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Perspective

Beyond right ventricular size and function: the importance of evaluating the right ventricle’s capacity for recovery Expert Rev. Cardiovasc. Ther. 12(11), 1269–1273 (2014)

Karima Addetia and Amit R Patel* Department of Medicine, Section of Cardiology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC5084, Chicago, Illinois 60637, USA *Author for correspondence: Tel.: +1 773 702 1843 Fax: +1 773 834 3274 [email protected]

Historically, the right ventricle (RV) has received less attention than the left probably because morbidity and mortality associated with left ventricular disease is clinically more apparent. Right heart disease, in contrast, tends to have a more prolonged and, in the early stages, often subclinical course. Furthermore, the left ventricle is easier to image, model and quantify, so that research has been successful at amassing a great deal of clinically useful information about the left heart while the right heart still remains, in many ways, a mystery. In this perspective, the authors sought to explore the topic of RV recovery potential that has important clinical implications in the evaluation and treatment of advanced right-sided valvular heart disease, congenital heart disease, pulmonary arterial disease and even lung disease which impacts the RV. We see a clear need for a better understanding of RV viability given our increasing appreciation that RV failure is a significant contributor to morbidity and mortality in many disease states and the fact that newer imaging modalities and innovative changes to older modalities make more comprehensive evaluation of the RV feasible. KEYWORDS: contractile reserve • perfusion reserve • right ventricle • right ventricle recovery • right ventricular dysfunction • viability

The concept of viability

Myocardial viability refers to the ability of myocardial tissue to improve in function or normalize after treatment. Detection of viable myocardium is critically important in coronary artery disease largely because there is little to be gained from revascularizing scar tissue [1]. Furthermore, the most important variable affecting long-term outcome in patients with coronary artery disease is the left ventricular (LV) function [1]. Interventions that improve LV function have shown survival benefits [2]. For the LV, therefore, it is appreciated that accurate assessment of viable tissue is important. Our assessment of the right ventricle (RV) is far less complete. Yet, we are aware of multiple clinical scenarios in which it would be beneficial to be able to predict RV recovery, since such knowledge may impact clinical decision-making.

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10.1586/14779072.2014.965147

Importance of being able to predict RV recovery

In order for clinicians to be interested in the assessment of RV recovery, there must first be strong evidence in the literature to suggest that RV recovery is predictable and that being able to predict recovery would alter clinical management. Recent studies demonstrate a relationship between RV mechanics and functional capacity; however, the specific mechanisms underlying RV failure are not clear [3]. For the most part, it has been shown that the RV and LV respond in a similar way to injury such as ischemia and increased afterload, and that triggers for fibrosis, collagen deposition and remodeling are common. Furthermore, therapy targeted toward decreasing afterload produces similar effects in both ventricles [4]. It is, therefore, reasonable to conclude that RV

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Box 1. Etiologies of right ventricular dilatation and failure. Intrinsic right ventricular cause • Right ventricular infarction • Right ventricular cardiomyopathy (e.g., ARVC)

Right heart lesions • Right-sided valvular heart disease (tricuspid/pulmonary valve Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Pennsylvania on 01/23/15 For personal use only.

disease) • Congenital lesions

– Shunts (ASD, VSD) – Epstein anomaly – Other Left heart lesions • Left-sided valve disease (aortic/mitral valve disease) • Cardiomyopathy (infiltrative, restrictive, dilated) • Any cause of left ventricular failure (coronary artery disease)

Any cause of pulmonary hypertension • Pulmonary arterial hypertension • Pulmonary embolus (acute and chronic) • Lung disease

– Interstitial lung disease – Chronic obstructive lung disease • Sleep apnea and alveolar hypoventilation Other/systemic causes • Sepsis • ARDS/mechanical ventilation ARDS: Acute respiratory distress syndrome; ARVC: Arrhythmogenic right ventricular cardiomyopathy; ASD: Atrial septal defect; VSD: Ventricular septal defect.

viability in large part can be predicted using the same methods as those used to predict LV viability. In the meantime, there is no shortage of scenarios in which knowledge of RV viability could impact clinical decision-making (BOX 1). The next few paragraphs describe some of these. In the case of valvular heart disease, tricuspid regurgitation is a common entity. Eighty percent of cases of tricuspid regurgitation are functional related to RV and annular dilatation [5]. The recent guidelines tell us that tricuspid valve surgery is recommended in severe tricuspid regurgitation if the patient is symptomatic and unresponsive to medication or if there is evidence of moderate or more RV dilatation or systolic dysfunction. Oftentimes, the patient presents with RV dilatation and dysfunction, and it is not clear to the clinician whether the process is still reversible or irreversible. The reported mortality for tricuspid valve surgery is of the order of 10–20% [6]. Elevated pulmonary vascular resistance, LV disease and RV dysfunction all predict increased mortality after tricuspid valve surgery [7]. It would, therefore, be of incremental value to know if RV recovery is possible in these patients. Such knowledge may impact on when and whether many of these patients would be sent for surgery. 1270

A similar case can be made for pulmonary regurgitation. Perhaps the most commonly encountered instance of pulmonary regurgitation is in association with repaired tetralogy of Fallot. Tetralogy of Fallot is the most common cyanotic congenital heart disease with a prevalence of approximately 33 per 100,000 live births [8]. Relief of outflow tract obstruction in these patients frequently involves the placement of a conduit which then leaves the patient with residual, often severe, pulmonary regurgitation. Patients are then followed with regular imaging studies to assess for post-operative complications including RV dilatation and dysfunction. Often, even if an intervention for pulmonary regurgitation is planned in these patients, within the suggested timeframe, in the current literature this would be before the RV end-diastolic volume exceeds 150 ml/m2 [9], not all patients recover RV function although the volumes usually normalize [10,11]. On cardiovascular magnetic resonance imaging (CMR), it is known that myocardial late gadolinium enhancement (LGE) occurs in locations of prior surgery, in the anterior RV free wall and in the interventricular septum. Several studies have shown that LGE of the RV is a marker of adverse outcomes and correlates with inferior clinical characteristics such as increased propensity to arrhythmia, decreased arterial oxygen saturation, increased RV systolic pressure, RV dysfunction and exercise intolerance [12,13], but its association with mortality is not known [8]. Current studies using both CMR and dobutamine are underway to better understand the relationship between LGE and outcome. Ultimately, this kind of information could aid in the timing for subsequent interventions on the RV outflow tract. Once again, the importance of being able to predict RV recovery is underlined. Pulmonary disease is also known to cause RV dysfunction. Chronic obstructive lung disease, acute and chronic pulmonary embolism and interstitial lung disease can all be associated with increased afterload on the RV resulting in RV dilatation and dysfunction. This can be of concern, for example, in the patient about to undergo lung transplantation. Rarely, however, is the severity of RV dysfunction taken into account in this situation. This may, in part, be due to the fact that most of these patients recover RV size and function post-transplantation [14]. CMR LGE imaging has recently been used in some centers to assess for RV viability in patients being considered for lung transplantation. However, there has been no study that quantifies LGE pre-surgically to determine if the presence or the quantity of LGE is associated with poor RV recovery or outcomes post-operatively. Such studies have been performed in aortic stenosis and have shown that fibrosis is a predictor of post-operative clinical outcome in patients with severe aortic stenosis and an independent predictor of mortality in patients with moderate and severe aortic stenosis [15]. Finally, pulmonary arterial hypertension is another disorder in which identification of the possibility for RV recovery and documenting the response to treatment would be valuable. The 6-min walk test is still used to approve new therapeutic agents [16] despite our knowledge that the number one Expert Rev. Cardiovasc. Ther. 12(11), (2014)

RV viability

predictor of outcomes in this disease is RV dysfunction [17]. Studies involving bosentan have shown that treatment improves RV function and increases LV end-diastolic volume and cardiac output. It is not known whether improvement in RV parameters in this disease would signify treatment, prolong life or eventually establish cure.

Perspective

about RV contractile reserve and is associated with prognosis [25]. While assessment of contractile reserve for the LV has a place in clinical assessment and management planning, it has yet to be determined what role assessment of RV contractile reserve would have in clinical decision-making. Nuclear imaging

Current state-of-the-art RV assessment Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Pennsylvania on 01/23/15 For personal use only.

Echocardiography

Echocardiography continues to be the mainstay for RV assessment. At the same time, the RV is more difficult to image using echocardiography because of its retrosternal location and crescentic shape. With 2D imaging, we can usually establish whether the RV size is normal; we can obtain a reasonable idea of RV function using parameters such as fractional area change, tricuspid annular systolic motion and Doppler-derived peak systolic excursion (S´), which are measures of RV systolic function and myocardial performance or Tei index, a measure of RV systolic and diastolic function. We can obtain an estimate of systolic, diastolic and mean pulmonary artery pressures and the degree of tricuspid and pulmonary regurgitation and/or stenosis. 3D RV assessment using echocardiography, although not mainstream, exists as an alternative approach to RV functional and volumetric assessment, which is both feasible and correlates well with CMR measurements [18] and may play a more important role in the future in serial imaging and quantification of RV size and function. Another promising echocardiographic tool is 2D longitudinal RV strain. Strain is defined as the percent change in myocardial deformation. It is angle-independent and, therefore, has an advantage over both tricuspid annular systolic motion and S´, which are both angle-dependent measures. RV longitudinal strain is computed using the RV free wall because the septum is believed to function mostly as part of the LV [19]. While there are, as yet, drawbacks to its use such as the need for high frame rates, experienced users and offline assessment, RV longitudinal strain might be a better index of contractility than the other measures currently used on 2D echocardiography and, in addition, it may enable the detection of subclinical RV dysfunction [20]. Recent studies suggest that RV strain patterns correlate well with survival in patients with pulmonary hypertension [21]. Strain assessment may prove useful in predicting RV performance and recovery; this is currently an area of ongoing research. From the studies done on LV, we have learned that preserved contractile reserve of the LV, defined as the ability to increase the stroke volume ‡20% above baseline with dobutamine infusion, is associated with improved outcome after aortic valve surgery for aortic stenosis [22]. In cases of right and left heart failure, contractile reserve of the RV may determine exercise capacity [23]. Contractile reserve of the RV in response to increases in dobutamine is associated with favorable short-term outcomes in patients with heart failure [24]. Similarly, exerciseinduced increase in systolic pulmonary artery pressure in patients with pulmonary hypertension may provide information informahealthcare.com

Nuclear imaging techniques allow prediction of LV viability by determining if the myocardium has an intact cell membrane, intact metabolic potential and sufficient perfusion. Techniques include thallium-201 imaging, technetium-99 m (Tc-99 m) sestamibi and tetrofosmin imaging using single-photon emission computed tomography, and F-2-deoxy-2-fluoro-D-glucose imaging using positron emission tomography [1]. Nuclear imaging of the RV has not been well studied. Lower overall isotope counts lead to inconsistent visualization of the RV and dampened enthusiasm for extensive research in this area. However, both single-photon emission computed tomography and positron emission tomography have been used to document decreased coronary perfusion of the RV in pulmonary hypertension in systole due to increased RV wall stress [26–28], signifying that the RV suffers from ischemia. With further study, this may prove to be an important finding to document and follow during treatment and perhaps to target for therapy. Positron emission tomography imaging has also been used to assess for shifts in myocardial metabolism from fatty acid uptake, which is the norm, to increased use of glucose (F-2-deoxy-2-fluoro-Dglucose), a finding typical of abnormal or ischemic myocardium. Although much of this work has targeted the LV, there has been some work on the RV in animal models of pulmonary hypertension and some small human studies [29,30] suggesting that it is possible to detect dysfunctional, yet viable RV myocardium. Cardiovascular magnetic resonance imaging

CMR is currently regarded as the gold standard for the assessment of RV volumes and ejection fraction. It is particularly wellsuited to evaluate the RV because it provides more complete visualization of this chamber, allowing volume and ejection fraction measurements to be performed in the same way as for the LV, that is, using the Simpson method of disks; it also allows for more precise endocardial border detection and has higher reproducibility [31]. CMR can also be used in the assessment of myocardial viability. Gadolinium-based contrast, when injected in a patient with evidence of myocardial damage, will collect in the abnormal area and produce a bright signal on inversion-recovery images. This technique is being used to assess viability for the LV and more recently has been proposed to assess scar tissue in the left atrium and the RV [32]. The RV is thin walled, so detection of LGE is somewhat challenging and requires dedicated optimization. LGE of the RV has been noted in studies involving patients with congenital heart disease [33] and systemic RVs, where LGE has been correlated with RV dysfunction, clinical events and electrophysiological parameters. In patients with pulmonary arterial hypertension, LGE has been described at the RV 1271

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Perspective

Addetia & Patel

insertion points [34,35]. A direct correlation has been noted between the amount of LGE and RV volumes, and an inverse correlation between the amount of LGE and RV ejection fraction [35]. Late gadolinium enhancement in many forms of left heart disease correlates with the risk factors for sudden death and, in transposition, it correlates with clinical events such as ventricular tachycardia [33]. RV myocardial fibrosis may be an important factor in predicting potential for recovery in these and, perhaps, in other patients with RV dysfunction and failure, but further studies are needed to confirm this. A related method called T1 mapping has been validated for the quantification of extracellular volume increase and has been shown to be feasible for the RV. T1 mapping is increasingly being used for evaluation of the presence of diffuse fibrosis and may prove to be a new way to assess for RV viability [36]. Other methods of RV assessment on CMR include: phase-contrast magnetic resonance imaging, [37] which has been shown to correlate well with mean pulmonary artery pressures and pulmonary vascular resistance potentially allowing noninvasive measurement of pulmonary pressures, strain encoding imaging which allows the computation of peak systolic circumferential and longitudinal strains of the RV [38]and calculation of RV myocardial stress perfusion reserve [39]. All these may, in future, be techniques that could give us more information about the RV potential for recovery.

Expert commentary & five-year view

Much time has been devoted to understanding the mechanisms associated with LV injury and recovery after ischemic or nonischemic insult. It is increasingly being realized that RV dysfunction is associated with high morbidity and mortality. A more thorough understanding of the mechanisms of RV dysfunction and the potential for RV recovery is pivotal in many disease states. Recent and ongoing advancements in noninvasive imaging prompt us that the tools are available; we only need to gain an understanding of how to use them. Research in this area, we believe, should be the focus over the next decade, so that the right ventricle can finally assume its rightful place in the clinical assessment scheme and its recovery a part of disease management strategy. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Right ventricular failure is associated with high morbidity and mortality yet mechanisms for right ventricular dysfunction and recovery are poorly understood. • There are numerous scenarios involving the right heart in which it would be of incremental value to clinical decision-making if it were possible to gain some insight into the potential for right ventricular recovery. • Multiple imaging modalities are available for right ventricular assessment in the current era. • Future research must focus on how information obtained by the various imaging modalities can be used to predict the recoverability of the right ventricle.

Failure. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114(17): 1883-91

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Beyond right ventricular size and function: the importance of evaluating the right ventricle's capacity for recovery.

Historically, the right ventricle (RV) has received less attention than the left probably because morbidity and mortality associated with left ventric...
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