CRT
Regression of dilated-hypokinetic hypertrophic cardiomyopathy by biventricular cardiac pacing
Department of Cardiology, The Royal Brompton and Harefield NHS Trust, Harefield Hospital, Middlesex UB9 6JH, UK
Manuscript submitted 26 July 2006. Accepted after revision 27 September 2006.
* Corresponding author: Tel: +44 77 89 77 8075; fax: +44 18 95 82 8277. E-mail address: ashrafian{at}hotmail.com
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Abstract |
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The evolution of hypertrophic cardiomyopathy (HCM) towards dilatation and hypokinesis is an increasingly recognized complication with a high incidence of adverse outcomes, including sudden cardiac death, requiring defibrillator implantation and cardiac transplantation. It is generally regarded as the irreversible ‘burnt-out’ end-stage manifestation of HCM. We report one of the first cases of profound regression of the dilated-hypokinetic state by the application of biventricular pacing and cardiac resynchronization therapy (CRT). Reviewing the literature on the role of pacing in HCM and the energetic rationale for CRT in HCM prompts us to suggest that further systematic studies are needed urgently to assess the role of CRT in HCM variants.
Key Words: Dilated-hypokinetic, Hypertrophic cardiomyopathy, Cardiac resynchronization therapy, Biventricular pacing
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Introduction |
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Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by left-ventricular hypertrophy (LVH) and myocardial disarray.1
While diastolic dysfunction (DD) is well recognized in HCM, systolic function [as assessed by left ventricular ejection fraction (LVEF)] has generally been regarded as normal. Although, recently, abnormal systolic function has been noted in the majority of HCM patients using derivatives of the sensitive tissue Doppler imaging,2 only a minority evolve to gross systolic dysfunction and LV dilation.3 This dilated-hypokinetic evolution is often termed burnt-out HCM. The prevalence of dilated-hypokinetic HCM has been reported to occur in between 5 and 15% of patients;3 it is regarded as progressive and irreversible being the most frequent HCM indication for heart transplantation. |
Case report |
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At the age of 11, our patient, whose mother and brother had been previously diagnosed as having HCM, exhibited a murmur and a ‘normal’ echocardiogram. Her relatives had remained well into their 60s and 40s, respectively, with no risk factors for malignant HCM. A repeat echocardiogram at the age of 21 suggested HCM. Her ECG manifested left ventricular hypertrophy (LVH) (Figure 1). Her echocardiogram demonstrated asymmetric LVH with a septal thickness of 30 mm. Invasive haemodynamic assessment demonstrated an LV outflow tract gradient of 70 mmHg at rest (100 mmHg post-ectopic). She complained of increasingly limiting angina and proceeded to septal myomectomy by which she was rendered asymptomatic. Her ECG manifested left bundle branch (QRS
170 ms, Figure 2); her echocardiogram, aside from persisting LVH, was reported as otherwise ‘normal’.
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At the age of 42, she complained of progressive dyspnoea (New York Heart Association Class III; NYHA III). In addition to palpitations, she described three syncopal episodes, one of which occurred at rest. Her ECG manifested left bundle branch (LBBB QRS
180 ms). A 48-h ECG showed no arrhythmias. Her repeat echocardiogram exhibited moderate-to-severe LV impairment with an estimated LVEF 35%. Her ventricle was dilated [LV end diastolic dimension (EDD)=59 mm] and had restrictive filling. A cardiac MRI demonstrated a dilated ventricle with LV end systolic volume (ESV) and LV end diastolic volume (EDV) of 98 and 206 mL, respectively, minimal fibrosis restricted to the site of myomectomy and marked contraction asynchrony. She was commenced on medical therapy (ramipril and bisoprolol). Despite the lack of documented arrhythmias, in light of the potentially malignant nature of her syncopal episodes, she was scheduled for an implantable defibrillator (ICD). Since asynchrony was noted on MRI and LBBB on ECG, a biventricular pacing device with ICD was implanted. Within 2 months of device implantation she was admitted with a syncopal episode; interrogation of her ICD revealed VF that responded successfully to ICD discharge. Amiodarone therapy was instituted. Her cardiopulmonary exercise testing revealed an MVO2 of 10 mL/kg/min with a respiratory quotient of 1.32. Her exercise tolerance continued to be severely limited.
At the age of 43, 9 months after device implantation, her progress was reassessed, especially as she had been counselled regarding cardiac transplantation. She reported complete resolution of her symptoms. She had unlimited exercise tolerance. Her ECG revealed atrioventricular (AV) sequentially paced rhythm (QRS 152 ms, Figure 3). Her echocardiogram manifested regression of LV dilatation (LVEDD = 48 mm, Figure 4) with mild LVH and improvement of systolic function (LVEF 72%). This clinical and echocardiographic improvement persists.
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Discussion |
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Progressive LV dilatation and heart failure are recognized in patients with HCM,4
particularly in those having undergone myomectomy. This adverse remodelling was noted in 18 of 106 patients in a post-myomectomy series during long-term follow-up.5 It is, however, unclear whether this evolution represents the natural history of the underlying disease or is the consequence of surgery. Although both may be pertinent, the former appears to be the dominant factor with recent data suggesting that the incident rate of dilation approximates to 0.5% per year particularly affecting those with profound LVH, disease presenting at a younger age, and with a family history of HCM.6 Controversy has surrounded the pathogenesis of this evolution; broad consensus invokes the burnt-out phase to imply myocyte loss and interstitial fibrosis as a substrate for this process.3 The basis for the myocyte loss has also been the subject of controversy but has recently been attributed to an energetic crisis.6,7 Irrespective of the precise aetiology of this dilated-hypokinetic evolution, as noted previously, the terms used to describe it such as burnt-out or end-stage HCM arise because this evolution is thought to be irreversible and a prognostically adverse complication. It carries a mortality of > 10% per year (in part from sudden cardiac death) and requires a low threshold for defibrillator implantation and/or heart transplantation.3,4
The benefits of pacing in HCM have been the subject of significant and ongoing debate. By altering the regional pattern of ventricular contraction, dual-chamber right ventricular (RV) apical (DDD) pacing has been proposed to reduce LV outflow tract gradients in severe HCM by a form of cardiac desynchronization. Accordingly, there is a rationale as well as evidence for the role of atrioventricular (AV)-delay optimized DDD pacing in those with severe, obstructive, symptomatic, medically refractory, and elderly HCM.8 In one of a number of studies assessing the role of DDD pacing in HCM, the Pacing in Cardiomyopathy (PIC) Study Group employed a revealing crossover study design by inserting pacemakers into all the study HCM patients. However, by inactivating them for one or other arm of the study, they effectively mitigated the placebo effect of pacemaker implantation. The PIC study and a number of other studies have demonstrated a sustained beneficial effect of DDD pacing on both objective and subjective parameters of HCM.9 Conversely, however, it has been noted that chronic DDD pacing while reducing obstruction may exacerbate diastolic dysfunction in HCM.10 While the sustained or prognostic benefits of DDD pacing in HCM have thus been questioned on the basis of both physiological observations of increased diastolic dysfunction10 and by randomized, double-blind, crossover studies,11 authorities have afforded HCM a Class IIB indication for DDD short AV delay RV apical pacing.1
No corresponding data are available for biventricular pacing.1 Our patient fulfilled criteria for cardiac resynchronization therapy (CRT) derived from trials showing a reduction in morbidity and hospitalizations12 and mortality13 in symptomatic patients with reduced ejection fraction and a QRS > 120 ms. The benefits of CRT have been noted in a single HCM patient with ameliorated diastolic dysfunction,14 in one with reduced outflow tract gradients15 and in the case of an HCM patient with a dilated-hypokinetic phenotype.16 However, in comparison with our patient (QRS 180 ms), the latter had a broad bizarre QRS complex (230 ms). Our patient's recovery appears to be more profound than any previously reported (LVEF from 35 to 72%). Thus, our patient represents one of the first, if not the first, reported cases of profound regression of an HCM heart with a ‘conventional’ dilated-hypokinetic phenotype.
Although CRT has been shown to be effective in patients with a broad QRS, corresponding to inter- or intra-LV mechanical dyssynchrony, improved mechanical synchrony and function do not necessarily correlate with increased electrical synchrony. Nevertheless, aberrant conduction patterns, as most strikingly manifest in RV apical pacing, have been noted to result in inhomogeneous thickening of the ventricular myocardium, myofibrillar disarray, fibrosis, disturbances in ion-handling protein expression, myocardial perfusion defects, alterations in sympathetic tone, and mitral regurgitation; all features reminiscent of HCM.17 Irrespective of the controversial impact of biventricular pacing on interstitial fibrosis or other histological features,16 it is recognized that biventricular pacing, especially in DCM patients with LBBB, enhances systolic function while lowering energy cost.18–20 This reduction in energetic burden in patients with HCM, and hence putative energy deficiency,7 may represent a rational therapeutic approach.
While anecdotal evidence derived from a single case cannot be regarded as proof, the remarkable clinical improvement of our patient paralleling her echocardiographic improvement provides hypothesis-generating data. CRT may represent an effective treatment, especially in subgroups of patients yet to be defined (e.g. profound LVH, minimal fibrosis on gadolinium-enhanced cardiac MRI, dilated-hypokinetic phenotype, DD, asynchrony on surface ECG or echocardiography, particular gene mutations, profound energy deficiency on MR, or other parameters), and may represent a highly effective therapy both early and late in the course of disease. ‘Biventricular pacing could become a useful tool in this subset of patients’,16 and should be investigated in well-designed clinical trials.
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References |
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