Abstract
Carvajal syndrome is a variant of Naxos disease characterized by a predominant left ventricular involvement, wooly or curly hair, and palmoplantar keratoderma or similar skin disorders. We describe the clinical and therapeutic course of a 14-year old boy affected by this syndrome, in whom a progressive biventricular failure developed at 13 years of age. The patient was hospitalized in the pediatric department 3 months earlier after the onset of cardiac arrhythmias and he critically worsened with signs and symptoms of biventricular cardiac failure. Over massive inotropic agent infusion, the patient was transferred to our intensive-care-unit in order to be haemodinamically stabilized with a ventricular assist device (VAD) and thereafter transplanted.
Introduction
Arrhythmogenic right ventricular dysplasia (ARVD) is an autosomal dominant heart muscle disease characterized by myocardial degeneration and fibro-fatty infiltration of the right ventricular free wall, the sub-tricuspidal region, and the outflow tract (1, 2). The estimated prevalence ranges from 6 per 10,000 in the general population to 4.4 per 1,000 in some areas with higher prevalence. For example the Veneto region of northern Italy seems to present an unusually high prevalence of the disease. Overall nine genetic loci are known. The corresponding gene has been identified for three of them: the autosomal dominant ARVD2 (3), the ARVD8 (4), and the autosomal recessive NAXOS1 (1). Few patients with ARVD have been successfully genotyped so far, and the listed genes account for a minority of the clinically affected patients. Consequently, it is rational to hypothesize that only a few ARVD cases are caused by a single gene mutation, whereas others might be due to environmental factors (e.g., viral myocarditis) acting on a vulnerable substrate, that, in turn, may be caused by several genetic factors, thus setting the picture of a polygenic disease. Two recessively inherited, familial cardiomyopathies ascribed to these mutations have been described: Naxos disease which gives rise to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and Carvajal syndrome, in which the cardiac pathology is primarily leftsided (5). Both are often found in association with diffuse palmoplantar keratoderma, and woolly or curly hair. Approximately two thirds of patients die prematurely of cardiac-related abnormalities, often suddenly (2). This is the first case ever reported in the literature of a patient suffering from Carvajal syndrome undergoing ventricular-assist-device (VAD) implantation through an anterolateral mini-thoracotomy and mid-mini-sternotomy as a bridge to transplant.
Case Report
The patient, a 14-year-old-male, was referred to our ICU for hemodynamic instability due to supraventricular and ventricular arrhythmias. Over the previous 18 months he had complained about dyspnea, orthopnea, and palpitation episodes. On the basis of clinical features (Fig. 1A) and genetic mapping (inherited homozygous mutation of exon 4 in gene DSP encoding for desmoplakin protein), a diagnosis of Carvajal syndrome had been made 18 months earlier. A resting 12-lead electrocardiogram showed low voltage with intraventricular conduction defects, left bundle branch block (LBBB) morphology, with a QRS axis of +70 degrees, and T-wave inversion (Fig. 1B). Chest X-ray revealed biventricular dilatation and pulmonary congestion. On echocardiogram and MR (Fig. 1C) the patient presented biventricular structural/functional abnormalities consisting of diffuse severe hypokinesia and dilatation. Despite maximal medical therapy, the symptoms were not relieved and anuria appeared. The patient was emergently scheduled for left and/or Bi-VAD implantation, given the severe biventricular dysfunction and nature of the cardiomyopathy. Through an anterolateral mini-thoracotomy, and through a mid-mini-sternotomy the patient underwent left VAD implantation (HeartWare International, Framingham, MA, USA) with the aid of femoro-femoral ECMO assistance (5-5.5 l/min) (PLS ECMO with a hollow fiber Quadrox PLS membrane oxygenator; MAQUET Cardiopulmonary AG, Hirrlingen, Germany). Once the LVAD was switched-on and gradually the pump speed increased (2, 000-2, 500 rpm) to achieve the desired flow (4-5 l/min), an attempt at ECMO weaning was soon performed intraoperatively. As expected, at 40% to 50% of ECMO assistance (2-2.5 l/min), right ventricular failure was observed, characterized by right ventricular dilatation on transesophageal echocardiography with diffuse hypochinesia, LVAD wave suction and flow reduction (2 l/min) with constant rpm, associated with hemodynamic impairment (mean systemic pressure <60 mmHg, and right atrial pressure >18 mmHg). Thus, through the same mid-mini-sternotomy, a vascular graft of 8 mm was anastomosed to the common pulmonary artery, and the ECMO assistance was transformed into a paracorporeal, centrifugal, right-VAD (Rotaflow RF-32; MAQUET, Fairfield, NJ, USA) by first eliminating the oxygenator, and second, by using the femoral-venous drainage as outflow line and the pulmonary graft as inflow line.
Immediately after the right VAD start, an improvement in cardiac output was obtained with 5.0 l/min of flow to the left and 4.5 l/min of flow to the right. Therefore, the patient was subsequently transferred to post-operative ICU in stable clinical condition and with good Bi-VAD flows (4.8 l/min for both VADs). Once awake, he was weaned from mechanical ventilation, achieving even better hemodynamics (mean systemic pressure, urine output, and LVAD flows increasing, right atrium pressure decreasing). Three days later, after a progressive reduction in RVAD flows (decrease of about 100 ml/min of blood flow every two hours), he was definitively weaned from right-VAD. By re-opening the mid-mini-sternotomy, under general anesthesia, we removed the assistance-lines. On post-operative day 15 the patient was discharged home and he was uneventfully assisted by single left ventricular VAD for 41 days (Fig. 2), before being successfully transplanted. The blood flows remained stable between 4.5 and 5 l/min for the duration of the left VAD assistance.
Apex HeartWare inflow cannula parallel to ventricular septum at echocardiography.
Discussion
We describe a boy with Carvajal syndrome who underwent Bi-VAD and later single-VAD assistance as a bridge to transplantation.
Carvajal syndrome is a variant of Naxos disease characterized by predominant left ventricular involvement (5). It accounts for up to 17% of all sudden cardiac deaths in the young. In Italy, the incidence is 40/10,000, making it the most common cause of sudden cardiac death in the young population. Epidemiological data are limited, although geographical clustering is evident, for example, in northern Italy. Our patient's family is Italian, and he comes from the north-eastern of Italy in the town of Belluno, located in the Veneto Region (6).
When faced with advanced heart failure, the prognosis is limited. In these cases heart transplantation offers the best opportunity. It is indicated if the arrhythmias are uncontrollable or even if a severe bi-ventricular heart failure is not more manageable with pharmacological therapy.
Our patient, already on a cardiac transplant waiting list, was worsening and an appropriate organ was not available. We opted for a HeartWare ventricular assist device (7), combining the benefits of a full-support LVAD with a minimally invasive surgical approach (mini-sternotomy, mini-thoracotomy, ECMO assistance). Due to the severe cardiac failure with orthotopic forced position, we performed the HeartWare implant with the aid of ECMO assistance. As there was evidence of significant biventricular involvement, we preferred to approach the aorta for the outflow anastomosis through a mid-mini-sternotomy instead of an already described right antero-mini-thoracotomy. After starting the LVAD flow pump, even though at partial flow support, we observed an abrupt right ventricle overload with consequent failure. Thus, we easily performed the pulmonary-artery-graft anastomosis, well exposed through this incision, to temporarily assist the failing right ventricle with a paracorporeal centrifugal pump. This anastomosis could be life-threatening if performed through a right lateral thoracotomy: since the pulmonary artery is hidden from the left aorta side, its position is distant from a right thoracotomy, making this approach potentially awkward and stressful.
Additionally, early post-operative extubation allows a rapid transit from pressure-positive mechanical ventilation toward a physiologic, negative-pressure, spontaneous breathing. This favous downloading of the right ventricle, frequently compromised in these patients. In fact, soon after weaning from mechanical ventilation, right ventricle recovery was obtained and R-VAD removal was possible. This case adds new concepts regarding the clinical management of patients with rare cardiomyopathies such the Carvajal syndrome at end-stage biventricular failure.
The use of mini surgical accesses allows the exposure of the precise areas necessary for LVAD implantation and the anterior left mini-thoracotomy exposes the apex of the heart without the need for cardiac displacement. Manipulation of the cardiac apex during anastomosis of the sewing ring is often poorly tolerated in patients with severe heart failure and even less when biventricular. The prevention of this event using ECMO perfusion not only allows an easier pump insertion in minimal surgical access, it also permits simple conversion to the RVAD paracorporeal support used in the first days after LVAD insertion to assist a failing right ventricle. This allows for later recovery with an excellent safety net.