Fig. 19.1
This block diagram organizes the different treatment modalities utilized in patients with chronic right heart failure. An attempt is made to list the effects on preload, contractility, and RV afterload. The (+) sign denotes a positive effect, the (−) sign a negative effect, and the (?) symbol indicates that the effect is uncertain or unknown
Reducing Afterload
Increased RV afterload often leads to RV dilation and the resulting increase in wall stress can cause RV ischemia and further aggravates ventricular dysfunction. This is extensively discussed in Chap. 10. The potential reversibility of RV failure is best illustrated by the restoration of RV function after normalization of the afterload after surgical thromboendarterectomy in CTEPH patients [6] or lung transplantation for PAH [7]. Such profound effects on pulmonary vascular resistance are only rarely achieved by the vasodilator drugs currently used to treat PAH. The indirect, after load-dependent, effects of these drugs on RV function are not the topic of this chapter. Here, it suffices to say that the effects on RV function of modest decreases in RV after load are unpredictable [4]. In this section we will summarize the limited body of evidence which has accumulated recently suggesting that these drugs also have direct, afterload-independent, effects on intrinsic RV function.
Oxygen
Hypoxic pulmonary vasoconstriction can be mitigated by administering supplemental oxygen to patients with hypoxemia. This is associated with a modest decrease in the pulmonary artery pressure and pulmonary vascular resistance. In hypoxemic patients with PH related to either COPD or ILD this is the treatment of choice. A target oxygen saturation of 90 % has been proposed [8]. Although supplemental oxygen can offer support to an RV prone to ischemia [9], theoretical negative effects on the RV, including formation of reactive oxygen species (ROS) and suppression of angiogenesis, have not been studied.
Calcium Channel Blockers
Calcium channel blockers are used in the small minority of patients with significant pulmonary vascular reactivity. Notwithstanding the negative inotropic effect of calcium channel blockers, their use in this group of patients is associated with a survival benefit [10] and with an improvement of the cardiac index in patients with a long-term favorable response to this drug [11]. Direct consequences for the RV have not been investigated, but it can be postulated that the negative inotropic effects of these drugs may be harmful, at least in the short term.
Anticoagulation
The risk of thromboembolic events in patients with chronic RV failure has not been well established. Although clinical practice varies, anticoagulation usually is recommended in patients with evidence of intracardiac thrombus, documented thromboembolic events and PAH (indirect evidence for idiopathic PAH and expert opinion for PH associated with scleroderma and CHD) [1, 10]. Anticoagulation is also advised for patients with paroxysmal or persistent atrial flutter or fibrillation, in combination with significant RV dysfunction or previous thromboembolic events [12, 13]. Direct effects of anticoagulation on the RV are not known, but there is no suggestion of harmfulness.
Prostacyclin Analogues
For more than two decades, intravenous Epoprostenol has played an important role in the treatment of PAH. The therapeutic effects of prostacyclin analogues are thought to be due to a combination of vasodilation and inhibition of platelet aggregation and vascular remodeling [14]. However, there is no proof that long-term prostacyclin treatment prevents or reverses lung vessel remodeling in PAH [15, 16]. At least part of the therapeutic effects of prostacyclin analogues has been attributed to improvement of RV function [17, 18]. In patients with severe heart failure prostacyclin treatment results in an immediate and substantial increase in cardiac output and a reduction in cardiac filling pressures [19]. Reflex tachycardia and pulmonary vasodilation seem to contribute to the increase in cardiac output, but a direct effect on the RV by improvement of contractility, reduction of fibrosis, and increase of capillary-to-myocyte ratio was also seen in several animal studies [20, 21]. Furthermore, prostacyclin analogues suppress pressure overload-induced cardiac hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac fibrosis [22, 23]. On the other hand, the increase in cardiac output that initially improves exercise capacity comes at the costs of higher myocardial oxygen consumption, which could be detrimental in the long run. This could be an explanation for the increased mortality which was seen after long-term Epoprostenol treatment in patients with severe left heart failure (LHF) [24, 25] and the negative results in PAH patients of the Beraprost Study Group [26]. The latter study is the only randomized clinical trial with a follow-up time of 1 year with specific PAH-therapy. In this study the initial increase in exercise capacity was transient and disappeared after 1 year. Taking all of the above into consideration, the direct effects of prostacyclin on the RV are still poorly understood.
Endothelin Receptor Blockers
Due to a number of different stimuli (vasoactive hormones, growth factors, shear stress, hypoxia, ROS), cardiomyocytes and endothelial cells produce more ET-1 in heart failure [27, 28]. ET-1 increases pulmonary vascular tone, enhances cardiomyocyte contractility, and has a role in the development of pressure overload-induced cardiac hypertrophy [27, 29]. These effects have also been shown to occur in the pressure-overloaded RV [30]. As such, treatment with ET-receptor antagonists could theoretically act as a double-edged sword in RVF: while RV after load can decrease via a reduction in pulmonary vascular tone, inotropic effects of ET-1 are nullified. Furthermore, cardiomyocyte apoptosis may be induced by treatment with ET-receptor blockers, which is potentially harmful. Galiè et al. have shown that in PAH patients, Bosentan improves RV systolic function and LV early diastolic filling and leads to a decrease of RV dilation and an increase in LV size is measured with echocardiography [31]. Whether these effects occur because of or despite of direct Endothelin-1 receptor antagonism in the heart remains to be determined.
In LHF clinical trials which assessed direct effects of ET-receptor antagonists on the heart, the results were not favorable [32–34]. It can be postulated that by increasing pulmonary vascular tone, ET-1 contributes to optimization of preload for the failing left ventricle, which when prevented would translate into another potentially harmful effect of ET-receptor antagonists in LVF.
Phosphodiesterase Inhibitors
cGMP is a ubiquitous intracellular secondary messenger and its action provides pulmonary vasodilation and suppression of cell proliferation. cGMP/PKG signaling protects the heart from apoptosis [35, 36], may decrease myocardial oxygen consumption [37], and blunts the hypertrophic response to pressure overload, with an associated enhanced systolic function [38, 39].
Type 5 phosphodiesterase (PDE5) degrades cGMP and an increase in cGMP availability in the lung (and subsequent vasodilation) explains the benefits of the PDE5 inhibitor Sildenafil in PAH [40]. PDE5 is expressed in the hypertrophic RV and not in the normal RV, and preclinical studies have shown that suppression of PDE5 activity is associated with a direct increase in right ventricular contractility [41].
In patients with PAH, Sildenafil reduces RV mass, improves the cardiac index and exercise capacity [42], and improves RV diastolic function [43]. The first clinical trials of PDE5 inhibition in patients with non-PAH heart failure with decreased [44, 45] and preserved ejection fraction [46] have shown positive results, but larger randomized controlled trials are necessary. It remains undetermined whether the benefit of PDE5 inhibitors in PAH is predominantly mediated through effects in the pulmonary vasculature or heart.
Possible Future Therapies in PAH
A new concept of a quasi-malignant behavior of endothelial cells in the PAH lung vasculature has fueled the investigation into a number of new targets for drug development [47]. These drugs are designed to interfere with increased cell proliferation, angiogenesis, and apoptosis resistance. The potential danger of these drugs lies in the fact that the failing RV may suffer from ischemia, capillary rarefaction, and cardiomyocyte apoptosis. These are mechanisms, which may be aggravated by the newer therapies with possible detrimental effects on RV function.
One of these potential new drugs is Imatinib, a kinase inhibitor affecting the Tyrosine domain of the platelet-derived growth factor (PDGF) receptor. PDGF signaling has many positive effects on the heart after myocardial infarction [48–50] and is an important element of adaptive remodeling of the pressure-overloaded LV [51]. Inhibition of PDGF-R by Imatinib could therefore negatively influence adaptive cardiac remodeling in PAH, regardless of its effects as a vasodilator of the pulmonary vasculature. Although Imatinib was beneficial in isolated PAH cases [52–55], a recent phase II study was negative in regard to its primary end point [56]. Studies of Imatinib treatment in selected groups of patients will follow. Another tyrosine kinase inhibitor that is currently tested in PAH is Nilotinib (ClinicalTrials.gov Identifier NCT01320865). It is hypothesized that Nilotinib provides clinical benefit to patients with PAH through inhibition of mast cell progenitor proliferation, mobilization, and differentiation. A possible cardiotoxicity of Nilotinib is not currently considered.
In PAH, positive effects of epidermal growth factor (EGF) receptor blockers can be anticipated on the pulmonary vasculature and the pressure-overloaded RV. MCT-induced PH in rats was improved by EGF receptor blockers [57]. Further research is needed to know whether EGF receptor blockers will have a role in PAH treatment. The same is true for Rho kinase inhibitors, which have beneficial effects on the pulmonary vasculature but as yet undetermined direct effects on the RV. HMG–CoA reductase inhibitors (statins) have been shown to effectively reverse pulmonary vascular remodeling and RV hypertrophy in a rat model [58], but the results of a recent trial in PAH patients were disappointing [59].
Optimization of Preload
In general, the RV adapts better to volume overload than to pressure overload. A rise in preload increases the stretching of the muscle fibers, causing the cardiac muscle to contract more forcefully according to the Frank–Starling mechanism. This allows the cardiac output to be synchronized with venous return. Overstretching of muscle fibers in severely volume-overloaded patients further increases RV dilation and wall stress, thereby impairing filling of the left ventricle. In these patients diuretic treatment leads to a decrease of preload and improvement of the Frank–Starling relationship, resulting in a relief of symptoms. However, this observation [56] is rather more based on clinical experience than on empirical evidence. In patients with severe RVF, an improvement in left ventricular function can be attained with a reduction in RV end diastolic volume, a diminution of the leftward interventricular septum shift and thereby improvement of left ventricular diastolic function.
Treatment with diuretics is not without risks (see also Chap. 9, The diabolical effects of preload reduction). Patients with RV failure are highly preload dependent and too rapid diuresis may result in a decline in stroke volume. Diuretic therapy with loop diuretics also predisposes patients to metabolic alkalosis and arrhythmias due to hypokalemia. The aldosterone-antagonist spironolactone has many potentially beneficial effects which are not mediated through effects on volume status. Spironolactone prevents hypokalemia and arrhythmias and is also associated with other beneficial effects, such as immune modulation and reversal of maladaptive remodeling [60]. Although its use has not yet been investigated in detail, spironolactone is recommended by the current treatment guidelines of heart failure and PAH [2, 61, 62]. In addition to diuretic therapy, PAH patients are advised to restrict their daily fluid and salt intake to optimize preload [61].
Improving Intrinsic RV Function
While the goal of PAH-specific treatment is to reduce pulmonary vascular resistance, patients die of RHF (see Chap. 13). The recognition of a key role of RV function in patient survival [4] has not yet resulted in a treatment to directly improve RV function. Mechanisms of RV failure are still not fully understood and often extrapolated from studies of chronic LHF, despite increasing evidence that mechanisms of left and right heart failure are not identical. Some LHF treatments were successfully applied in models of experimental PAH, but others have shown adverse effects. Perhaps the only uniformly accepted form of RV-directed therapy in PAH is aimed at the maintenance of sinus rhythm [63–65].
In LHF, a close correlation has been demonstrated between an increase in heart rate and progression of HF and mortality [66]. When atrial fibrillation develops, there is no active atrial contraction to force an additional volume of blood into the ventricles (“atrial kick”) resulting in a 20–30 % decline in stroke output and a decrease in cardiac output [67, 68].
Patients with RV failure are at risk for atrial tachyarrhythmias, mostly atrial flutter and atrial fibrillation. These arrhythmias, as well as tachycardia, cause impairment of the ventricular function, can lead to hemodynamic instability, and are associated with an increased morbidity and mortality [12, 69–72]. In addition to its hemodynamic consequences, a rise in heart rate is also associated with increased myocardial oxygen consumption [73], which could also partially explain the detrimental effects of tachycardia in the long run. In the aggregate, maintenance of sinus rhythm and heart rate control are essential in RVF treatment.
Digoxin
Digoxin is an oral cardiac glucoside with a positive inotrope and negative chronotrope effect. In patients with left ventricular systolic dysfunction, digoxin provides symptomatic benefits, but in RHF digoxin is only indicated for rate control in patients with atrial tachyarrhythmias [61]. Rich et al. showed that digoxin improved cardiac output in patients with idiopathic PAH, but the efficacy of chronic digoxin treatment remains unknown [64]. Detrimental effects are suggested, including pulmonary vasoconstriction [74, 75]. Additionally, digoxin toxicity may occur, particularly in patients with hypokalemia induced by diuretics and hypoxemia—both conditions which are common in RVF.
Beta-Blockers
In analogy to the treatment of LHF, the increased activity of the neurohormonal axis in PAH is a potential treatment target [76]. Although it is uncertain whether increased sympathetic activation is a cause or a consequence of right heart failure, sympathetic overdrive is clearly associated with a poor prognosis of PAH patients [77].
Increased sympathetic activity is an acute compensatory mechanism to maintain cardiac function by increasing contractility and heart rate, but in the long run chronic adrenergic overactivity has detrimental effects on cardiac function. This is the fundamental basis for beta-adrenergic receptor blockade in current LHF management, which has been demonstrated to reduce LV remodeling and mortality by about 30 % [2]. Heart rate reduction is thought to be one of the main factors contributing to the beneficial effects of beta-blockers on survival in patients with LVF [78].
Notwithstanding the substantial evidence for their beneficial effects in LHF, the use of beta-blockers in patients with PAH has been considered contraindicated [61]. This recommendation is based on the fear of systemic hypotension due to acute negative inotropic effects and a decreased heart rate. Provencher [79] and Peacock [80] described the improvement of exercise capacity after withdrawal of a nonselective beta-blocker in patients with portopulmonary hypertension and negative effects of beta-blocker therapy in one unstable patient with portopulmonary hypertension.
In contrast, three preclinical studies were performed that assessed the long-term effects of AR-blockers in rats with PAH. The studies of Bogaard et al. and De Man and Handoko et al. both show several beneficial hemodynamic and morphological effects in experimental PAH in rats and it has been demonstrated that Carvedilol and Bisoprolol delayed the progression towards right heart failure in experimental PAH [81, 82]; these findings are associated with specific changes in gene expression [83]. Despite the fact that current guidelines prohibit the use of beta-blocker therapy in PAH [61], So et al. reported a prevalence of beta-blocker use of 28 % in a Canadian PAH cohort. At follow-up, no detrimental effects on clinical, functional, and hemodynamic outcomes have been observed in this group compared to PAH patients not treated with beta-blockers [84].
These findings are the foundation of a phase I–II study assessing the safety and efficacy of Bisoprolol treatment in patients with PAH, which will report its results in 2014 (Clinicaltrials.gov identifier NCT01246037).
Ace Inhibitors and AT1R Antagonist
Along with the sympathetic nerve system, the renin-angiotensin-aldosterone-system (RAAS) is activated in PAH [85]. Although an early increase in cardiac output can result from RAAS activation, the long-term effects of an overactive RAAS are assumed to be harmful for the RV. Nevertheless, the use of ACE inhibitors and AT1R antagonists in PAH is controversial. This is due to the systemic vasodilatation that these drugs can induce, which can be life threatening. Conclusions from animal studies are discrepant: in rabbits with PH due to pulmonary artery banding (PAB) an improvement in systolic function was seen [86], but in the SU5416/hypoxia rat model of severe PAH no effects on RV hypertrophy were found [87]. Whether ACE inhibitors or ATIR antagonists have additional effects in patients already taking aldosterone-antagonists is doubtful.
Inotropic Agents
As discussed extensively in Chap. 9, intravenous inotropic agents including dobutamine (a beta-adrenergic receptor agonist), Milrinone (a selective phosphodiesterase-3 inhibitor), Norepinephrine (an α1/β1-receptor agonist), and Levosimendan (a calcium-sensitizing agent) may help to stabilize patients with acute RVF. All of these agents increase right ventricular contractility, as well as decrease afterload by inducing pulmonary vasodilatation and their primary side effect is systemic hypotension.
In chronic left ventricular failure, inotropic drugs are considered to be harmful long term and there is no reason to believe that it would have substantially different effects in patients with right ventricular dysfunction. However, these days a more prolonged infusion of dopamine may be useful as a bridge to lung transplantation in patients with refractory right heart failure in PAH [88].
Exercise
Exercise training (or regular physical activity) is recommended as safe and effective for patients with LHF who are able to participate in exercise programs in order to improve their functional status [2, 62]. After Hambrecht et al. proved that exercise training corrected endothelial dysfunction and improved exercise capacity in chronic heart failure [89], the first randomized control trial on the effects of exercise rehabilitation in PAH was conducted [90]. After a 4-month training program, the mean difference in 6 min walking distance between intervention and control groups was 111 m. This is a considerably larger effect than the observed improvement in most PAH medication trials. In other recent studies in PAH patients, 10 weeks of exercise training was associated with increased physical activity and decreased fatigue [91], and 10 weeks of brisk treadmill walking improved 6MWT distance, cardiorespiratory function, and patient-reported quality of life [92]. These data strongly suggest that exercise is beneficial for patients with PAH, but whether the results can be extrapolated to other forms of RVF has not been tested.
Iron and Anemia
Ruiter et al. have shown that iron deficiency is frequently present in patients with IPAH and associated with a lower exercise capacity. The small response to oral iron in 44 % of the treated patients suggests impaired iron absorption in these patients [93]. Intravenous treatment of iron deficiency in patients with chronic LHF reduces the risk of hospitalizations without increasing adverse events [94]. This suggests that intravenous iron treatment could have a place in the iron-deficient patient with RVF. Whether iron supplementation leads to improvements in cardiac function or skeletal muscle function remains to be determined.
As in acute RVF, anemia in chronic HF is associated with an increased risk of mortality, and therefore treatment should be considered [95].
Other Possible Future Therapies
A wide range of possible therapies is in more or less advanced stages of clinical and preclinical testing with the aim to improve RV function. Among these strategies are neutral endopeptidase (NEP) inhibitors [96, 97], i.v. recombinant human BNP (Nesiritide) [98], adrenomedullin [99–102], growth hormone substitution [103–107], antioxidants [108, 109], cyclosporin [110], and immune-modulating therapy [111, 112]. Perhaps attempts to control of gene expression by histone deacetylase inhibitors [113] or antagonists of microRNAs [114] and the targeting of myocardial energy metabolism by dichloroacetate [115] may be added to the RVF treatment arsenal.
Palliative Care
RVF is a chronic and progressive disease that is eventually fatal if organ transplantation is not possible. In their final year of life, patients often have many complaints despite maximal medical therapy. In this terminal stage, symptoms of dyspnea and fatigue are followed by pain, nausea, constipation, a dry mouth, cough, cachexia, depression, and anxiety [116]. These symptoms have profound effects on patients’ quality of life and need to be addressed. In addition to symptomatic treatment, effective communication with the patient and family are of greatest importance, and coordination of care can alleviate complaints and improve patients’ satisfaction with the received care [117].
In patients with terminal HF, there is a delicate balance between volume over- and under filling. An elevated preload can give complaints of congestion, while a reduced preload can cause hypo-perfusion of the brain and the kidneys, which can lead to renal insufficiency and somnolence. The latter is generally preferred in end-stage disease [118]. The therapeutic options suggested below are mostly based on research in left HF, but it can be argued that these measures can also bring relief to patients with terminal RVF.
Dyspnea is one of the main complaints of patients with terminal HF. When a patient remains symptomatic despite maximal treatment of all possible causes, treatment with morphine could be considered to numb the sensation of dyspnea [119, 120]. A fan to stimulate the flow receptors in the face of patients is thought to bring relief of breathlessness; however, the evidence is weak [121]. Often, dyspnoea is accompanied by anxiety for which benzodiazepines could bring relief. Treatment needs to be tailored to the individual [122].
Constipation is a problem in 37 % of the patients with chronic LHF and is often caused by a combination of opioid treatment, immobility, and decreased motility of the bowel by edema [122]. For this reason, laxatives should be started. In our clinical experience, PAH patients suffer far more often from diarrhea. This can be caused by PAH-specific medications, as ERAs, PDE5 inhibitors, and prostacyclins all have diarrhea as a side effect. It is unknown whether bowel edema contributes to this problem as well. In case of diarrhea loperamide can be considered.
Pain in terminal PAH patients is frequently abdominal pain and can be due to liver congestion, bowel ischemia, ascites, or constipation. Leg pain can be caused by edema, muscle cramps, or gout. Aminocetophen (paracetamol) is the painkiller of first choice and when insufficient, opioids can be added. NSAIDs are contraindicated as they can aggravate fluid retention and can precipitate kidney failure. In patients with gout, colchicine or prednisolone should be considered [122]. Some patients may benefit from relaxation techniques for the relief of chronic pain [123].
Fatigue is a major symptom of heart failure, with 69 % of the patients in the last year of life and 78 % of the patients in the last 2 weeks of life feeling very tired [122]. There is no other treatment than maximal heart failure treatment and limitation of exertion. Methylphenidate is contraindicated as it increases sympathetic nerve activity and could thereby worsen HF.