Abstract
Juvenile onset systemic sclerosis is a rare chronic multisystem connective tissue disease characterized by skin induration, microangiopathy, autoimmune disturbances and widespread fibrosis of internal organs. Primary cardiac involvement in systemic sclerosis (SSc) is associated with a variable phenotype, including heart failure and arrhythmias, which lead to poor short-term prognosis. Isolated heart transplantation is a rare approach for the treatment of advanced heart failure in patients with systemic sclerosis. We report on two juvenile SSc patients receiving cardiac transplantation due to heart failure with malignant arrhythmias. One patient presented with severe dilated cardiomyopathy with recurrent ventricular tachycardia. Following the appearance of Raynaud phenomenon, he was subsequently diagnosed a rare form of systemic sclerosis sine scleroderma, without cutaneous manifestations or other organs involved. His cardiac condition was unresponsive to antiarrhythmic therapy and immunosuppression used to treat SSc, therefore he underwent successful heart transplantation. The second patient presented diffuse scleroderma with mild pulmonary, esophageal and renal involvement. While extracardiac manifestations were effectively kept under control with immunosuppressive therapy, cardiac involvement rapidly progressed with detection of fibrosis at cardiac magnetic resonance imaging and appearance of severe ventricular arrhythmia. Herein, an extensive multidisciplinary evaluation was pivotal in defining the entity and clinical stability of extracardiac involvement, and thus the patient could profit from heart transplantation. Our experience highlights the importance of considering heart transplantation in carefully selected SSc patients with primary cardiac involvement as a lifesaving procedure.
Background
Juvenile onset systemic sclerosis (jSSc) is a rare chronic multisystem connective tissue disease characterized by skin induration, microangiopathy, autoimmune disturbances and widespread fibrosis of internal organs. As in adults, there are three main subtypes of jSSc: diffuse cutaneous, limited cutaneous, and overlap. Systemic sclerosis sine scleroderma (ssSSc) is a subset of SSc defined by absence of skin fibrosis and presence of Raynaud’s phenomenon and/or digital vasculopathy, positive antinuclear antibodies (ANA) and internal organs involvement typical of scleroderma. ,
Cardiac involvement may either be a direct consequence of SSc, with progressive cardiac inflammation and fibrosis leading to conduction defects, arrhythmias, heart failure, or a secondary phenomenon due to pulmonary arterial hypertension, interstitial lung pathology and kidney disease. The heart is one of the internal organs affected in SSc, although its presence is probably underestimated due to the occult nature and variable reports on prevalence. Nevertheless, it accounts for a significant proportion of SSc-associated mortality, in both juvenile and adult population, , with an intractable course towards end-stage heart failure or sudden cardiac death as first manifestation of the disease. Heart transplantation (HTx) is rarely considered in patients with SSc, given the possible concomitant involvement of other organs. We present our monocentric experience of two cases of jSSc with severe cardiovascular phenotype, presenting with life-threatening arrhythmia, and different degrees of systemic and cutaneous involvement, who underwent successful cardiac transplantation after failure of medical treatment.
Case Report 1
Patient 1 was detected multiple premature ventricular contractions at resting EKG during a routine sports medicine check at the age of fifteen. An initial transthoracic echocardiography (TTE) demonstrated left ventricular (LV) dilatation with an ejection fraction (EF) of 46% while cardiac magnetic resonance (CMR) showed diffuse chronic myocarditis with signs of active inflammation, therefore treatment with beta blockers was started. The patient reported dyspnea due to moderate exertion (New York Heart Association class II). He was transiently lost to follow-up. One year later, he was admitted to emergency room because of chest pain and ventricular tachycardia, with a contextual mild rise in TnI HS (28 mg/L, n.v<15) and NT-proBNP (626 ng/L, n.v 125 ng/L). At that time TTE was suggestive of dilated cardiomyopathy (EF 30%) and speckle tracking echocardiography (STE) showed severe impairment of LV global longitudinal strain ( Fig 1 ). Cardiac catheterization revealed normal coronary arteries while endomyocardial biopsy revealed myocyte hypertrophy with diffuse fibrosis (60% of the specimen), focal necrosis and lymphocytic infiltration (CD3+, CD 20-, CD 68+); no viral genomes were detected by polymerase chain reaction. Several episodes of sustained ventricular tachycardia occurred during hospitalization, thus an implantable cardioverter defibrillator (ICD) was inserted. Symptoms of Raynaud’s phenomenon, cool fingertips and digital pitting scars of three fingers prompted further rheumatological evaluation: autoantibody profile showed positive ANA (titre>1:1280 with speckled pattern) and positive anti-RNA polymerase III. Capillaroscopy revealed an early scleroderma pattern. No muscular, pulmonary or renal involvement was observed. Given the absence of skin induration, a diagnosis of systemic sclerosis sine scleroderma was established.
Despite immunosuppressive treatment with rituximab (discontinued because of urticaria), mycophenolate mofetil (MMF), low-dose prednisone and antiarrhythmic therapy (beta-blockers, amiodarone and mexiletine), cardiac involvement progressed unfavorably with recurrent episodes of sustained ventricular tachycardia requiring multiple ICD interventions (with both anti-tachycardia pacing and shocks). Echocardiography ultimately revealed severe biventricular dilatation and dysfunction (with LV end-diastolic volume of 130 ml/m 2 , LVEF of 24%), while cardiopulmonary exercise testing showed decreased VO2 peak of 8.4 ml/kg/min. Given the progressive deterioration of cardiac function and uncontrollable arrhythmia symptoms, extensive diagnostic workup was performed in order to exclude manifestations of systemic sclerosis in other organ systems: pulmonary involvement was ruled out by high-resolution computer tomography (HRCT) of the lung and normal pulmonary function testing; due to dyspepsia a gastroscopy was performed, highlighting fibrinous ulcerations of the distal esophagus, interpreted as a collateral effect of mexiletine therapy. Finally, a right-side catheterization demonstrated a pulmonary pressure of 20/8 mmHg, a mean pulmonary pressure of 12 mmHg and wedge pressure of 8 mmHg. Calculated pulmonary resistance was evaluated at 1.35 wood units/m 2 , while cardiac output and cardiac index were normal (5.62 l/min and 2.96 l/min/m 2 ). Nine months after listing, aged 20, the patient underwent successful orthotopic cardiac transplantation and ICD removal. Heart removed at transplantation showed diffuse fibrosis of substitutive type involving both ventricles with a spotty pattern ( Fig 2 ). Following induction therapy with anti-thymocyte globulin, post-transplantation immunosuppression consisted of cyclosporine, MMF and prednisone tapered to zero over the course of months. Postoperative recovery was uneventful, except for one early episode of acute cellular rejection, occurred one month post-transplant, which was treated successfully with intravenous steroids. Fifty-nine months after HTx, the patient is free of symptoms related to heart failure and shows no signs of cutaneous involvement, whereas the dyspepsia has completely recovered after discontinuation of mexiletine. Furthermore, routine follow up assessments with echocardiography and coronary computed tomography angiography have always confirmed preserved left and right ventricular function and ruled out coronary allograft vasculopathy.
Case Report 2
The second male patient was diagnosed with ANA-positive and anti-topoisomerase I (Scl70) positive jSSc at the age of 13, after the appearance of digital tip ulcers, myositis, and Raynaud phenomenon. Slight dysmotility of the lower esophagus was detected by transit scintigraphy. Capillaroscopy pointed out an active scleroderma pattern. HRCT scan of the lungs showed a small area of subpleural interstitial thickening and ground-glass change in the anterior segment of the upper right pulmonary lobe, suggestive of early interstitial lung disease. Pulmonary function tests were slightly impaired: forced vital capacity 79 % of predicted, FEV1 90% of predicted, and carbon monoxide diffusion 72% of predicted. Laboratory assessment showed proteinuria (1.64 g/24h) with preserved renal function, mild increase in creatin kinase, normal troponin I and NT-pro-BNP levels. Early echocardiographic routine assessments with traditional echocardiographic parameters revealed normal biventricular volume and preserved systolic function, while repeated evaluations with speckle tracking imaging suggested progressive subclinical impairment of systolic function (LV GLS decreased from -19% to -14%, RV strain decreased from -38% to -2% ( Fig 3 ). Only in the later course of the disease progressive dilatation and overt systolic dysfunction of both ventricles occurred. CMR confirmed moderate dilatation and hypokinesis of both ventricles (LV tele-diastolic volume of 129 ml/m2 with EF 45%, right ventricle tele diastolic volume 119 ml/mq, EF 48%) and revealed subendocardial late gadolinium enhancement with patchy distribution of the septum, anterior wall and papillary muscles ( Fig 4 ). During follow up the patient developed a permanent elevation of HS troponin I, while 24-h electrocardiography unraveled frequent ventricular ectopy and recurrent episodes of non-sustained ventricular tachycardia (NSVT), thus a single-chamber ICD was inserted. An appropriate shock was delivered 14 months later, and remote ICD monitoring pointed out numerous episodes of VT. Given the multiorgan involvement, the patient was extensively treated with immunosuppressive therapy (rituximab, MMF, cyclophosphamide pulses, corticosteroids, tolicizumab), vasodilators (iloprost, bosentan) and support treatment with neurohumoral inhibitors (ACEI and beta-blockers). Renal, interstitial lung and skin involvement were kept at bay with immunosuppressive therapy, whilst myocardial involvement was triggering malignant arrhythmias. Thus, we prepared the patient for HTx listing through comprehensive assessment: cardiac catheterization showed normal pulmonary artery and wedge pressures, normal cardiac index of 4,75 L/min/mq and normal calculated pulmonary vascular resistances (1.04 wood units/m 2 ). Pulmonary function testing had improved over time (FVC 99%, FEV 1 109%) while DLCO was substantially unchanged (67% of predicted). General reassessment confirmed complete remission of proteinuria, whilst the results of HRTC scan, transit esophageal scintigraphy and capillaroscopy were unvaried. After discussion in our interdisciplinary transplant conference, the patient was listed for isolated HTx and four months later, aged 18, he underwent successful orthotopic Htx. The heart removed at transplantation showed a dilatation of the left ventricle and fibrosis mainly confined to the epicardial anterior region of the left ventricle, a fibrosis of band like pattern in the right ventricle side of the septum and in the sub endocardium of the right ventricle ( Fig. 5 ). The initial immunosuppressive treatment, consisting of tacrolimus, MMF and prednisone was changed into cyclosporine, everolimus and prednisone following an acute cellular rejection, occurred 20 days post-transplant and treated with parenteral steroids. Everolimus was temporarily discontinued four months post-transplant, due to an episode of neutropenia and fever. Seven months after HTx, the patient is in NYHA class I, with good biventricular function of the graft and no signs of rejection at routine endomyocardial biopsy. After multidisciplinary discussion, MMF has been restarted, being the drug that in this specific patient better combines efficacy in preventing the progression of pulmonary interstitial fibrosis and good tolerance as immunosuppressive agent. The therapy with bosentan was retained for scleroderma treatment.
Discussion
Systemic sclerosis is a rare disease and its occurrence in childhood and juvenile age even more so: it has been estimated that less than 10% of all the patients with systemic sclerosis have onset before the age of 20 years and jSSc represents 4-9% of all cases of scleroderma. , ssSSc accounts for less than 10% of cases in both adult and juvenile population. ,
The onset of the disease is usually insidious, potentially leading to a delay in recognition and treatment: isolated Raynaud phenomenon is usually the presenting symptom along with nailfold capillary changes and positive nuclear antibodies and scleroderma-related autoantibodies. Skin changes gradually evolve with oedema, skin induration and atrophy. Other organ manifestations include the gastrointestinal tract (hypomotility of the esophagus and incompetence of the lower esophageal sphincter), pulmonary interstitial fibrosis, renal damage, arthritis and myositis. Pulmonary arterial hypertension may occur, either as an isolated vascular complication or a consequence of pulmonary fibrosis. Cardiac involvement in SSc is diverse and can be classified into direct myocardial involvement and indirect effects caused by other organs involvement (i.e pulmonary hypertension, renal damage causing arterial hypertension). Direct cardiac involvement is related to progressive myocardial fibrosis, which is reported to be found in 100% of endomyocardial biopsy specimens, with a variable area percentage of 8% to 32%. Other findings include microvascular remodeling, focal ischemic injuries and contraction band necrosis and also various grades of myocardial inflammation in the early stages of disease. Noteworthy, patients with a higher degree of myocardial fibrosis and inflammation show a worse prognosis. , Recently, new noninvasive assessment tools such as CMR and speckle tracking strain rate echocardiography (STE) have been introduced for the early detection of cardiac involvement. Latest improvements in CMR, including combination T1 mapping, extracellular volume (ECV) fraction, and T2 weighted early and LGE, can reliably detect the presence of inflammation, diffuse fibrosis and focal fibrosis with nonischemic distribution in early phases of the disease, when significant impairment of cardiac function abnormalities haven’t yet appeared. Moreover, a higher burden of both LGE and ECV is predictive of future development of severe ventricular arrhythmic events. , STE-derived global longitudinal strain detects subclinical changes of myocardial contraction, independent of myocardial translational motion, and is far more sensitive than conventional echocardiography in earlier stages of the disease, when ejection fraction is still preserved. ,
Clinical manifestations of primary cardiac involvement are reported less frequently in juvenile than in adult SSc: in the largest cohort of juvenile patients, 8,4% showed signs of cardiac disease at onset and in 24% during overall course; pericarditis was observed in 10% of cases, 10% developed arrhythmia and 7% heart failure. Among adult population clinical symptoms of heart failure or arrhythmias have been observed in 15-35% of patients with SSc. Conversely, ssSSc is more aggressive in children than in adults, carrying a longer delay in diagnosis and a higher cardiorespiratory morbidity and mortality. In all groups, the occurrence of cardiac involvement implies poor prognosis and represents leading cause of death. Both our patients were male, although SSc globally mainly affects females. This aspect is consistent with previous findings indicating that male patients carry a higher risk of early and severe cardiovascular involvement. ,
Pharmacological management of SSc is challenging because no single drug has demonstrated unequivocal benefit: digital ulcers can be treated with calcium channel blockers, phosphodiesterase type 5 inhibitors, iloprost, endothelin receptor antagonists, low-dose methotrexate (Methotrexate) and MMF; cyclophosphamide, MMF or monoclonal chimeric antibodies are adopted for rapidly worsening interstitial lung disease; symptomatic treatment includes low-dose glucocorticoids for the treatment of musculoskeletal manifestations ad ACE inhibitors for hypertension and renal crisis treatment. However, evidence-based recommendations regarding cardiac specific treatment of scleroderma are lacking. The European Society of Cardiology suggests immunosuppressive therapy for treatment of biopsy-proven infection-negative myocarditis in SSc patients, but no preferred medication is specified. Immunosuppression, which is also adopted for treatment of lung, skin and musculoskeletal involvement, has been reported to be beneficial in cases of active myocardial inflammation and lower degree of fibrosis, thus in early stages of the disease. However, in spite of a clinical improvement and normalization of cardiac biomarkers, immunosuppression did not prevent from sudden cardiac death. , Both our patients have been extensively treated with immunosuppressive therapy, with favorable response of other systemic involvement. Conversely, intractable episodes of ventricular tachycardia had an inadequate response to both immunosuppressive and anti-arrhythmic therapy. While lung transplantation and lung-heart transplantation are not novel in patients with SSc-related interstitial lung disease and pulmonary hypertension, published evidence on isolated HTx in the context of SSc is scarce. In an extensive review of the literature, we found 18 patients with predominant cardiac involvement who had undergone Htx ( Table 1 ). Of those, 12 have been described in peer-reviewed journals, while a larger cohort of six patients was reported as a conference abstract. Only six of them were juvenile patients. The reluctance to refer SSc patients for Htx is likely related to the systemic nature of the disease, making them poor transplant candidates. On the other hand, HTx is increasingly been considered a viable option in other systemic diseases with cardiac involvement, such as amyloidosis or sarcoidosis, provided optimal timing and careful patient selection. Our two patients, both presenting with intractable arrhythmia as main indication for HTx, had very different degrees of noncardiac involvement: the first patient presented with an early selective cardiac involvement, which is uncommon occurrence, but is consistent with the diagnosis of ssJSSc. This case points out that it is important to suspect SSc in patients with unclassified cardiomyopathy, associated or not with Raynaud phenomenon. In these cases, the search for ANA and SSc-specific autoantibodies is crucial to speed up the diagnosis. The second patient also displayed signs of cutaneous, muscular, gastrointestinal and pulmonary affectation. In this case, extensive invasive evaluation and multidisciplinary approach were pivotal in defining that systemic, and in particular pulmonary involvement were less severe, and well controlled with pharmacological therapy, while the cardiac impairment was strong and rapidly progressive, thus the patient could profit from HTx. Among previously reported cases, all patients had at least another systemic involvement, mostly musculoskeletal. Noteworthy, three patients presented associated pulmonary involvement, one of them with a 36-months uneventful post-transplant follow up. , ,
