTEPH); and (5) PH with unclear or multifactorial mechanisms.2 Although these entities are distinct from a pathogenetic perspective, they may all cause severe PH, representing an increased right ventricular (RV) afterload and, as a common final path, eventually lead to right-sided heart failure (HF), which aggravates symptoms and results in a high mortality risk.3 Strikingly, deterioration in RV structure and function greatly exceeded corresponding changes in the left ventricle (LV) during long-term follow-up in patients with left-sided HF with preserved ejection fraction.4 In addition, PH and RV dysfunction are often accompanied by hypoxemia, which can have multiple, often co-existing causes, and affect multiple organ systems (Figure 1). Interorgan crosstalk involves circulating pro-inflammatory cytokines that act locally, but may also affect other organ systems distant from their origin (Figure 2). While the systemic character of PH and right-sided HF is often neglected or underestimated, such consequences place additional burden to patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the systemic consequences of PH and right-sided HF in multiple organ systems.
Left Ventricle
Eccentric remodeling and contractile dysfunction of the right heart in patients with PH or pulmonary arterial hypertension (PAH) have an important impact on the LV, as they may result in impairment of LV geometry, structure, and function (Figure 3). Given the interdependency of the left and right sides of the heart, which is determined by shared myocardium (septum), pericardial restraint and the serial nature of the circulatory system, right ventricular strain directly affects the left ventricle. Increases in RV size and pressure cause mechanical septal leftward shift leading to LV compression,5 which is visualized by paradoxical septal movement, a “D-shaped” left ventricle, and an increased LV eccentricity index. A low stroke volume and cardiac output from RV dysfunction may contribute to underfilling of the LV, particularly during exercise.6 Diastolic ventricular interaction is also important in PH/RV failure, because right heart overload and pericardial restraint may cause elevation in left heart filling pressures even when LV preload is reduced and the LV is underfilled.7,8
Because the heart muscle constantly adapts to its demands, reduced work load and chronic underutilization of the LV lead to deconditioning and atrophic remodeling in PAH, characterized by reductions of LV end-diastolic volume and LV mass by ≈10–20% and 5–15%, respectively, and reductions in LV systolic strain, stroke volume and ejection fraction.8–10
At the cellular and molecular level, the LV myocardium of patients with end-stage PAH displays cardiomyocyte atrophy and contractile dysfunction, as indicated by substantial reductions in the cross-sectional area and the maximal force-generating capacity of cardiac myocytes by ≈30% and ≈25%, respectively, as well as lower cellular content of the contractile protein myosin, impaired phosphorylation of sarcomeric proteins (cardiac troponin I, myosin-binding protein C), reduced number of available myosin-based cross-bridges, and a leftward shift in the force [Ca2+] relationship.11 The latter indicates an increase in the [Ca2+] sensitivity of force generation and may be viewed as a compensatory mechanism for the reduced force-generating capacity,11 but may also provide an explanation for impaired LV diastolic function in PAH.8
The importance of an atrophic and malfunctioning LV becomes particularly evident in the context of lung transplantation in end-stage PAH, where increased postoperative filling and the inability to handle a normalized preload may lead to LV failure.12 This temporary phenomenon may effectively be bridged by veno-arterial extracorporeal membrane oxygenation after lung transplantation to allow the LV to adapt to normalized hemodynamics.12
In addition to its consequences on LV myocardium, severe PH may also affect coronary perfusion. Because of the topographical proximity, pulmonary artery dilation may occasionally cause compression of the left main coronary artery (left main compression syndrome), and may trigger myocardial ischemia and arrhythmias.13 Indeed, a significant number of PAH patients die from sudden death, and a pulmonary artery diameter ≥48 mm was associated with a 7.5-fold increased risk for sudden unexplained death in patients with severe PAH or CTEPH.14 As improved treatment options have led to prolonged survival in PAH, physicians should be alert for such emerging risk factors in long-term survivors.
Liver
The liver of patients with PH and RV failure may be exposed to decreased arterial perfusion, hypoxemia, and venous congestion.15 Relatively little research has been done on liver dysfunction in patients with PAH, while there is abundant literature on the effects of HF on liver function in patients with underlying LHD. In the aggregate, there is a strong body of evidence suggesting that liver dysfunction in these patients is closely related to right-sided HF rather than to LV dysfunction.
Acute right- or left-sided HF with shock and hepatic hypoperfusion may result in ischemic hepatitis (Figure 4A, right). Its histological hallmark is centri-lobular necrosis.15 Characteristic laboratory findings are rapid increases in serum amino-transferases (>20 times the upper level of normal) and lactate dehydrogenase. Serum bilirubin is only mildly elevated, except for cases that progress to liver failure or secondary ischemic cholangiopathy. The majority of cases are reversible if the underlying cause is resolved, although progressive liver dysfunction and acute liver failure have been reported. Pre-existing hepatic venous congestion caused by right-sided HF seems to increase the risk of acute ischemic hepatitis.16
Chronic congestive hepatopathy has commonly been described in patients with underlying LHD, but its degree is not related to LV dysfunction but to the presence of PH and elevated right-sided filling pressures.17,18 Chronic hepatic congestion may result in liver fibrosis or, occasionally, in cardiac cirrhosis.19 In patients with congestive HF, the extent of hepatic fibrosis was associated with right atrial pressure, right atrial dilatation, and right ventricular dilatation (Figure 4A, left).17 The authors concluded that hepatic fibrosis correlated with the degree of right-sided HF, irrespective of the cause. Consistently, in patients with precapillary PH, elevated levels of liver fibrosis marker, P4NP 7S (7S domain of collagen type IV), were associated with higher central venous pressure, right-sided volume overload, and mortality.20
Patients who develop congestive hepatopathy are typically those with severe and prolonged right-sided HF. Presenting features include signs of systemic venous congestion such as enlarged and pulsating jugular veins and edema, as well as jaundice and ascites. Larger amounts of ascites in the absence of edema may indicate cardiac cirrhosis. Laboratory findings include elevated levels of yGT (y-glutamyl-transpeptidase), ALP (alkaline phosphatase) and bilirubin, and normal or mildly elevated serum aminotransferases.15,19 Impaired synthetic liver function with reduced serum albumin may be encountered in advanced cases,21 and hepatic drug metabolism may also be impaired.15 Characteristic changes in hepatic blood flow patterns may be observed with ultrasound. Taniguchi et al recently demonstrated that liver stiffness, as assessed by elastography using a Fibroscan device correlated with variables indicating right-sided HF, was associated to the clinical severity of HF, and predicted clinical outcomes.22 Elevated serum bilirubin levels are associated with an increased mortality risk in patients with PAH, at least in univariate analyses.23,24
Kidneys
Elevated serum creatinine concentrations and/or a low estimated glomerular filtration rate are present in 12% to 29% of PAH patients and are associated with poor outcome.25,26 In the REVEAL registry (Registry to Evaluate the Early and Long-term Pulmonary Arterial Hypertension Disease Management), a large US based registry of PAH patients, an association between renal insufficiency and death was found in both univariate and multivariate analyses.24 Even slight abnormalities are clinically significant,25 with both the absolute value and a ≥10% decline in estimated glomerular filtration rate from baseline over ≥1 year associated with an increased risk of death in the REVEAL registry.27
In PH, the heart aims to accommodate increased PVR by balancing pre- and afterload, which may be accomplished by neurohormonal activation (eg, arginine, vasopressin, endothelin-1). This however leads to water and salt retention, venous congestion, and reduced cardiac output. In states of diminished cardiac output or impaired contractile reserve, renal dysfunction is traditionally thought to occur secondary to renal hypoperfusion (Figure 4B, right).28,29 Accordingly, markers of low cardiac output or tissue hypoxia, including uric acid, correlate with disease severity and mortality in PAH.31 However, chronic venous congestion resulting from right-sided HF also appears to play a central role in distant organ malfunction including acute and chronic kidney injury, and central venous pressure has been found to be one of the most important hemodynamic determinants of worsening renal function in both PAH and HF.26,32 In PAH patients, both decreased cardiac index and increased right atrial pressure were independent determinants of reduced estimated glomerular filtration rate over time.26
Renal congestion results from backward transmission of elevated central venous pressure as a consequence of right-sided HF and is characterized by renal edema, increased interstitial pressure, tubular compression, and intracapsular tamponade, which may further aggravate back pressure and thus decrease renal perfusion pressure and glomerular filtration rate (Figure 4B, left). A recent Doppler ultrasonography study in HF patients revealed that intrarenal venous flow patterns, rather than arterial resistance index, related to central venous pressure and strongly correlated with clinical outcomes.34 Furthermore, activation of venous endothelium acts as a stimulus for release of inflammatory mediators, which in turn may act locally (causing structural glomerular and interstitial damage, sclerosis/fibrosis as well as functional abnormalities such as diminished tubular reabsorption, proteinuria, and retention of salt and water)28,29 or affect distant organ systems (Figure 2), including the lung.35
During the course of PH progression, it is likely that repetitive episodes of subclinical acute kidney injury occur, which depict a slow progressive degenerative process and predispose to the development of subsequent chronic kidney disease.36 Sensitive markers of early kidney injury include L-FABP (L-type fatty acid-binding protein), NGAL (neutrophil gelatinase-associated lipocalin, and KIM-1 (kidney injury molecule-1).37,38 Even mild proteinuria indicates endothelial dysfunction, and tubulo-interstitial fibrosis best correlates with the development of chronic kidney disease.
In the setting of decompensated PH, RV failure, and acute kidney injury, deterioration of either organ function may result in a vicious circle leading to refractory congestive right-sided HF. Patients with acute-on-chronic renal injury have a narrow window for fluid management of venous congestion and are at high risk of worsening cardiorenal function and death. However, in the setting of acute decompensated HF with worsening renal function, it is important to note that although intensive volume removal initially resulted in worsening of creatinine and a rise in tubular injury biomarkers (NAG, KIM-1, NGAL), renal function recovery over time was superior, suggesting that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers.39
Notably, there is crosstalk between the pulmonary vasculature, the (right) heart, and the kidney.28 While the kidney is dependent on blood flow and perfusion pressure generated by the heart, the heart is directly dependent on the regulation of fluid homeostasis and the body´s salt and water content by the kidney. Furthermore, renal dysfunction itself may aggravate PH, because circulatory factors have been implicated in the pathogenesis of pulmonary inflammation after renal injury, which may aggravate pathomechanisms of PH.28
Few data are available on the impact of targeted PAH therapies on renal function. In a post hoc analysis of the SUPER-1 study (Sildenafil Use in Pulmonary Arterial Hypertension-1), treatment with the phosphodiesterase type 5 inhibitor sildenafil was associated with improved kidney function.40 The impact of other targeted PAH therapies on renal function merits further investigation.
Gut and Bowel
Altered gut permeability resulting in bacterial translocation and endotoxinemia was described in patients with congestive HF and has been linked to impaired arterial perfusion and venous congestion.41 Similar mechanisms are to be expected in patients with PH and right-sided HF. Mechanistically, bacterial translocation occurs when the edematous or ischemic gut mucosa loses its barrier function. Bacteria and toxins penetrate through the intestinal epithelium and are carried by lymphatic drainage to mesenteric lymph nodes from where they reach other organs and the blood stream.42
Niebauer and coworkers have shown that in patients with congestive HF and edema, elevated endotoxin levels could be normalized with diuretic treatment,43 suggesting that venous congestion of the bowel wall was the main cause of a leaky bowel. Bacterial translocation from the bowel may also explain, at least partly, why nonpneumogenic sepsis and sepsis-like illness without documented bacteremia were relatively frequent causes (15%) of intensive care unit admissions in patients with PAH.44 Furthermore, C-reactive protein levels were elevated in the vast majority of PAH patients admitted to the intensive care unit, in particular in patients who did not survive.44 Although speculative, it is possible that a leaky bowel may have been a main source of inflammation in these patients.
Recently, Ranchoux et al proposed a gut-lung connection in PAH where intestinal leakiness and endotoxinemia, potentially occurring as a consequence of right-sided HF and intestinal congestion, may promote exacerbated inflammation and pulmonary vascular remodeling,45 thus contributing to a self-perpetuating process. Specifically, they showed that lipopolysaccharide translocation from gut lumen to bloodstream activated pulmonary and systemic TLR4 (Toll-like receptor 4), the main receptor for lipopolysaccharide, which was associated with increased levels of soluble CD14 (cluster of differentiation 14 lipopolysaccharide-binding protein), a marker of macrophage activation. The blood levels of lipopolysaccharide, TLR4 and soluble CD14 were markedly elevated in patients with idiopathic PAH (IPAH) or heritable PAH, supporting that both bacterial translocation and macrophage activation occur in PAH.45 Furthermore, lipopolysaccharide serum levels were substantially lower in treated versus untreated PAH patients, and TLR4 deficiency completely protected against experimental PH. Interference with gut microbiota or TLR4 may thus be effective in disrupting this vicious circle.
Bowel dysfunction in patients with HF has been linked to the development of cachexia, which again seems to be closely associated with the presence of RV rather than LV dysfunction.46 In a recent study among patients with left-sided HF, the presence of cachexia was related to bowel wall thickness, elevated right atrial pressures and RV dysfunction, but not LV ejection fraction.47 Bowel wall thickness, in turn, correlated with C-reactive protein levels, suggesting a link between elevated right-sided filling pressures, bowel congestion, and systemic inflammation. In patients with intestinal congestion and cachexia, gut microbiota may also contribute to progression of the HF syndrome and mortality.48 While data on cachexia have been generated primarily from patients with PH-LHD, similar mechanisms likely apply to other forms of PH.
Iron Homeostasis
Iron deficiency (ID) is common in patients with idiopathic PAH, with prevalence ranging from 30% to 63%,49,50 and occurring independently of anticoagulation status. In a study where the prevalence of ID was 30%, patients with mutations in BMPR2 (bone morphogenetic protein receptor type 2) appeared to have the highest point prevalence of ID at 60%.50 In the same study, patients with CTEPH had lower point prevalence of ID than idiopathic PAH despite higher rates of anticoagulation and being older.50 While not entirely consistent across studies, ID appears to be associated with worse World Health Organization Functional Class, lower exercise capacity, worse hemodynamics, and higher serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels in idiopathic PAH.49,50 In addition, ID (defined as soluble transferrin receptor levels >28.1 nmol/l or by the soluble transferrin receptor index) was associated with increased mortality.49
Enteric iron absorption is negatively regulated by hepcidin, which is released from the liver in the presence of iron loading. Hepcidin levels were inappropriately elevated in patients with IPAH, which may contribute to ID49 and explain the poor response to oral iron replacement, through presumed decreased gut absorption.51 The inappropriate elevation of hepcidin in idiopathic PAH appears to be independent of IL-6.49 When BMPR-2 is knocked down in HepG2 cells (hepatoma cell line G2), BMP-6–mediated hepcidin expression is further increased,49 possibly providing a connection between altered BMP signaling in PAH and ID.
It has not yet been established whether ID is simply a bystander (risk marker) or disease-modifying risk factor in PAH. In humans, there are fairly compelling data that iron is a significant regulator of pulmonary vascular tone. Otherwise healthy individuals with ID have exaggerated hypoxic vasoconstrictive response which can be corrected with intravenous iron replacement.52 In addition to its effects on pulmonary vascular tone, ID may also affect vascular remodeling, although this is less clear.
ID may thus be mimicking a pseudohypoxic stimulus to the pulmonary vasculature. Iron is a cofactor in the prolyl hydroxylation of hypoxia-inducible factor (HIF) 1α and 2α, which targets it for ubiquitination and degradation. Thus, ID leads to stabilization of HIFs and increased HIF-dependent transcription. Conversely, in the presence of ID, depletion of iron-sulphur clusters allows iron-regulatory protein-1 to bind to cis-regulatory iron response elements, leading to translational repression of HIF2α, which prevents expression of erythropoietin.53 In addition to direct effects on the pulmonary vasculature, ID is associated with reduced myoglobin, impaired mitochondrial oxidative capacity, and anemia, limiting the aerobic capacity of muscle tissue, and may also affect myocardial metabolic substrate use through mitochondrial dysfunction.54
Two open-label studies of intravenous iron replacement in patients with ID and PAH have demonstrated improved exercise capacity and delayed time to the anaerobic threshold.55,56 No changes were seen in right ventricular function, yet skeletal muscle biopsy samples showed improved oxygen handling through increased myoglobin and mitochondrial oxidative capacity, suggesting that the benefits of iron repletion may not be acting only through changes in central cardiopulmonary hemodynamics.56
Skeletal Muscles and Diaphragm
Reduced cardiac function with impaired oxygen delivery to skeletal muscles during exercise is the predominant mechanism by which exercise is impaired in PH. Yet, skeletal muscle function, including that of respiratory muscles,57 may be affected in PAH independent of cardiac output. Maximal volitional and nonvolitional strength of the skeletal muscle is not dependent upon blood flow and is therefore an independent indicator of muscle function. In PAH, both the quadriceps and inspiratory muscles have impaired strength which correlates with exercise capacity.
Studies investigating the mechanisms involved have yielded inconsistent findings, although overall, there is a tendency towards decreased maximal tension, but with variable findings of muscle fiber size, fiber subtype, and capillary density.57 Diaphragm samples obtained at the time of pulmonary endarterectomy in patients with CTEPH showed that slow twitch fibers displayed decreased maximal force generation, which correlated with maximal inspiratory pressure.58 No difference was seen in fiber cross-sectional area between patients and controls undergoing elective surgery, but calcium sensitivity of force generation was reduced in fast twitch fibers, which could be restored with troponin activation.
Mechanisms leading to muscle dysfunction are not fully understood but may be both systemic and local in origin. Circulatory pro-inflammatory cytokines are postulated to lead to muscle fiber atrophy and impaired contractile function through proteolysis.59 More specifically, increased circulating GDF-15 (growth differentiation factor-15) correlates with muscle fiber diameter and strength, which may be mediated through phosphorylation of TAK1 (TGFβ-activated kinase 1) and reversed by TAK1 inhibition.60 Reduced physical activity in PH but increased ventilatory demand may be expected to lead to relative protection of respiratory muscle function compared with peripheral muscles, but in turn, this may make them more vulnerable because of increased protein turnover and thus susceptible to systemic factors.57 Deconditioning of peripheral muscles is associated with reductions in capillary density, and systemic factors such as iron deficiency and reduced cardiac output/oxygen delivery further contribute to impaired aerobic capacity of muscle tissue.
Endocrine System
Thyroid Disease
Patients with PAH have a high prevalence of thyroid disease of ≈20%,61 and thyroid disease is a predictor of poor prognosis in PH. A recent registry analysis of 1756 patients with various forms of PH determined that untreated hypo- or hyperthyroidism measured by thyroid stimulating hormone levels predicted mortality in IPAH patients.62 Patients with treated thyroid disease had a better survival and reduced free triiodothyroine levels predicted death in PAH and CTEPH patients with untreated thyroid disease.62 Even subclinical hyper- or hypothyroidism are associated with an increased risk of incident atrial fibrillation,63 which is detrimental in PH.
Hypothyroidism
The prevalence of hypothyroidism in IPAH is 10% to 24%.64 Despite data on its association beginning over 2 decades ago, information about the direct relationship of hypothyroidism and the pulmonary circulation remains limited. One observational study of 63 patients with PAH found that ≈50% had concomitant autoimmune thyroid disease.61 Notably, patients with PAH have an increased prevalence of both antithyroglobulin and antithyroperoxidase antibodies.61
Hyperthyroidism
The development of hyperthyroidism itself can lead to arrhythmias and worsening right-sided HF and is magnified in PH patients. Thyroid hormone directly affects the heart, and the peripheral and pulmonary vascular systems. Besides increasing myocardial inotropy and heart rate, a low peripheral vascular resistance may be the direct result of thyroid hormone on arteriolar smooth muscle tone, as it enhances the signaling pathway related to PI3K/akt (phosphatidylinositol 3-kinase/protein kinase B) thus increasing 3 nitric oxide synthase isoforms in endothelial and muscular cells.65 A high cardiac output state in the setting of hyperthyroidism may aggravate PH and exacerbate RV dysfunction, which may result in cardiac decompensation. In addition, hyperthyroidism may also exert direct remodeling or functional effects on the pulmonary vasculature and heart.65 Possible mechanisms include enhanced catecholamine sensitivity, increased metabolism of intrinsic pulmonary vasodilators, and decreased metabolism of vasoconstrictors. In patients with hyperthyroidism, Grave’s disease antibody levels directly correlated with pulmonary artery pressure.
Metabolic Syndrome and Diabetes Mellitus
The metabolic syndrome is highly associated with PH-LHD.66 Loss of myocardial compliance because of metabolic derangements of cardiac muscle and increased LV mass lead to increased afterload and resultant postcapillary PH. Patients with PAH and metabolic syndrome associated comorbidities did worse in the REVEAL registry, including reduced exercise capacity (hypertension, diabetes mellitus, obesity), higher functional class (obesity), and higher mortality (diabetes mellitus).66
Registry data indicate a higher than expected prevalence of diabetes mellitus in PAH patients.67 Older patients are more likely to have diabetes mellitus, and the combination of diabetes mellitus and PAH is associated with a higher mortality.67 While epidemiologic data indicate an association, they cannot show that diabetes mellitus itself leads to PAH or accelerates the disease, or vice versa. Research however indicates that the effects of hyperglycemia and insulin resistance on pulmonary microcirculation, and perhaps the RV, may modify the course of PH.68
Insulin resistance is linked to deficiency of the nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma), which is also reduced in human PAH and is involved in growth and apoptosis regulation of endothelial cells and smooth muscle cells.69 Accordingly, targeted deletion of PPARγ in smooth muscle cells led to development of PH in animal models, and treatment with PPARγ activators halted the progression of experimental PH,70 and prevented right HF via fatty acid oxidation.71 Furthermore, hyperglycemia inhibits endothelial NO synthase and promotes the liberation of reactive oxygen species and activation of protein kinase C, leading to vasoconstriction and inflammation.68
In addition to its impact on the pulmonary vasculature, the role of diabetes mellitus in RV fibrosis and ischemia also likely influences disease course and prognosis of PAH patients. As in the microcirculation, local hyperglycemia in the RV stimulates the expression of growth factors such as endothelin-1, platelet-derived growth factor and TGF-β, resulting in fibrosis and inflammation.68 Likewise, insulin resistance in the heart upregulates the diabetic marker microRNA miR-29 family, causing cardiac fibroblasts to increase collagen production and myocardial fibrosis.72 Although not specifically shown for the RV, the impact of diabetes mellitus on microvessels promoting ischemia in numerous vascular beds is well established. Given the impact of diabetes mellitus on RV fibrosis and the microvasculature, the diabetic milieu in the right heart likely deteriorates the adaptation of the RV to an increased afterload, and thus RV/pulmonary artery coupling in PAH.
Inflammation and Immune System, Coagulation Disorders, and Platelets
Inflammation and Immune System
Inflammation is involved in PAH pathobiology and may occur as a consequence of PAH in the lungs and various other organ systems. There is systemic interaction between lungs, heart, and kidney, where soluble inflammatory mediators and regulators of innate and adaptive immunity are secreted in response to PH-associated RV hypertrophy/dilation and kidney injury, which may act locally or affect distant organs.28 Consequently, patients with PAH have elevated circulating levels of inflammatory mediators in the blood and lungs, which are predictive for survival.73 Classic severe PAH lesions contain pulmonary perivascular inflammatory infiltrates composed of T and B lymphocytes, mast cells, dendritic cells, and macrophages.74 The pulmonary vasculature responds to circulating inflammatory stimuli by increased proliferation or migration and apoptotic-resistant phenotype producing smooth muscle cell hyperplasia, adventitial remodeling, and endothelial dysfunction.74 Both B cells and T cells contribute to the pro-inflammatory environment. The increased production of interleukin-1 and interleukin-6 promotes activation, proliferation, and differentiation of B lymphocytes.73 Regulatory T-cells are dysfunctional in various forms of PAH, which occurs in a leptin-dependent manner in idiopathic and connective tissue disease-associated PAH, but irrespective to leptin levels in heritable PAH.75 Circulating autoantibodies against endothelial cells and smooth muscle cells, which alter different components of the vascular wall in various tissues, have been described in patients with IPAH and scleroderma-associated PAH.74,76 Whether immune dysregulation may represent the cause or the effect of PAH is not entirely known, but the systemic character of circulating inflammatory mediators and organ interaction should be recognized.28,74
Coagulation System
Increased plasma concentrations or plasma activities, respectively, of procoagulatory factors such as fibrinogen, von Willebrand factor, and plasminogen-activator inhibitor-1 have been described in patients with PAH and CTEPH.77 Some patients with high pulmonary shear stress conditions may develop an acquired von Willebrand syndrome.78 On the other hand, thrombi are commonly detected in the small pulmonary arteries in IPAH.79 While anticoagulation was previously recommended in all patients with idiopathic, heritable, and anorexigen associated PAH, the overall level of evidence to support this is weak, and current guidelines now recommend that this decision be made on a case by case basis for the above subgroups, and recommend against routine anticoagulation for other PAH subgroups.80 In contrast, lifelong anticoagulation is strongly recommended for CTEPH.
Thrombocytopenia
Thrombocytopenia (ie, platelet count <150 × 109/L) has been reported in up to 20% of patients with idiopathic PAH and seems to be related to disease severity.81 Thrombocytopenia is also commonly found in patients with portopulmonary hypertension as a result of hypersplenism. The mechanisms causing thrombocytopenia in IPAH are enigmatic. However, the observation that it is almost exclusively found in patients with severe disease may suggest a pulmonary thrombotic microangiopathy in these patients. There is no evidence that other forms of PH are also associated with thrombocytopenia, except for some hematological conditions and PAH patients with Eisenmenger syndrome who have a higher platelet size, mean platelet volume, thrombocytopenia, and platelet dysfunction, all of which may contribute to the higher risk of thrombosis and bleeding seen in these patients.82 Chronic platelet activation as evidenced by higher plasma P-selectin, β-thrombo-globulin, and platelet factor-4 may play a role in Eisenmenger patients with erythrocytosis.83
Cognitive Function, Depression, and Anxiety
As is the case in many chronic disorders, anxiety and depression are common in PH and are associated with disease severity;84 however, impairment of cognitive function has also been noted in PH.85 One study of 46 patients with PAH demonstrated cognitive sequelae in 58% of patients. Moderate-to-severe depression and anxiety were also present in 26% and 19% of patients, respectively.86 A lower quality of life was not seen in patients with worse cognitive function, although quality of life was associated with working memory. There were no clear differences in disease severity between those with and without cognitive impairment.
It has been suggested that cognitive impairment may relate to impaired cerebral tissue oxygenation. In an interventional study examining the impact of PAH therapies on cognitive function, baseline cerebral tissue oxygenation as measured by near-infrared spectroscopy and 6-minute walk distance were the two independent predictors of cognitive function and cerebral tissue oxygenation on multiple regression analysis.86 After the introduction of PAH therapies there was a significant improvement in cognitive function on an array of tests, but no change in cerebral tissue oxygenation, and indeed there was no correlation between change in cerebral tissue oxygenation and improvement in cognitive function.
Pulmonary endarterectomy in CTEPH patients involves deep hypothermic circulatory arrest and there have been concerns that this may result in cognitive impairment. A randomized trial was conducted to compare deep hypothermic circulatory arrest with antegrade cerebral perfusion, which showed no difference between the two techniques in terms of impact on cognitive function.87 Rather, there was an improvement in both groups by 12 weeks after surgery, possibly linking cardiovascular with cognitive function.
Eyes
Ocular involvement in patients with PH has not been systematically studied. Several case reports have described open-angle glaucoma, retinal detachment, venous stasis retinopathy, ciliary detachment, and central retinal vein occlusion in patients with PAH, most of whom presented with elevated right-sided cardiac filling pressures.88,89 It is conceivable that not PH itself, but systemic venous congestion affects the eyes, in particular by causing choroidal and retinal venous stasis. However, the frequency and clinical relevance of such findings are unknown.
Autonomic Function and Peripheral Endothelial Function
While PAH is primarily recognized as a pulmonary vascular disease imposing hemodynamic stress on the RV, the course of the disease may be subject to variation by circulating neurohormonal mediators (eg, sympathetic nervous system, renin-angiotensin-aldosterone system) and autonomic dysfunction which may act as disease modifiers.90 In PAH, as well as in other forms of PH, there is compelling evidence for both sympathetic and parasympathetic abnormalities that are not restricted to advanced stages of RV failure but also occur in early stages. For instance, elevated circulating levels of norepinephrine are found in IPAH and associated forms of PAH, which act systemically and represent an independent predictor of clinical deterioration.90
Altered autonomic function in PH thus has several important consequences: (1) Adrenoceptor (α1, β1, D1-5) downregulation and desensitization, caused by adrenergic overspill and mediated through GRK2 (G-protein-coupled receptor kinase-2), represent hallmarks of maladaptive RV remodeling and may explain the poor long-term response of the failing RV to inotropes;90 (2) Impairment of autonomous control reduces heart rate variability in right HF, which correlates with pulmonary artery pressure in patients with IPAH and has prognostic significance in various cardiac diseases;91 (3) Lower adrenergic baroreflex sensitivity in PAH patients is associated with a greater susceptibility to systemic (orthostatic) hypotension, cerebral hypoperfusion, and syncope, which is also indicative of poor outcome;92 (4) It was recently shown in animal models that sympathetic overactivity and electrophysiological cellular remodeling in experimental PH were linked to an increased vulnerability to atrial fibrillation and atrial flutter,93 which are associated with poor outcome in human PAH;94 (5) There is also a link between immune dysregulation, autonomic dysfunction, and endothelial dysfunction in PAH.74 Several studies have shown that patients with PAH display impaired peripheral endothelial function as assessed by measurement of brachial artery flow-mediated dilation or the peripheral arterial tone ratio.95
Although several recent studies have investigated a potential role of pharmacological (β-adrenoceptor blockade [95]) or interventional approaches (pulmonary artery denervation, renal denervation)96 to modify autonomic function in PAH, such approaches may be detrimental and are yet to be properly assessed.
Sleep and Hypoxemia
Patients with PH frequently report poor sleep quality which associates with worse functional status, exercise capacity, quality of life, and psychological disorders.97,98 Sleep-disordered breathing is common in patients with various forms of PH. Wide variations in the rates of central and obstructive sleep apnea have been reported,97,98 with rates of obstructive sleep apnea varying from 10% to 50%. Furthermore, because of the underlying gas exchange disturbances in PH, hypoxemia may occur or worsen at night, and daytime measurements may underestimate nocturnal oxygen desaturations.99 In a cohort of 46 patients with PAH and CTEPH, nocturnal hypoxemia was observed in 83% of patients, with the major mechanisms being ventilation-perfusion mismatch in 76%, obstructive sleep apnea in 66%, and overlap in 45%.97 The degree of nocturnal hypoxemia correlated with worse daytime PaO2 and distal airways narrowing (FEV25-75). No significant differences were found between patients desaturating and those not desaturating in terms of PH severity, however, numbers were small, and multivariate logistic regression showed that a higher pulmonary artery pressure and lower FEV25-75 predicted overnight hypoxemia.
There are insufficient data to evaluate whether sleep-disordered breathing or nocturnal hypoxemia adversely affects long-term outcomes. However, nocturnal oxygen therapy over 1 week improved 6-minute walking distance, nocturnal heart rate, and corrected QT interval in patients with precapillary PH and isolated nocturnal hypoxemia or >10 oxygen dips per hour.100
Treatable Traits: Towards Precision Medicine in PH
Recognizing PH as a disease with various systemic implications leads to the identification of treatable traits in individual patients and to a personalized treatment approach. Assessments and interventions most strongly recommended in current PH guidelines include routine measurement of renal function, anemia, and thyroid function, and periodic assessment of oxygen saturation during both the day and night. Treatment should include correction of hypoxemia if present, use of diuretics in patients with fluid retention from right heart failure, and supervised exercise training in patients with deconditioning.80 Other interventions may be considered on a case by case basis, as shown in Figure 5.
Conclusions
Although a large body of evidence indicates that systemic consequences of PH and right-sided HF place additional burden on patients and contribute to adverse outcome, this is often underestimated. Regardless of the underlying cause of PH, the common final path is right-sided HF. As a consequence, both systemic venous congestion caused by RV dysfunction and impaired peripheral perfusion caused by right-left heart interaction and diminished systemic output contribute to insult to multiple organ systems and interorgan crosstalk, which may result in a systemic inflammatory state that needs to be further characterized. It should be pointed out that many of the available evidence on secondary organ damage (particularly on liver and kidney impairment) is primarily related to left HF, whereas the consequences of isolated right-sided HF caused by PAH or other forms of precapillary PH are far less well studied and require further research (Table). However, when summarizing the available evidence, it becomes clear that even in patients with LHD, right-sided rather than left-sided HF is the main driver of secondary organ dysfunction. The important role of the right heart in this context is frequently underestimated in clinical practice and needs to be further studied. This knowledge is key to the understanding and treating of secondary organ dysfunction in patients with left heart disease as well as other forms of PH leading to right-sided HF.
| Organ System Affected | Consequence of Right-Sided HF and PH | Type of PH/HF in Which Evidence was Obtained | Gaps in Knowledge and Needs for Further Study | Refs. |
|---|---|---|---|---|
| Left heart | LV compression or underfilling; cardiomyocyte atrophy | PAH | Relevance of secondary LV dysfunction for outcome | 5-11 |
| Interdependence between RV and LV; (RA and LA) | Mainly HFpEF, (PAH) | Further studies needed for better pathophysiological understanding (rest and exercise) | 5-8 | |
| Disparity between RV hypertrophy and LV atrophy | PAH, PH-LHD, HFpEF | Incompletely understood; data are not entirely consistent; needs further study | 9-11 | |
| Left main compression syndrome (LMCS) | PAH | Prevalence and impact on outcome? | 13 | |
| Liver | Ischemic hepatitis | Acute/chronic HF (with shock) | Relevance of preexisting RV dysfunction/congestion for low-perfusion liver injury? | 15,16 |
| Congestive hepatopathy | Chronic LHD/HF; closely related to RV (rather than LV) dysfunction | Prevalence of liver dysfunction in PAH, and impact on outcome | 17-21 | |
| Kidneys | Low perfusion renal injury | Congestive HF (HFrEF) | Impact of systemic flow/perfusion vs. venous congestion on renal function in PAH | 28,29,31 |
| Chronic congestive nephropathy | Chronic LHD/HF; closely related to RV (rather than LV) dysfunction (PAH) | Precise diagnostic evaluation of renal congestion in P(A)H and HF | 28,29 27,32 34-40 | |
| Correlation between RV (vs. LV) dysfunction and kidney function | ||||
| Prediction on need for renal replacement therapy in PAH or PH-LHD | ||||
| Impact of renal dysfunction on outcome in PAH or other PH groups | ||||
| Impact of PAH therapies on kidney function | ||||
| Interorgan cross-talk and pathogenic role of kidney-derived, circulatory inflammatory mediators | ||||
| Gut/Bowel | “leaky bowel syndrome”; bacterial translocation | Congestive HF, venous congestion | Impact of “leaky bowel” and bacterial translocation in PAH and other PH groups | 42,43 |
| Gut microbiota, endotoxinemia, inflammation (LPS/TLR4) | PAH | Further mechanistic insights | 44,45 | |
| Cachexia | HF (HFrEF); related to RV dysfunction | Mechanisms and impact of cachexia in PAH and other forms of PH | 46-48 | |
| Iron homeostasis | Iron deficiency | HF (HFrEF), preliminary evidence in PAH | Impact of iron supplementation on exercise capacity and morbidity/mortality in PAH; RCT needed | 49-56 |
| Altered hepcidin levels; connection to BMPR2 mutations and hypoxia | PAH | Further mechanistic studies needed for better under-standing; role of congestion? | 49,52,53 | |
| Skeletal muscle | Muscle dysfunction/weakness/deconditioning (fiber size/atrophy, contractile dysfunction, calcium sensitivity) | PAH, CTEPH | Further mechanistic insights needed | 57-60 |
| Establish interventions to maintain/improve skeletal muscle function | ||||
| Endocrine system | Thyroid disease (hypo-/hyperthyroidism) | PAH, CTEPH (PH-LHD, PH-CLD) | Precise mechanisms and prognostic relevance not entirely clear; needs further study | 61-65 |
| Metabolic syndrome | PH-LHD, PH-CLD (COPD) | Relation between P(A)H and MS/DM needs to be further established (cause/consequence of pulmonary vascular disease, RV dysfunction) | 66 | |
| Diabetes mellitus | PAH, PH-LHD | 67-72 | ||
| Inflammation and immunity | Increased circulating inflammatory mediators; inter-organ cross-talk | PAH, PH-LHD | Further characterization of inflammatory mechanisms | 28,73-75 |
| Perivascular inflammatory infiltrates | PAH, PH-LHD | Assessment of anti-inflammatory therapies | 74 | |
| Coagulation system | Hypercoagulatory state (Fibrinogen, vWF, PAI-1) | PAH, CTEPH | Not clear whether cause or consequence of PH; Role of anticoagulation not established (except for CTEPH) | 77-79 |
| Thrombocytopenia | Severe IPAH | Mechanism(s) enigmatic | 81-83 | |
| Central nervous system | Impaired cognitive function | HF, PH | No clear correlation with disease severity of PH | 85-87 |
| Depression/anxiety | HF, PH | 84 | ||
| Eyes | Several ocular disorders (open-angle glaucoma, retinal detachment, venous stasis retinopathy, ciliary detachment, central retinal vein occlusion) | PAH, systemic venous congestion | Clinical relevance and frequency need to be systematically studied | 88,89 |
| Skin | Prurigo simplex | (severe PH, advanced right heart failure) | Author´s experience, evidence and mechanisms need to be established | — |
| Autonomic function | Sympathetic/parasympa-thetic dysregulation | PAH, other forms of PH | Not a target of current therapies | 90-95 |
| Reduced heart rate variability Lowered adrenergic baroreflex sensitivity | PAH; right heart failure | Potential assessment of PA denervation; renal denervation; RCTs needed | 91,92 | |
| Increased susceptibility of atrial flutter/fibrillation | Experimental PH; Association with poor outcome in PAH | Impact of rhythm control/interventional therapy on hemodynamics, RV function and outcome in PAH and PH-LHD; RCTs needed | 93,94 | |
| Enhanced postganglionic peripheral muscle sympathetic nerve activity | PAH | Impact of targeted therapies and/or exercise | 90 | |
| Endothelial dysfunction | HF, PAH | 95 | ||
| Sleep/Hypoxia | Sleep disturbances, poor sleep quality | Several PH groups including PAH and PH-LHD | Impact on QoL and outcome | 97,98 |
| Sleep-disordered breathing (central/obstructive sleep apnea), nocturnal hypoxemia | PAH, CTEPH, HF | Insufficient data on impact on long-term outcomes | 97-100 | |
| Daytime hypoxemia | IPAH/HPAH | Prognostic impact unclear | 100 |
CLD indicates chronic lung disease; COPD, chronic obstructive pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; DM, diabetes mellitus; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HPAH, heritable PAH; IPAH, idiopathic PAH; LA, left arterial; LHD, left heart disease; LV, left ventricle; MS, metabolic syndrome; PA, pulmonary artery; PAH, pulmonary arterial hypertension; P(A)H, PH or PAH; PAI-1, plasminogen activator inhibitor-1; PH, pulmonary hypertension; RA, right arterial; RV, right ventricle; and vWF, von Willebrand factor.
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© 2020 American Heart Association, Inc.
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Published online: 24 February 2020
Published in print: 25 February 2020
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Dr Rosenkranz has received remunerations for lectures or consultancy from Abbot, Actelion, Arena, Bayer, Gilead, GSK, Merck, Novartis, Pfizer, and United Therapeutics. His institution has received research grants from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Dr Howard has received fees for lectures or consultancy from Actelion, Bayer, GSK, and Merck. His institution has received research grants from Bayer. Dr Gomberg-Maitland served as a consultant and as a member of steering committees and DSMB/event committees for Actelion, Bayer, Gilead, Medtronic, UCB, Bellerophon (formerly known as Ikaria), and United Therapeutics. She has received honoraria for CME from Medscape and ABComm. Actelion, Bayer, Gilead, Medtronic, Lung Biotechnology, and Reata have provided funding to the University of Chicago during the last year to support her conduct of clinical trials. She is a member of the PCORI Advisory Panel on Rare Diseases and a Special Government Employee for the FDA Cardio-Renal division. Dr Hoeper has received fees for lectures or consultancy from Actelion, Bayer, Gilead, GSK, Merck, and Pfizer.
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This work was supported in part by the Deutsche Forschungsgemeinschaft (GRK-2407 to Dr Rosenkranz).
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