Elevated left ventricular filling pressures are a general feature and hallmark of heart failure resulting from cardiac dysfunctions, essentially arising from and affecting the left ventricle [1, 2]. These disorders include heart failure due to diastolic and/or systolic malfunction, as such heart failure with preserved (HFpEF) and without preserved, reduced (HFrEF) ejection fraction; valvular diseases; congenital cardiomyopathies; and congenital and acquired afflictions of left heart inflow and/or outflow tract [2, 3]. Thereby, the pressure of the left atrium will be elevated, either subsequently due to the increased LV-filling pressure [1, 4], or even primarily in case of mitral stenosis [5]. In any case, left heart disease (LHD) is generally characterized by elevated left-sided filling pressures [4, 6]. These augmented left-sided filling pressures are transmitted backwards, downstream, thereby causing an increase in pulmonary venous pressures [1, 5–7], a condition “of passive or congestive nature” as associated with pulmonary venous congestion [6]. In the literature this issue has, in the past, been called pulmonary venous hypertension (PvH) [8], or post-capillary pulmonary hypertension [9] or passive pulmonary hypertension [10]. Consequently, with the rise in pulmonary venous pressure, pulmonary artery pressure (PAP) also increases [11].

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure ≥ 25 mmHg at rest measured invasively by right heart catheterization [12–14], and PH due to LHD requires in addition a PCWP > 15 mmHg [5, 12, 13] or a LVEDP > 15 mmHg [5, 12, 13] (> 18 mmHg [15]) – group II PH.

In all other forms of pulmonary hypertension (groups I, III, IV, V—see below), PCWP is and has to be, per definition, ≤15 mmHg [12, 13], characterizing pre-capillary PH as the pulmonary veins remain basically unaffected [16–18].

Commonly, PH is applied equivalent to, and thus is supposed to be associated with, elevated pulmonary vascular resistance (PVR) [7]. However, PH simply indicates elevated pressures in the pulmonary circulation, rather than explicitly indicating pulmonary vascular alterations, which are reflected by an elevated PVR [7, 19, 20]. Moreover, in case of acutely elevated left-sided pressures [21, 22] and in the early phase of venous PH, with passive increase of the pulmonary venous pressure due to elevated LVEDPs and/or LA-pressures [22], PVR is usually pretty normal [13]. There is no evidence at all that this acute and non-sustained post-capillary rise in pulmonary pressure is accompanied by any kind of dysfunction inherent to the pulmonary vessel system [21]. Accordingly, although in most circumstances PAP enhancements are related to an increase in PVR, an increase in PAP is not inevitably coupled with an increase in PVR [23, 24].

Pulmonary hypertension is classified in five categories [3, 12, 13].

Group I: Pulmonary arterial hypertension (PAH)

as classified by Simenneau [14] and modified by Rosenkranz [25]

Group III: Pulmonary hypertension due to lung diseases and/or hypoxia

Group IV: Pulmonary hypertension due to chronic thromboembolic disease (CTEPH)

Group V: Pulmonary hypertension with unclear/multifactorial mechanisms

Pulmonary hypertension ranks third, after coronary artery disease and arterial hypertension, in the number of incidences of cardiovascular diseases [26]. LHD is the most common cause of PH [17, 27], and accounts for 65–80% of all PH cases [17, 28, 29]. PH is far more common in patients suffering from heart failure (HFrEF and HFpEF), as traditionally assumed. In a study by Butler, who considers a PVR above 1.5 WU (130 dyn s cm⁻²) to be elevated, 36% of the patient group, suffering from HFrEF, showed a mildly elevated PVR, 17% a moderate elevation, and 19% a severe one [24]—consequently 72% of the patient group was afflicted with a relevant PH associated with pulmonary vascular disease. Lam demonstrated in a community-based study of HFpEF patients, that 83% of patients had PH, defined as a systolic pulmonary pressure of >35 mmHg [8]. Schwartzenberg recently studied patients with HFrEF and HFpEF and found that 80–90% of the patients exhibit a PVR > 1.7 WU (about 136 dyn s cm⁻²) and thus vascular inherent PH [30]. Bursi, defining PH as being present if the systolic PAP exceeds 35 mmHg, confirmed Schwartzenberg’s results in a community-study, finding an incidence of PH in 79% of heart failure patients in his study (HFrEF and HFpEF) [31].

Accordingly, in both HFrEF and HFpEF, PH is frequently present: As study results demonstrate, PH occurs in roughly 80% of all patients suffering from primarily left-sided heart failure [24, 30–36], whereupon PH is even more present in HFpEF than in HFrEF. Moreover, diastolic dysfunction, as the central pathology in HFpEF, has been identified as being the predominant cause of PH in LHD [17].

Unfortunately, if PH is present, increased morbidity and mortality have been verified in both HFrEF [6, 21, 31, 37, 38] and HFpEF [6, 31, 34, 36]. It has been demonstrated, that systolic PAPs exceeding 35 mmHg are independently associated with decreased survival in both, HFpEF and HFrEF patients [8, 31]. Moreover, the presence of PH is even associated with poor prognosis and high mortality in the general population, not only in those with heart failure [34]. Up to 73% of patients suffering from primarily mitral valve disease develop PH as a complication [39, 40]. PH is also reported to be as high as 30–50% in patients with aortic stenosis [41, 42]. In valvular heart disease, the presence of PH indicates poorer survival after valve surgery [43]. Ensuing right heart dysfunction/failure in chronic LHD is shown to be predictive of clinical events and reduced survival [44–46].

Pulmonary hypertension in general results from increases in pulmonary vascular resistance (PVR), pulmonary blood flow, pulmonary venous pressure, or a combination of these features [2, 6, 19]. More specifically, and in differentiation to pulmonary venous hypertension (PvH), pulmonary arterial hypertension (PAH) with idiopathic arterial pulmonary hypertension (IPAH, formerly called primary pulmonary hypertension) as the classical disorder in this group of maladies, results from (a) vascular wall remodelling, (b) (micro)thrombosis, and (c) vasoconstriction [47, 48].

Elevated left-sided filling pressures are a fundamental and characteristic feature in patients with LHD [12, 13]. Since PH is verified to depend on elevated filling pressures (and on the degree of mitral regurgitation [49]), diastolic cardiac properties, rather than systolic LV function, are determining this disorder [50–52]. Increased LV—filling pressures are, in any case, passively transmitted backward, downstream, and thus have a substantial impact on LA pressure and on pulmonary venous pressure (PvP), facilitating the development of pulmonary venous hypertension [1, 5]. As such, elevated left heart filling pressures are recognized to cause PvH [53] irrespective of LV-EF [54]. Even milder elevations of LVEDP and consecutively or initially raised LA-pressures may display PvH, since, due to the anatomically serialised vascular structures, the transmitted pressure adds up to the resistive and flow-related PA-pressure [7]. Concomitantly with the rise in pulmonary venous pressure, pulmonary artery pressure (PAP) increases [11]. Moreover, downstream pressure has (compared to the systemic arterial circulation) a marked impact on the pressure level within the pulmonary circuit, as it may contribute up to 50% (systemic circulation 5% to MAP) to total PAP [21].¹

Acutely elevated and pathologically high pulmonary venous pressures may cause so-called “alveolar-capillary stress failure” [55], facilitating acute pulmonary edema formation [21, 22]. “Overt pulmonary edema is the clinical correlate of alveolar- capillary stress failure” [22]. This condition, histologically indicated by ultrastructural alterations of the alveolar-capillary unit due to an abrupt rise in pulmonary capillary hydrostatic pressure, is characterized by a disruption of the capillary endothelial and alveolar epithelial cellular layers resulting in endothelial cell dysfunction, capillary leakage and increased permeability of the alveolar-capillary barrier [22, 55], accordingly promoting acute pulmonary congestion [56] or even pulmonary edema onset[5, 21, 22, 57]. Acute pulmonary congestion or edema, arising from acutely increased left-sided filling pressures, are definitely caused by the raised hydrostatic capillary pressure, hence denoted hydrostatic or hemodynamic edema [58]. However, a rise in the permeability of the alveolar-capillary membrane, the predominant disruption in non-cardiogenic edema as described in the literature [58, 59], is supposed to contribute to the primarily cardiac initiated congestion/edema formation, and as such, both mechanisms, of course with quite different emphasis, may participate in the pathobiology of pulmonary edema development in LHD [5, 56, 60, 61]. Fortunately, there is good evidence suggesting that these ultrastructural abnormalities, indicating acute alveolar-capillary stress failure, are fully reversible if PvP and thus capillary hydrostatic pressure returns to normal values after a more or less short spell [62, 63]. Elliot [64] demonstrated complete restoration of the alveolar-capillary unit after normalized LA-pressure, indicating a quite impressive plasticity of this alveolar-vascular interface. Yet, acute alveolar-capillary stress failure may serve as a trigger for maladaptive processes ensuing, namely in the pulmonary vessel tissue structure [63].

On the other hand, if the elevation of the pulmonary venous pressure is sustained and PvH persists for a length of time, or pressure exacerbations occur repetitively [21], both the alveolar-capillary membrane [65, 66] and the pulmonary vessel network, including veins, arterioles and arteries [67], may suffer from an irreversible remodelling: The basement membrane composition changes and the membrane thickens, mainly attributed to considerable deposition of collagen (type IV) [65, 66]. These modifications may have a protective effect against further pressure damage and prevent edema formation [60], may substantially affect alveolar diffusion capacity (membrane conductance) and as such blunt gas exchange and remarkably limits exercise tolerance [21, 56, 68].

This process of remodelling of the alveolar-capillary unit, caused by injury through elevated hydrostatic pressures in the capillaries of the alveolar-capillary unit, attributed to LHD with backward transmitted elevated left-sided filling pressures, is associated with and considerably influenced by an inflammatory response, decisively mediated and “orchestrated” by the endothelial cells [53, 69–71]. Vascular stretch is attested to possibly initiate an inflammatory response [72, 73], and hydrostatic pressure is known to be one of the highest potential biomechanical stimuli for endothelial cells to display a pro-inflammatory, pro-oxidant and vasoconstrictive milieu [74]. Of special interest is the impact of the endothelium on local hemodynamics, substantially regulating the vascular tone [75–77]. By communicating and interacting with the vascular smooth muscle cells, the endothelial cells try to provide a well-balanced vascular tone and blood flow, meeting cellular and tissue metabolic demands [75, 76, 78]. Imbalanced production and release of vasoactive agents, notably blunted NO synthesis in response to vascular pressure stimuli of the endothelial mechanoreceptors, and increased generation and release of ET-1, as occurring in endothelial dysfunction due to LHD with sustained PvH [79], implies impaired smooth muscles cell relaxation, and subsequently substantial increases in pulmonary microvascular tone arise, enhancing PVR [79–82]. PVR is crucially determined by the balance between these opposing mediator resources [79, 80]. Furthermore, a NO deficit results in the loss of the physiological oscillation in endothelial calcium handling, thus the cytoskeleton organisation will be considerably disturbed [83]. Alongside, a variety of local pro-inflammatory mediators including TNF-α, angiotensin II and endothelin-1 (ET-1), circulating immune competent cells, (myo)fibroblasts, etc., as well as hypoxia are also involved in the alterations induced, ending in a histological structural remodelling of the alveolar-capillary unit [22, 63].

Beyond this microcirculatory remodelling, pulmonary veins, arterioles and small and medium arteries are affected by the functional and structural remodelling [4, 53]. The imbalance between vasodilative and vasoconstrictive mediators, in case of group II PH in particular the blunted capillary and arteriolar NO synthesis in response to mechanical and receptor-mediated stimuli [79], favouring vasoconstriction, provokes a marked rise in the tone of pulmonary resistive vessels, significantly driving the PVR up [5, 27, 79, 80, 84]. Furthermore, media hypertrophy of the veins potentially leading to so-called pulmonary venous arterialization (histologically presenting as muscularisation of arterioles, hypertrophy of the intima and the media of the arteries) [5, 21, 67], are structural abnormalities inevitably resulting in increased PVR, due to a reduced area of the pulmonary vessel system [5, 85]. Noteworthy, these substantiated histological alterations are quite similar to those we come across in primary pulmonary hypertension [4, 86].

PVR increases, and pathologically high values are associated with and indicate, “pulmonary vascular disease” [5, 7, 20, 86, 87]. PVR may be considered to predominantly represent the functional condition of the coupled unit, composed of pulmonary endothelium and adjacent smooth muscles cells [88–90]. Increases in PVR indicate significant reductions of functional, or even structural, capacity (diminished cross-sectional area) of the pulmonary vessel system, mainly of the small, resistive distal pulmonary arteries and arterioles [5, 85]. Moreover, at least in acutely elevated left-sided pressures [21, 22], and in the early phase of venous PH with passive increase of the pulmonary venous pressure due to elevated LVEDPs and/or LA-pressures [22], PVR is usually pretty normal [13]. Most patients suffering from HFpEF show some degree of PvH, but may have normal PVR, however, a substantial subset will develop pulmonary vascular disease [91].

Accordingly, patients suffering from LHD and consecutively persistent venous pulmonary hypertension may, although the increased pulmonary pressures are basically of backward transmitted, passive nature, develop functional and structural modifications of the pre-capillary, namely of the arterioles and the small arteries, segments of the pulmonary vessel system [5, 67, 79, 80, 82]. These alterations cause an increase in PVR and concomitantly, a (further) considerable rise in pulmonary pressures [5, 21, 85]. Indeed, vasoconstriction of functional nature and/or structural reductions in the area of the pulmonary arterioles and arteries, inevitably provokes an “out of proportion” increase in the pulmonary pressures, hence in addition to the PvH, a pulmonary “arterial” component to the (total) PAP is recognized [6, 19, 20, 47]. As such, study results reporting disproportionate PAP increases, clearly above of those expected from (measured) left atrial pressure/LV-filling pressures, are very well explained by this superimposed pre-capillary, reactive component contributing to the PH found in a substantial number of patients with LHD [4, 9, 92, 93]. Of course, not all patients are affected, and as such, the response and the consequences to PvH varies widely [4]. However, the majority of patients suffering from mitral stenosis [93], HFrEF [24, 38], and HFpEF [8] show a pre-capillary component to their pulmonary hypertension.

LA dysfunction characterized by increased LA size, interstitial LA fibrosis (causing increased LA stiffness), reduced LA compliance, and impaired LA contractility, contributes to the disease process by affecting left ventricular filling, enhancing LA and pulmonary venous pressures, provoking a rise in pulmonary vascular resistance and in PAP, amplifying the development and manifestation of “combined” PH [94–97]. Ensuing heart failure symptoms relate to LA dysfunction in patients with HFpEF [98]. Increased pressure and dilatation of LA are likely to be necessary adaptions to compensate for increased LV-filling pressures in order to maintain LV filling in HFpEF patients [99–101].

Furthermore, the development of relevant functional mitral regurgitation (MR), often exercise—induced and thus reiteratively occurring [50, 102–104], is demonstrated to augment LA pressure, since the pressure effected by the systolic part of regurgitation volume adds up to systolic LA filling pressure [103, 104]. The insensitivity of the pulmonary vasculature to vasodilators including NO and natriuretic peptides [6, 79, 93] and the neurohormonal activation are considered to potentially contribute to the disease process leading to combined PH.

In HFrEF, the extent of (functional) MR is considered crucial for the quantity of PH [50]. Hypoxemia related to congestion and obstructive sleep apnoea, often seen in patients with LHD, may also worsen PH [6]. Finally, even genetic factors predisposing patients to maladaption of the pulmonary vessel network are being discussed [105].

This increase in pulmonary vascular resistance and PAP markedly impacts the impedance (rises) of the pulmonary artery and the RV outflow tractus, after-loading the right ventricle [106–109], with relevant consequences for RV-PA-coupling and RV-performance [5, 53, 106, 110, 111]. The dynamic interplay between pulmonary vascular resistance, the pulmonary vessel compliance, and the wave reflections determine RV-afterload [111]. Increases in PVR are the most common cause for increases in RV-afterload [112]. PVR reflects the resistive RV-load, however, vascular resistance and vascular compliance (representing the pulsatile load) are inversely related to each other in pulmonary circulation [113]. Consequently, a relevant decrease in vascular compliance will occur with increasing PVR [113]. This “special” relation is explained by the fact that in the pulmonary circuit, compliance is distributed over the whole vascular network, while largely located in the aorta within the systemic circulation [114]. Indeed, Stenmark [115] provides evidence that more than 1/3 of the increase in RV-load due to an increase in PAP is caused by pulmonary artery/large pulmonary arteries stiffening. Additionally, stiffening of the pulmonary artery/arteries is reported to increase while PH progresses [116]. Thus, large pulmonary artery stiffness causes significant increases in RV afterload [20, 111], notably in case of persistently high pulmonary venous pressure and in advanced stages of vascular remodelling [87, 111].

RV afterload is a major determinant of RV systolic function [117], and as the performance of the right ventricle crucially depends on its afterload, even more than the LV [106, 118], it is more than reasonable to consider RV and pulmonary vasculature as one unit: “PAH is a disorder affecting both the pulmonary vasculature and the right heart” [29, 119–121]. Accordingly, enhanced afterload effects RV systolic function and as mean PAP is inversely related to RV-EF [117], increasing PAP impairs RV-EF [122]. Therefore, in patients with PH, decreases in RV-EF generally reflect an increase in RV- afterload rather than a compromised RV systolic function/contractility [123].²

Furthermore, Di Salvo [124] and Ghio [37] both found that RV-EF provides, in addition to PAP, independent prognostic information, emphasizing the necessity to consider the RV-pulmonary circuit as a unit in patients with LHD and consecutive PH [119]. Several studies demonstrated that both, PH and the (subsequently) compromised RV-function, henceforth called the RV-pulmonary unit, considerably affect the prognosis of patients with LHD [31, 37]. Moreover, ventriculo-arterial coupling specifically refers to the relationship between ventricular contractility and afterload [113] and as such, ventriculo-arterial coupling, indicated by the E_a-pul/E_es-RV ratio, is an important determinant of net cardiac performance [125] and cardiac energetics [126]. Only appropriate matching between the right ventricle and the pulmonary arterial system results in an optimal transfer of blood from the RV to the pulmonary circuit without excessive changes in pressure, an optimal or near-optimal stroke work, and energetic efficiency [127]. Interestingly, RV-PA uncoupling occurs in chronic pressure overload following PH due to LHD [128], while in idiopathic PAH RV-PA coupling is preserved [129].

As described in Chap. 4 in more detail, a rapid (and substantial) rise in PAP causing acute pulmonary hypertension with concomitantly enhanced RV wall tension, immediately leads to RV-dilatation [106, 130], which is accompanied by increases in RVEDV [107, 109, 130] and RVEDP [131, 132], compromised RV contractility [37, 108], impaired RV-EF [130, 133], RV pump failure and even cardiogenic shock may promptly ensue [134]. These hemodynamic alterations are largely a result of the thin-walled RV, which is physiologically coupled to, and ejects the blood into a low pressure highly compliant compartment [27, 85, 112], and therefore is only poorly capable to respond to, and suitably face, an acute increase in afterload [135]. Even mild acute PH, following an increase in RV-afterload, may lead to substantial RV-PA-uncoupling, indicating that the RV is not able to match the combined load of elevated PVR and augmented vascular/ventricular elastance [136]. Due to PH, which precipitates RV stiffening [137], and as such results in increased RVEDP [137] and RV-dilatation, tricuspid regurgitation [138] arises. Furthermore, diastolic ventricular interaction (DVI) applies, compromising left ventricular filling and (even further) deteriorating global cardiac function and systemic circulation [138–140]. DVI, coming in general and particularly into effect with increasing RVEDP, as for example when RV loading conditions change [141, 142], substantially contributes to acute RHF pathobiology and makes a crucial hemodynamic impact on right heart and subsequently systemic cardiovascular functions [143]. Beyond, RV-dilatation directly affects LV geometry, impairing LV filling [144], and subsequently compromises LV contractility with considerable effect on RV performance—as about 1/3 (20–40%) of systolic RV pressure generation and output results from LV contraction [143, 145, 146]. Furthermore, neurohormonal and endothelial—immunologic/inflammatory cascades acutely activated in cardiocirculatory challenge, markedly influence the acute pathology [119, 147–149]. As such, stimulated sympathetic discharge (including increased systemic catecholamines levels) and excited activation of the renin-angiotensin-aldosterone cascade, specifically angiotensin II, as well as enhanced endothelin-1 release, and all that in the presence of blunted and imbalanced counter-regulatory mechanisms such as natriuretic peptides, substantially co-determine the acute pathophysiology of right heart dysfunction [149–154].

In these circumstances, sufficient and consistent adaption may fail as the initial heterometric response may not be replaced by enhanced ventricular performance [155]: The so-called heterometric adaption (coping beat-to-beat changes) applies, when the ventricle is faced by an abrupt rise in afterload, using the Frank-Starling mechanism, and thus allowing to maintain SV at the expense of increased end-diastolic filling volume [156, 157]. However, within a couple of minutes, ventricular elastance, and thus systolic performance, will match the increased load by full homeometric adaption, replacing the initial heterometric response [158]. This may not be the case in acute RHF thereby keeping the “compensatory” mechanisms activated and running.

In case of a gradual increase in PAP and PVR as is usual in LHD, so-called homeometric contractility adaption to afterload, according to Anrep’s law [159], may ensue [155]. The homeometric adaption and remodelling is characterized by an increase in ventricular systolic function (e.g. contractility) without chamber dilatation, in order to meet the load the ventricle is facing [156]: The right ventricle adapts to the increased afterload by increasing its wall thickness and contractility [113]. Homeometric adaption is shown to be the predominant feature of RV to face increased afterload and to ensure preserved RV-PA-coupling [155, 160]. However, if the load rises further, becoming too high for too long a period, or if these compensatory mechanisms are insufficient to match the load imposed, RV-PA uncoupling, associated with a (further) increase in RVEDV occurs [155, 156], and a heterometric adaptive response, indicating RV dysfunction [113], or even RV-failure, rapidly ensues [155, 160]. Severe inflammatory conditions (e.g. septicaemia), long-term increase in PVR or advanced heart failure, are disorders predisposing RV-PA uncoupling and RV-dysfunction [155, 160]. Indeed, it is essential to mention that, for sure, further, supplemental features (in addition to the pulmonary vascular and pressure alterations and their consequences for the RV and the RV-PA unit) are involved and contributing to the complex pathobiology of (developing) RV-dysfunction/failure including persistent neurohormonal activation and inflammation, apoptosis, persistent oxidative stress, metabolic derangements, the results of remodelling like hypertrophy and fibrosis, and, not least, RV ischemia [113, 148, 161].

To summarise, in the first instance, LHD leads to pulmonary venous hypertension attributed to passive, backward transmission of the elevated left heart-sided filling pressures [1, 5, 7], mainly precipitated by LV dysfunction, many a time by LV diastolic dysfunction [162, 163]. Mitral regurgitation, often exercise-induced and thus occurring repeatedly, and the loss of LA compliance may amplify the pulmonary venous pressure increase and thus PvH [94]. Abrupt increases in left-sided filling pressures may cause alveolar-capillary stress failure [55], facilitating acute overt pulmonary edema formation [21, 22]. The main pathophysiological feature, and driving force precipitating pulmonary congestion or pulmonary edema, is the increased hydrostatic capillary pressure in the alveolar-capillary unit [58]. Alveolar-capillary stress failure is potentially fully reversible, as long as pulmonary venous pressures return to normal in good time [62–64]. However, persistent or recurrent elevated pulmonary venous pressures have been shown to cause functional and structural alterations not only at the alveolar-capillary unit [4, 65, 66], inducing irreversible remodelling, but also notably of the arterioles and the small and medium-sized pulmonary arteries [67] (the pre-capillary segments of the pulmonary circuit [5, 21]). Endothelial dysfunction, and the activated inflammatory cascade, decisively determine and integrate the incipient processes [53, 69–71]. This leads to both, functional alterations (mainly a significant rise in pulmonary vascular tone in microcirculation and resistive vessels, augmenting PVR [5, 27, 79]), as well as to structural vascular remodelling (including intima and media hypertrophy of the pulmonary arteries and arterialization of the veins) [86, 164], reducing the area of blood flow and thereby driving the PVR up [4, 5, 27, 85]. Accordingly, PVR rises considerably [5, 7, 27], indicating pulmonary vascular disease [5, 87]. Subsequently, a further increase in pulmonary hypertension arises [5, 85], as the change in PVR is superimposed on the elevated PvP [86, 93]. Elevated PVR and the disproportionate (in excess to the left-sided filling and consecutively pulmonary venous pressures [162, 163]) rise in PAP, indirectly confirm a pre-capillary, pulmonary arterial component, superimposing the PvH and contributing to the considerable PH, recognized in a significant number of patients suffering from LHD [4, 27, 87]. As such, reactive PH displays and represents a complex reaction to chronically elevated filling pressures of the left heart side, including structural (pulmonary venous arterialization of small and medium-sized vessels [164]) and functional alterations such as ED associated imbalances between NO and ET-1 production fascilitating vasoconstriction [79, 80]. Consecutively, a marked load, largely attributed to the rise in PVR and to the stiffening of the large(r), central pulmonary arteries [115, 165], is imposed on the right ventricle (RV-PA unit) [106–109], crucially affecting RV-PA-coupling and RV function, potentially provoking RV failure [87, 113, 128].

The symptoms patients with PH complain of, are non-specific and comprise amongst others, dyspnoea, fatigue, chest discomfort or pain, palpitations, syncope and peripheral edema [2]. Especially remarkable, and most common symptoms, are exertional dyspnoea and a noticeable exercise intolerance, which patients with PH suffer from, due to LHD [21].

The pathophysiology underlying exertional dyspnoea is complex and several mechanisms are interrelated and contributing [21]. However, the basic pathology may be that the pulmonary circuit in PH, due to LHD, is unable to accommodate the increased blood flows during exercise [166], and contrary to the physiologically expected PVR fall [167] and moderate increase in PAP [168], abnormally high pressures occur (rising PCWP, PAP and/or PVRs) [166]. One feature of the predominating pulmonary vascular pathophysiology is the impaired physiological dynamic pulmonary vasodilation, which subsequently imposes a considerable load on the RV during stress [169].

Exercise, provides a powerful tool to examine the response of the cardiovascular system to stress and to assess its functional reserve [170], and may reveal early stages of heart failure, especially in HFpEF [92]. Patients with normal filling patterns at rest may exhibit dyspnoea and PH during exercise [92, 166].

Ventilatory abnormalities, particularly oscillatory breathing patterns during exercise due to pulmonary vasoconstriction, compromised right ventricular performance and low total CO [171, 172], and the limited cardiac reserve and thus limited CO increase [85, 173], provoke a lower anaerobic threshold and contribute to dyspnoea [2].

Breathing alterations are common in group II PH, as such, periodic breathing is related to sympathetic activation [174], enhanced incidence of sleep apnoea, and especially patients with HFrEF and PH show inefficient ventilation with high expiratory volumes per time in relation to the carbon dioxide exhaled, hence are often hyperpnoic [175].

Syncope may appear due to exercise or arrhythmias. Chest pains, attributed to maladjusted coronary perfusion in the presence of elevated RV pressures [176], befall even more predisposed patients with coronary artery disease and/or RV hypertrophy, particularly if there is a low MAP (due to poor LV function) [2].

Peripheral edema formation may be the result of tricuspid regurgitation and RV dysfunction, leading to venous congestion, subsequently affecting abdominal organs, particularly incipient renal venous congestion which impairs renal function (called cardio-renal syndrome, see Chap. 7), will all complicate the malady [4, 11, 177, 178].

Moreover, Rosenkranz [28] even indicates that the clinical picture in patients with PH, due to LHD, may be completely dominated by signs and symptoms typical and characteristic for (acute) right heart failure. The spectrum of the clinical presentation of this patient group is broad, ranging from a more or less `pure` decompensated left heart phenotypic picture, to an appearance which is dominated by features representative of an acutely decompensated right heart [28].

Chest X-ray may indicate pulmonary vascular congestion or even pulmonary edema and pleural effusion in or without the presence of cardiomegaly. Of note, co-existence of pulmonary edema and signs of right heart failure is rare, possible due to that fact that the vascular alterations of the pulmonary vessel network protect against pulmonary fluid transudation [21]. Computer tomography may denote ground-glas opacities and mosaic perfusion patterns consistent with chronic interstitial edema [21].

Echocardiography is an essential tool and the method of choice to detect PH [4, 13] and thus is an indispensable procedure in the assessment of patients suspected of PH [2, 6, 13]. Systolic pulmonary pressures (sPAP) become assessable, if tricuspid regurgitation is present [180]. Systolic pulmonary pressures > 35 mmHg are suggestive for PH [181]. Both, under- and overestimations (if pressures are normal or only mildly elevated) are not infrequent [182], and estimated sPAPs between 35 and 45 mmHg need careful interpretation [183] and should only be apprised in the clinical context. Echocardiographically calculated sPAPs between 35 and 45 mmHg are considered to indicate mild PH, pressures between 46 and 60 mmHg represent a moderate and those above 60 mmHg a severe PH [184]. PH and its severity are determined by elevated filling pressures which can be echcardiographically evaluated by the severity of diastolic dysfunction [50–52]. As such, E/A-ratio and the E/e’-ratio are reported as the echocardiographic parameters which most reasonably reflect end-diastolic filling pressures [49, 50, 185]. Restrictive filling patterns (E-wave deceleration rate) and the degree of mitral regurgitation turned out to be the strongest independent predictors of PH [49, 186].

Furthermore, the presence of LHD/LV dysfunction may be assessed, or even recognized, by echocardiography. Signs suggestive of LV dysfunction include LA dilatation, LV hypertrophy, more severe mitral valve regurgitation, and indicators of elevated LV filling pressures [187–189]—further details see Chap. 5 HFpEF. As RV-function encroaches upon the prognosis in patients with LHD and PH, assessment of the right heart is absolutely essential [2, 190, 191].

The gold standard in diagnosing PH is right heart catheterization (RHC), and the current guidelines even require RHC in order to reliably diagnose PH [10, 13]. Clinical and/or echocardiographic evidence for PH should lead to RHC [2, 6].

Importantly, invasively derived pressure measurements should be registered only in end-expiration as the pressures recorded may significantly differ between inspiration (lower) and expiration (higher) while PH definition and specified limits are standardized to end-expiratory measurements [28, 192, 193]. Furthermore, LVEDP depends on loading conditions [28], and changes may induce a considerable modification of hemodynamics and thus the magnitude of pressure values recorded: especially patients suffering from PH caused by HFpEF are highly sensitive to even small changes in volume and/or BP [30, 127, 194, 195]. As such, after diuretic therapy, the presence of elevated left sided filling pressures, and subsequently PH, may be missed, just because the patient has been volume unloaded [196]. Volume depletion can underestimate left heart filling pressures [197]. On the other hand, in balanced fluid conditions, a standardized fluid challenge (500 mL normal saline infused within 5–10 min) may unmask a post-capillary, venous PH component present in patients with PH, clearly identifying LHD as the cause for PH [197–199]. If a PCWP of >18 mmHg can be recognized in response to the fluid applied, a left heart dysfunction, whether systolic or diastolic, should be assumed [198]. Extraordinarily and remarkably, Fujimoto [198] showed that even in healthy volunteers, a transient but significant increase in filling pressures (right and left sided) can be observed when infusing fluids rapidly (1 L of normal saline within 5 to 10 minutes): mean PAP, PCWP and RA-P were all significantly raised in all groups, young, old and HFpEF patients, but increased the most in patients with HFpEF. Causative, pericardial constraint was demonstrated to be largely responsible for the increase in filling pressures, indicating that non-myocardial structural changes caused the elevation in pressures [198, 200, 201]. Thus, no change in myocardial stiffness occurred [202, 203]. Accordingly, the results of fluid infusion in order to identify occult venous pulmonary hypertension need superb interpretation!

PVR—defined by [PVR = mean PAP – PCWP]/CO [85], which equals PVR = TPG/CO, is a commonly used parameter in daily practice [87]. Increased PVR represents pulmonary vascular disease, and as such, pulmonary arterial hypertension [24, 204]. PVR is found to be sensitive to both, changes in flow and filling pressures, however PVR may not sufficiently indicate changes of the pulmonary circulation at rest [162, 205]. PVR values of ≥3 Woods (240 dyn s cm⁻²) are highly suggestive of pulmonary vascular disease [10, 206].

The new recommendations based on the 5th Symposium on PH in Nice, France, in 2013 encourage practitioners to include PVR in the characterization of PH—with an elevated PVR (>3 WU) in the presence of a mean PAP ≥ 25 mmHg and a PCWP ≤ 15 mmHg (normal left heart-sided filling pressures) is indicating pre-capillary PH—but PVR should not be part of the general definition of PH [12]. In case of combined PH, attributed to LHD, PCWP > 15 mmHg and PVR > 3 WU are required.

High mean PAP, PCWP, PVR, and reduced PA compliance are indicative of poor survival and as such provide prognostic information [37, 207, 208].

Of special note, in case of RV failure, PAP may decline despite considerably high PVR and thus may underestimate the extent of pre-capillary PH [21].

The so-called transpulmonary pressure gradient (TPG), the driving pressure across the pulmonary circulation [27] (defined as TPG = mean PAP – LA-P, respectively PCWP [162]), has been shown to rise “out of proportion” to wedge pressure PCWP (left-sided filling pressure), concomitantly accompanied by disproportional increases in PAP [209], in patients with LHD suffering from combined post-and precapillary PH [24, 204]. As such, an elevated transpulmonary gradient (defined as calculated values exceeding 12–15 mmHg [41, 52]), reflects pre-capillary contribution to pulmonary hypertension in LHD patients [1, 21, 91]. Accordingly, in case of LHD, reflected by a mean PAP ≥ 25 mmHg and a PCWP > 15 mmHg:

Elevated TPGs, in the presence of heightened PVR and impaired pulmonary vascular compliance, confirms significant pulmonary vasculopathy [21, 91].

In recent years, diastolic pressure difference or gradient (defined as DPG = diastolic PAP – PCWP [87]), is the preferred parameter used to identify a pre-capillary component contributing to PH in patients with LHD [87]. Diastolic PAP is, compared to mean PAP and systolic PAP, less influenced by changes in loading conditions, for example by PCWP (≈LA-pressure) and SV [28, 162, 163]. This effect is even more evident when SV increases, such as during exercise [162, 163]. Changes in mPAP consecutively have an impact on TPG. Therefore, TPG is affected by all determinants of mPAP including flow, resistance, and left heart filling pressures [162, 205]. Accordingly, mPAP, TPG and PVR may be “too” unspecific as indicators of pulmonary vascular remodelling [210]. Furthermore, the prognostic impact of TPG is poor [211]. As a consequence, DPG is considered to be the most reliable approach to identify pulmonary vasculopathy and hence pre-capillary input to PH in LHD patients [87, 162, 212]. In a landmark study, Gerges and co-workers [212] investigated the role of DPG in predicting outcome and, using a receiver-operating analysis, identified and determined cut-off points for DPG: They established “mixed” PH to be present, if DPG ≥ 7 mmHg or TPG > 12 mmHg. Patients with PH due to LHD and with a TPG > 12 mmHg and a DPG ≥ 7 mmHg, had an inferior outcome after 78 months than those with a TPG of >12 mmHg, but a DPG < 7 mmHg [212]. However, the study has a couple of limitations including: being retrospective in nature; having a bias in the population (patients presented a negative DPG, further a number of patients with a TPG of <12 mmHg had a DPD ≥ 7 mmHg); the patient group had been a selected population (referred to a tertiary centre for their PH); they had a burden of ischemic heart disease; and the patients suffered from severe heart failure. Nevertheless, the cut-off ranges found their way into newly published diagnostic recommendations [162, 212], as such:

However, a very recent study challenged the value of the newly introduced DPG: In a study by Tampakakis [214], investigating in a retrospective analysis the John Hopkins Cardiomyopathy Database, DPG failed to provide sufficient prognostic information, and a correlation between DPG value and survival could not be established. They found that in patients with PH, increasing TPG and PVR were significantly related to a higher all-cause mortality, even after adjustment for standard variables.

As such, the DPG parameter, relatively independent of influences from varying CO and elevated filling pressures on pulmonary arterial compliance [87, 162], has not withstood real world scrutiny, and its implementation in the standard diagnostic may be premature [210]. Moreover, as discussed above, the pulmonary vessel system, with its properties, and the right heart and its performance, have to be considered and have to be seen at as a unit because they substantially interact and influence each other [1, 215]. Insofar, the metric DPG parameter may preferably and uniquely refer to and indicate pulmonary vascular disorders [212], but does not reflect right heart properties and function in the setting of pulmonary vascular pathology. Thus, an integrated approach relating pulmonary vascular pathology, indicated by PVR, TPG, DPG, etc., to RV-PA function and performance, e.g. RV-PA-coupling ratio, is potentially able to translate into prognostic significance [210].

However, clinical assessment and judgement remains crucial: Thenappan et al. have demonstrated in a study on “clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction” [91], that clinical, echocardiographic, and hemodynamic features are able to distinguish PH in LHD from PAH, and from patients with HFpEF but without PH.