The global hypothesis is that the health of the lung circulation determines the health of the cardiac microcirculation. This postulate views the lung microcirculation as the emitter of information which either causes or contributes to the development of a microangiopathy of the heart and shifts the attention in severe PH from the visible coronary arterial disease to the function of the myocardial capillaries. Applied to the RV dysfunction or RV failure in chronic lung diseases with involvement of the pulmonary circulation, the specific hypothesis is that pressure overload per se is insufficient to cause RV failure [10]. Instead activation of the neuroendocrine axis and of inflammatory pathways drive the RV into failure [11, 12]. Of interest is also the correlation between percent emphysema and impaired left ventricular filling [13]. RV failure can be histologically defined by the presence of apoptosis, capillary loss and capillary endothelial cell dysfunction, and myocardial fibrosis.

Perhaps of equal importance is a second contribution: the reprogramming of the cardiac microcirculation by factors emanating from the sick lung vessels [14]. The major histological features of remodeled lung vessels are pulmonary arteriolar muscularization, intima fibrosis, angioobliterative occlusions, plexiform lesions, and loss of lung vessels including capillary rarefaction [15]. Lung endothelial dysfunction has been documented in COPD/emphysema [16, 17] (see also Chap. 18) as well as systemic endothelial cell dysfunction [18] and also in idiopathic pulmonary arterial hypertension (IPAH) [19], thromboembolic PAH [20], and in sickle cell disease [21]. Endothelial cell dysfunction likely also alters the adhesive properties of the lung vessels facilitating in situ thrombosis and impairment of the removal and breakdown of vasoactive substances from the circulation. Another manifestation of endothelial cell dysfunction is the decreased expression of the prostacyclin gene and protein, resulting in diminished prostacyclin production by the hypertensive lung vessels [22, 23]. Thus loss of prostacyclin synthase expression is a hallmark of phenotypically altered lung vascular endothelial cells in PH. Whether prostacyclin synthase expression is reduced or lost in the microcirculation of the failing heart is unknown. It appears that the prevailing and understandable emphasis of contemporary interventional cardiologists on reperfusion and revascularization of acute coronary syndromes may have overshadowed the interest in researching the coronary microvessels and their function and dysfunction. Left and right ventricular microvascular disease has been long appreciated as a primary myocardial involvement in scleroderma [24–26]. Contributions to the myocardial angiopathy by the sick lung circulation have not been investigated. In a recent review [14], we have compared pulmonary emphysema, as a primary lung parenchyma disease, with a primary mitral valve disease and hypothetically connected in both disorders lung vessel and lung capillary damage, factors produced and released from the diseased lung vessels and heart failure. Today this concept appears plausible and almost intuitive, however, direct evidence in support of this concept is still lacking.

Against the background of the cancer paradigm of angioproliferative PAH [27], which is based on the hallmarks of cancer discussed by Hanahan and Weinberg [28] and which characterizes the intrapulmonary vascular cell growth as “quasi malignant,” circulating progenitor cells were postulated to perform in a quasi-metastatic [29] fashion, in analogy to mechanisms of tumor emboli-induced PH [30]. Such cells could be released from the remodeled lung vessels and implant in injured lung vessels after recirculation. The first report on circulating endothelial cells in PH appeared in 2003 [31]. About 50 % of the cells expressed CD36, a marker of microvascular endothelial cells; and 25 % expressed E-selectin, a marker of endothelial cell activation [31]. Schiavon and coworkers found higher levels of lung tissue resident, but not circulating, endothelial cell progenitors in patients with idiopathic PAH [32]. Sickle cell disease patients with PAH have less circulating endothelial cell precursor cells when compared with sickle cell disease patients without PAH [33]. The peripheral blood monocytes from patients with scleroderma-associated PAH express markers of the endoplasmic reticulum stress [34] and Hansmann et al. [35] designed a microfluidic endothelial cell precursor chip to capture such cells in peripheral blood samples from PAH patients. Functional studies of circulating late outgrowth progenitor cells showed a hyperproliferative phenotype with the inability to generate vascular networks [36]. Finally circulating endothelial cells have also been identified in the blood from patients with congenital heart disease associated with PAH [37] and fibroblasts were identified in blood samples from adult patients and children with PH [38].

Cell fragments are produced by injured or dying cells, and it now has been widely appreciated that such microparticles affect the function of endothelial cells. Lewis et al. showed in 1988 that vesicles released from injured endothelium displayed platelet activating factor (PAF)-like activity which could be blocked by PAF receptor antagonists [39]; polymorphonuclear leukocytes, after adhesion, release microparticles with PAF-like phospholipids attached to them [40]. Circulating procoagulant microparticles have been measured and found to be increased in the lung blood effluent from patients with severe PAH [41] (Fig. 14.2). Circulating endothelial cell microparticles may be a signal of early lung tissue destruction in cigarette smokers (Fig. 14.3) [42] and endothelial cell microparticles were reported in the blood from patients with COPD in the MESA COPD study [43]. Amabile and coworkers discussed cellular microparticles in the context of the pathogenesis of pulmonary hypertension (Fig. 14.4) [44] and Diehl et al. [45] in the context of coagulation and inflammation. Cell–cell interactions and intercellular exchange pf proteins and RNA-containing microparticles have been recognized as part of information transfer and signaling between different organs. A mechanistic systems biology analysis of multi-organ dysfunction takes circulating vesicles and particles into account as carriers of information. For example, mesenchymal stem cells contain phospholipid-rich 55–65 mm diameter vesicles which contain miRNA; these vesicles are taken up by cultured myocardiocytes [46]. Recently it has been shown that circulating platelet microparticle-derived miR-223 is taken up by endothelial cells and can likely exert heterotypic regulation of gene expression in endothelial cells [47]—in so many words: micro particle microRNA can be taken up by endothelial cells and reprogram these cells. Monocytic microparticles can activate endothelial cells in an IL-1β-dependent manner [48].

After more than 20 years of investigation of mediators circulating in the blood of patients with PH, it is reasonable to assume that any single molecule or the combination of factors is of pathobiological importance. Elevated levels of von Willebrand factor [49] likely reflect activation and or injury of endothelial cells and platelets, and other signals are secreted by activated immune-and-inflammatory cells; for example, there is release of granulysin by lymphocytes [50], a tumoricidal, chemoattractant molecule which also can induce mitochondrial damage and apoptosis. The recognition that all of the circulating blood cells including red blood cells, in patients with PAH are constantly exposed to the multitude of circulating microparticles and protein and lipid mediators led to the postulate that the gene expression pattern of the peripheral blood monocytes would be categorically altered in patients with PAH and, perhaps show different expressions, when the peripheral blood monocytes from different forms of chronic PAH were compared [51]. Such circulating particles and factors could explain observations of increased miR-145 in tissue samples from PAH patients—downregulation of miR-145 patients protects against the development of PAH [52]—and the observation of impaired systemic microvessel endothelium-dependent vasodilation in patients with scleroderma-associated PAH [53]. Cell-free double-stranded DNA has been found to be elevated in plasma in experimental acute pulmonary embolism [54] and mitochondrial DNA that escapes from autophagy has been shown to cause inflammation and heart failure [55]. Thus, taken together, circulating protein and lipid mediators as well as circulating DNA can be injurious to endothelial cells, including those of the myocardial microcirculation.

Expression of miRNAs was studied in the pulmonary artery endothelial cells and pulmonary artery smooth muscle cells from explanted lungs from patients with heritable PAH and in vitro cell proliferation was correlated with miR-21 levels [56]. In lung tissue samples from patients with COPD 70 miRNAs and 2,667, mRNAs were differently expressed between smokers with and without COPD [57]. While a number of recent studies are descriptive surveys, there are a few reports which begin to connect miRNAs with disease. One example is the study of Kim et al. [58] who investigated apelin deficiency in pulmonary arterial endothelial cells from patients with PAH; they found that apelin deficiency in these cells increased the expression of FGF2 and its receptor FGFR1 as a consequence of downregulated expression of miR-503 and miR-424. Reconstitution of these miRNAs in animal models of PAH ameliorated PH. Apelin levels in the serum of PAH patients are reduced [59] and likewise in the failing right ventricle from experimental pulmonary hypertensive animals [60]. Finally, a consortium of investigators reported the association of reduced plasma levels of miR150 with survival of PAH patients [61]. Remarkably, growth factor receptors have been linked to miRNAs. Especially during hypoxia EGFR can inhibit miRNA processing from precursor miRNAs to mature miRNAs [62].

The sick lung circulation, together with a stressed and uneconomically working RV, generates conditions which can best be examined by applying a “systems” approach (Fig. 14.5). Recent studies of embryonic development of mice using lineage tracing methods have revealed the co-development of the cardiovascular and pulmonary systems. Cardiopulmonary mesoderm progenitors arise from cardiac progenitors and they generate the lineages within the cardiac inflow tract and lung including cardiomyocytes, pulmonary vascular and airway smooth muscle, vascular endothelium and pericytes [63]. Thus, another rationale for a systems approach is the coordinated heart and lung codevelopment. Signals emanating from the lung circulation are received by the capillaries of the heart, which form a complicated network of microvessels which are connected by anastomoses (Fig. 14.6). The heart, under pressure-and-oxidant stress, secretes a number of factors, the cardiac secretome [64], some of which affect the kidney function, while adrenal aldosterone participates in myocardial fibrosis. Maron et al. [65] recently showed that aldosterone can inactivate the endothelin B receptor which has as a consequence the decrease of pulmonary endothelial nitric oxide generation. Whether aldosterone also affects myocardial nitric oxide production is unknown. Lastly, angiogenic factors like VEGF promote the release of bone marrow cells which can attach themselves to the lung vessels and vascular lesions; such cells are endothelial and hematopoietic precursor cells, megakaryocytic, mast cells, and dendritic cells which, under the influence of VEGF, can transdifferentiate into endothelial cells. This system of circulating cells, circulating microRNA-containing particles, mediators of cell growth and death, and mediators of inflammation connects lungs, heart, and bone marrow through multiple feedback and feed forward loops—many of which still undiscovered. Much can be learned from investigating these multiple complex interactions in PAH patients before and after thromboendarterectomy and before and after single lung transplantation.