Biochemical and molecular correlates of acute RVF include cardiomyocyte death, influx of pro-inflammatory cells, chemokine/cytokine activation, and oxidative stress. Cardiomyocyte death is a consequence of ischemia, substrate depletion, and impaired mitochondrial energy metabolism. Intracellular calcium overload and oxidative stress are additional contributors to cell death. Significant biochemical alterations are observed within 24 h of RV injury.

PE is the prototype of acute RV injury. The abrupt increase in the afterload results in RV muscle stretch and shear stress, increased wall tension and dilation, elevated heart rate, and increased oxygen demand in the face of decreased RV coronary perfusion. The result is a poorly contractile, dilated, thinned, and pale-appearing RV [56] (Fig. 9.3a + b). Histologically, these changes are accompanied by cardiomyocyte lysis and an inflammation. Influx of neutrophils, lymphocytes, and macrophages occurs within hours of the insult [57–59] (Fig. 9.3e–g). Macrophages exhibit an M1 pro-inflammatory phenotype, and compared to neutrophils (which decrease within 1 week) they are still present at 6 weeks (then characterized by a M2 wound repair phenotype) [57]. Myeloperoxidase, MCP1, CINC1, CINC2, MIP1α, and MIP2 are activated/increased within 18 h of the insult, and are accompanied by matrix metalloproteinase activation, cardiomyocyte necrosis, and mitochondrial damage [56, 60]. Similar changes with activation of pro-apoptotic pathways and local overexpression of TNF-alpha were also seen in an acute PA constriction model, where these changes occurred within 2 h of RV injury [61]. Pro-inflammatory biomarkers (e.g., myeloperoxidase) can also be detected in the serum of patients with acute PE [62–64]. Inflammation is pathogenetically relevant, since treatment with anti-PMN or anti-CINC (CXCL1) antibodies or with the nonsteroidal anti-inflammatory drug ketorolac reduces RV inflammation and improve contractile function [56, 65, 66]. Reactive oxygen species (ROS) can be demonstrated within 24 h of acute PE [60]. The RV outflow tract is particularly affected by acute afterload stress [57, 67] (Fig. 9.3a–f). RV deformation normalizes with time in cases of less severe cases of acute PE; however, in more severe PE, RV dilation, thinning, and scarring may remain permanent, leading to persistently impaired contraction [68] (Fig. 9.3h).

Though not specifically described for the RV, experimental data suggest that cardiomyocyte stretch leads to activation of an angiotensin II- and endothelin (ET)-mediated increase in cytosolic calcium and subsequent activation of NFAT, Ca²⁺/calmodulin-dependent kinase II, and PKC signaling [69]. Calpain activation contributes to contractile dysfunction in acute RVF and is associated with decreased abundance and organization of the adhesion protein talin [70, 71]. Lastly, a switch to the fetal gene program similar to what is observed in chronic RVF has also been described for acute RV injury. For example, in a rat model of acute PE, a decrease in the expression of genes, encoding proteins involved in fatty acid transport, activation, and β-oxidation occurs within 18 h of injury [72]. This is accompanied by activation of hypoxia-inducible factor (HIF)-1α, suggesting that—as in chronic RVF [53]—HIF-1α activation is a key regulator of these metabolic changes.

In general, the RV fails as a consequence of alterations in preload, contractility, and/or afterload [2, 8, 26]. While a separation into these three entities helps understand and identify etiologies of RV dysfunction or failure, many conditions can alter several of these components simultaneously (e.g., sepsis, which may alter preload, contractility, and afterload [11]). The following section discusses the clinically most relevant etiologies of acute RVF. A detailed overview of the various etiologies is provided in Table 9.1 and Fig. 9.1.

The most common etiology underlying acute RV failure is decompensated LVF [8]. The development of RVF in LV disease is multifactorial, and includes pulmonary venous congestion, ventricular interdependence, left-sided arrhythmias, and/or myocardial ischemia [8, 29, 73].

Acute PE and acute PH are also common causes of acute RVF [2, 8, 19, 26, 35, 74]. In many ways, these two syndromes are the prototypes of acute RV dysfunction caused by an excessive increase in afterload. In the early 1970s, McIntyre and colleagues documented, using pulmonary angiography, the tight correlation between pulmonary vascular occlusion and pulmonary hypertension in patients without preexisting lung disease [75, 76]. In previously healthy patients, at least 40 % of the cross-sectional area must be obstructed to significantly increase the PAP and produce abnormalities in RV morphology and function on echocardiography [77, 78]. However, in patients with preexisting lung disease, the size and mass of the PE affects the PVR and RV injury. In general, the degree of pulmonary vascular obstruction on CT pulmonary angiography is a poor predictor of outcome, although a central location of clots tends to worsen prognosis [79]. Cardiogenic shock occurs in 10 % of acute PE cases, with a mortality rate of up 52 % [80]. RV dysfunction is observed in about 40–60 % of normotensive patients with PE. While mortality in the latter patients is only 8–10 % [35, 81, 82], RV dysfunction persists in approximately 40 % of previously healthy patients, manifesting itself as an abnormal RV on echocardiogram and/or as persistent exercise intolerance [83, 84]. While it has traditionally been thought that acute PE increases the afterload by mechanically obstructing the pulmonary vasculature, it has now been established that the release of platelet- and endothelial-derived mediators (e.g., serotonin, endothelin-1, thromboxane-A2, prostaglandin F2α) exerts vasoconstrictor effects even in non-obstructed areas and further contributes to the increase in PAP [65, 85, 86]. Similarly, PE-associated intracardiac hemolysis (resulting from severe tricuspid regurgitation and turbulent flow across the pulmonary valve) contributes to vasoconstriction and an increase in the afterload via nitric oxide scavenging by free hemoglobin and via l-arginine depletion (the latter via release of erythrocyte arginase) [87–89]. In fact, plasma haptoglobin concentrations decrease as the severity of PE and the elevations in RVSP increase [87]. Other embolism syndromes associated with acute RV dysfunction include fat, amniotic fluid, cement, or tumor emboli [90–92].

Although any form of chronic PH can result in acute RV dysfunction, overt RVF is frequently encountered in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) [31, 93, 94]. In both syndromes, acute RVF can be the initial presentation of the disease, or present as acute-on-chronic RV failure. Acute PH and RVF are serious problems after cardiothoracic surgery. Mechanisms are multifactorial and include depression of preload and cardiac contractile strength in response to a systemic inflammatory response syndrome, as well as increased afterload from lung vascular microembolism, effects of mechanical ventilation, cardiac restrictive physiology, and the superimposed negative inotropy by drugs required for sedation or heart rate control [95–97]. Specific risk factors for the development of perioperative RVF include the use of cardiopulmonary bypass, RV ischemia-reperfusion injury, and placement of left ventricular assist devices (LVADs) [98, 99]. The etiology for RV dysfunction in the latter case has not been fully characterized; changes in geometry and contraction patterns after LVAD placement have been proposed (see below) [100–102]. Sickle cell crisis, specifically the acute chest syndrome (ACS), has also been characterized by marked elevation in tricuspid regurgitant jet velocity in as many as 60 % of patients [103]. Cor pulmonale has been described in as many as 13 % of ACS patients [103]. The mechanism underlying the development of PH and subsequent RVF in the setting of ACS is multifactorial and includes hyperhemolysis, HPV, pulmonary microvascular embolism and thrombosis, bone marrow emboli, and coronary hypoperfusion [103–105]. Importantly, ACS-associated PH and RV dysfunction are associated with cardiac biomarker elevation and a higher risk of death [105].

Hypotensive states, such as sepsis, shock, hemorrhage, or severe hypovolemia, compromise both RV filling as well as RV coronary perfusion [2]. Sepsis and shock have complex effects on RV function, as they—in addition to decreasing preload—can directly decrease RV contractility via negative inotropic effects of bacterial endotoxins and/or pro-inflammatory cytokines (e.g., TNF-alpha, IL-1beta, IL-6) [4, 106]. Furthermore, sepsis-induced endothelial dysfunction with pulmonary vasoconstriction and pulmonary microthrombi can significantly increase RV afterload [4, 107]. Lastly, treatments employed for sepsis and/or shock (MV, overzealous volume resuscitation) can negatively affect RV function [2, 8, 31].

Severe respiratory disease can cause significant RV dysfunction, as hypoxemia and hypercapnea may impair RV performance via vasoconstrictor effects, and potentially also via direct effects on the myocardium [2, 8, 31, 108, 109]. ARDS has been associated with increased transpulmonary gradients in 73 % of patients in the ARDSnet cohort [110], and acute cor pulmonale occurs in 25–50 % of ARDS patients, depending on the severity of the syndrome [21, 111, 112]. In addition to hypoxic/hypercarbic vasoconstriction, mechanisms of ARDS-induced RV dysfunction include pulmonary microthrombi, pro-inflammatory cytokine activation, and negative effects of MV (see below) [21, 111, 113, 114]. An increased alveolar dead space, resulting from either precapillary occlusion or globally reduced lung perfusion from RV failure, independently increases the risk of death from ARDS [115, 116]. A recent study identified infection-induced ARDS and airway pressures as independent predictors of ARDS-induced cor pulmonale [112]. Another study identified a PaCO₂ ≥ 60 mmHg as a risk factor [113]. However, while ARDS-induced PH and cor pulmonale have been identified as risk factors for death, these results have not been uniformly confirmed [110, 112, 113]. Lastly, exacerbations of chronic obstructive airway diseases may be accompanied by air trapping; the letter may negatively impact pulmonary venous return to the RV (see also Chap. 18).

Mechanical ventilation may also adversely affect RV function, especially in the setting of preexisting chronic RV dysfunction, and if high pressures and/or high tidal volumes are employed. The dynamics of the effects of positive pressure ventilation on RV mechanics are complex and involve reduction in RV preload, increase in afterload (by converting West zone 3 to zone 1 or 2 conditions), and impaired LV filling [117–119]. Severe hypoxemia and/or hypercapnea are commonly encountered in patients requiring MV and likely contribute to RV dysfunction [113].

In LVAD recipients, both short- and long-term outcomes largely depend on RV performance after installation of the circulatory support device [98, 100, 120, 121]. Unfortunately, the development of RVF after LVAD implantation occurs in up to 30 % of cases [98, 122]. Whether this is the result of inducible RV dysfunction or simply “uncovering” a preexisting RV dysfunction remains controversial. Some earlier experimental models suggest that during LVAD support, despite initial improvements in reduction in RV afterload, RV contractility is significantly impaired due to geometrical changes in the LV and subsequent leftward shift of the IVS [100, 101]. However, a recent study of 130 patients with chronic LVF who underwent placement of continuous-flow LVAD actually showed significant improvements in RV performance as determined by an increase in RVEF, RV stroke work index, tricuspid annular plane systolic excursion (TAPSE), and reduction in RV end-diastolic dimensions [120].

Because of these conflicting findings, there has been a strong interest in predicting which patients are at risk of developing progressive RVF after initiation of LVAD support. It is known that patients requiring late biventricular VAD (BiVAD) support have poor outcomes [123–126]. For example, among LVAD recipients who eventually required additional RVAD support, only 35.7 % were bridged to transplantation when compared to 89.9 % of those with LVAD therapy alone [124]. Similar outcomes (40 % survival at time of transplant in those needing BiVAD support vs. 100 % in the LVAD group) were reported in another study [126]. Early installment of BiVAD therapy in high-risk patients significantly improves survival compared to patients with delayed insertion of RVAD support (51 % vs. 29 %) [123]. Patients requiring aggressive inotropic support or intra-aortic balloon counterpulsation devices prior to installation of VAD therapy are among the highest risk patients for developing deterioration of RV function post-VAD placement [99]. Obesity, severe hemodynamic alterations such as elevated PVR, and use of LVAD as destination therapy were also found to be strongly associated with development of RVF [99].

Intrinsic cardiac disease, including acute RV myocardial infarction (RVMI), acute valvulopathies (e.g., mitral or tricuspid regurgitation), viral myocarditis, septic cardiomyopathy, and pericardial disease (e.g., cardiac tamponade) can be complicated by acute RVF [8, 127, 128]. RVMI has been traditionally associated with hypotension, distended jugular veins, and clear lung fields in patients suffering from an acute MI [129]; however, hemodynamically significant RVMI presenting with hypotension actually occurs less than 10 % of the time [129]. Typically the RCA is the culprit vessel, with more extensive RV myocardial necrosis associated with the proximity of the occlusion [130]. The prognosis of RVMI largely depends on presence of complications, such as ventricular arrhythmias or a high-grade atrioventricular block, underlying RV dysfunction, and the success of angioplasty to restore coronary reperfusion [8, 130–132].

An interesting recently identified cause of acute RV dysfunction and sudden cardiac death is the syndrome of arrhythmogenic RV dysfunction in endurance athletes [133] (see Chap. 16). Similarly, it has recently been demonstrated that acute, high-intensity exercise can result in acute dysfunction and cardiomyocyte damage of the RV, but not the LV [134] (see Chap. 15). A decrease in RV function can also be seen after brain death and—in case of heart transplantation—may contribute to early postoperative RV failure in the recipient [135, 136].

Lastly, patients with comorbidities associated with chronic RV dysfunction (e.g., obstructive sleep apnea, chronic lung disease, chronic LV dysfunction, PAH) are at risk for acute decompensation of RV function either due to progression of their underlying disease, or as a consequence of an additional insult to the RV (Table 9.2).

The management of acute RVF begins with recognizing the key signs and symptoms to make the initial diagnosis. Currently available tools include history and physical examination, electrocardiography, biomarkers, imaging studies, noninvasive hemodynamic monitoring devices, and invasive cardiopulmonary hemodynamic monitoring. Importantly, the same tools used for diagnosing RV dysfunction have also been applied to predicting patient outcomes, and are being used for both risk stratification and management of acute RVF (Table 9.3).

History, Patient Factors, and Physical Examination: As in chronic RVF, signs and symptoms of acute RVF tend to be nonspecific and late. While patients typically present with new onset signs and symptoms of RVF, in cases of acute-on-chronic RVF patients likely have preexisting symptoms and physical examination findings. As in chronic RVF, symptoms of chest pain, lightheadedness, and syncope, as well as findings such as hypotension, cyanosis, and cool extremities represent severe and advanced RV dysfunction [137–139].

Over recent years, the patterns of clinical presentations of acute RVF have been included in the risk stratification and management strategies of these patients. For example, syncope in patients with acute PE or advanced PAH strongly correlates with severe RV dysfunction and is associated with increased overall mortality [19, 139, 140]. Signs of hemodynamic instability (i.e., hypotension and tachycardia) also are strong predictors of poor outcomes in patients with PAH [141] or acute PE [19, 35, 142]. Similarly, an altered mental status predicts poor outcomes in acute PE and is included as a component of a recently published severity index [143]. Age and comorbidities influence the prognosis in acute PE [35, 81, 144], and have been included in both the Geneva and pulmonary embolism severity index (PESI) scores [145, 146]. Male sex is a risk factor for death in PAH [147]. Connective tissue disease is a risk factor for death in PAH patients admitted with RVF [141]. Knowledge of these prognostic findings is fundamental in early risk stratification and allows the opportunity for initiation of appropriate therapies.

The key principle in the management of acute RVF focuses on determination and treatment of the underlying etiology. Specific therapies are usually complemented by supportive strategies focused on improving RV function via volume optimization, enhancing contractility, and reducing afterload (Fig. 9.5). These goals are achieved through a combination of appropriate volume management, vasopressors and/or inotropic agents, pulmonary vasodilators, and interventional or surgical strategies [2]. Unfortunately, no RV-specific therapies exist, and most of the interventions aimed at improving RV performance and/or PA vasomotor tone concomitantly affect the systemic vasculature and/or the LV. In addition, studies specifically evaluating patients with RVF are few, limited by small patient numbers and they are usually not prospective. The management of patients with acute RVF should always incorporate general preventative measures, supportive care, and specific interventions aimed at the underlying cause.