Electrocardiogram in Friedreich's ataxia: A short-term surrogate endpoint for treatment efficacy

Friedreich's ataxia is a rare degenerative neuromuscular disorder, caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene, with a broad clinical phenotype characterized by progressive gait and limb ataxia, dysarthria, and loss of lower limb reflexes; cardiac involvement is represented by hypertrophic cardiomyopathy, ventricular arrhythmias, and sudden cardiac deaths. Currently, no definite therapy is available, while many drugs are under investigation; for this reasons, we need markers of short- and long-term treatment efficacy acting on different tissue for trial evaluation. We describe the case of a 21-year-old patient affected by Friedreich's ataxia on wheel-chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment-related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich's ataxia.     

Electrocardiogram in Friedreich's ataxia: A short‐term surrogate endpoint for treatment efficacy

Friedreich''s ataxia is a rare degenerative neuromuscular disorder, caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene, with a broad clinical phenotype characterized by progressive gait and limb ataxia, dysarthria, and loss of lower limb reflexes; cardiac involvement is represented by hypertrophic cardiomyopathy, ventricular arrhythmias, and sudden cardiac deaths. Currently, no definite therapy is available, while many drugs are under investigation; for this reasons, we need markers of short‐ and long‐term treatment efficacy acting on different tissue for trial evaluation. We describe the case of a 21‐year‐old patient affected by Friedreich''s ataxia on wheel‐chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment‐related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich''s ataxia.     

Friedreich's ataxia associated with idiopathic hypertrophic subaortic stenosis

Friedreich's ataxia and idiopathic hypertrophic subaortic stenosis (IHSS), both diseases of unknown etiology, both result in hypertrophy and degenerative changes of the myocardium. Both diseases lead to nearly identical electrocardiographic changes. We report a patient who developed classical signs of Friedreich's ataxia several years after he was found to have moderately severe IHSS. This observation prompted a hemodynamic study of five other patients with Friedreich's ataxia in search of a more common association and thus a possible etiological link between the two diseases. Cardiac catheterization was performed under local anesthesia. Catheters were inserted into the right ventricle, the pulmonary artery, the left ventricle, and the aorta. Isuprel infusion up to 6 μg per minute was used in an attempt to induce an abnormal pressure gradient across the right or left ventricular outflow tract. Both right and left ventricular cineangiograms were obtained for evaluation of ventricular kinetics and wall thickness. Right and left heart pressures were normal at rest in all patients. During Isuprel infusion a 40 mm. pressure gradient was induced across the left ventricular outflow tract in only one patient. A second patient developed a 16 mm. gradient across the right ventricular outflow tract. All patients had low normal cardiac outputs. The angiograms demonstrated increased left ventricular wall thickness in all patients. It is concluded that systolic left and/or right ventricular out-flow tract obstruction is only infrequently present in Friedreich's ataxia and is mild in degree. An etiological link between Friedreich's ataxia and IHSS is not known at the present but may possibly exist and should be investigated.     

Spectrum of cardiac involvement in Friedreich's ataxia: Clinical,electrocardiographic and echocardiographic observations

Combined 2-dimensional and M-mode echocardiography was used to assess the cardiac status of 22 patients with Friedreich's ataxia, and the findings were correlated with the clinical and electrocardiographic (ECG) data. Mean age at onset of Friedreich's ataxia was 8 years (range 3 to 18); mean age at echocardiography was 18 years (range 8 to 39). Echocardiographic findings were abnormal in 19 patients (86%). The 3 patients with normal echocardiographic findings did not have cardiac symptoms, but 1 had ECG repolarization abnormalities. Concentric left ventricular (LV) thickening, the most common echocardiographic finding, was found in 15 patients (68%) and in all 15 the papillary muscles were thickened. These 15 patients had ECG repolarization abnormalities and 5 had left-axis deviation; however, only 3 satisfied ECG criteria for LV or right ventricular hypertrophy. Two of the 15 patients (9%) had symptoms of heart failure. Two patients had asymmetric septal thickening without clinical evidence of LV outflow tract obstruction; neither had cardiac symptoms, but both had ECG repolarization abnormalities. Two patients showed a dilated cardiomyopathy pattern; both had heart failure and atrial flutter. One of these patients died, and necropsy revealed 4-chamber cardiac dilatation, biventricular hypertrophy and histologic findings of diffuse interstitial fibrosis, myocellular hypertrophy and necrosis. This study revealed a wide spectrum of cardiac abnormalities in patients with Friedreich's ataxia.     

Friedreich's ataxia associated with hypertrophic cardiomyopathy and coronary vasospasm

A rare patient with Friedreich's ataxia and hypertrophic obstructive cardiomyopathy who showed evidence of coronary artery vasospasm on ambulatory electrocardiographic monitoring is presented.     

Microvascular Permeability Changes Might Explain Cardiac Tamponade after Alcohol Septal Ablation for Hypertrophic Cardiomyopathy

Various sequelae of alcohol septal ablation for hypertrophic obstructive cardiomyopathy have been reported. Of note, some cases of cardiac tamponade after alcohol septal ablation cannot be well explained. We describe the case of a 78-year-old woman with hypertrophic obstructive cardiomyopathy in whom cardiac tamponade developed one hour after alcohol septal ablation, probably unrelated to mechanical trauma. At that time, we noted a substantial difference in the red blood cell-to-white blood cell ratio between the pericardial effusion (1,957.4) and the peripheral blood (728.3). In addition to presenting the patient''s case, we speculate that a possible mechanism for acute tamponade—alcohol-induced changes in microvascular permeability—is a reasonable explanation for cases of alcohol septal ablation that are complicated by otherwise-unexplainable massive pericardial effusions.     

Severe ataxia caused by amiodarone

Neurologic toxicity is an infrequently reported and under-recognized consequence of amiodarone, symptoms of which may include tremor, peripheral sensorimotor neuropathy, proximal weakness, and ataxia. The investigators report the rapid and complete remission of 4 months of progressively debilitating ataxia with the discontinuation of small-dose amiodarone in an elderly woman with hypertrophic obstructive cardiomyopathy and paroxysmal atrial fibrillation. Despite the long half-life of amiodarone, her symptoms began to reduce after several days, and she was walking without assistance within 1 week. Wider recognition of this syndrome may avoid unnecessary and lengthy diagnostic evaluation and promote earlier neurologic recovery.     

Provocation of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy

Several provocation maneuvers are described in hypertrophic cardiomyopathy to Doppler echocardiographically distinguish the obstructive from the non obstructive type. No data are available about the value of orthostasis testing in comparison with nitrate application in this disease. In this study, 16 consecutive patients with hypertrophic cardiomyopathy were examined. 11 patients with hypertrophic cardiomyopathy were classified as obstructive, 5 patients with hypertrophic cardiomyopathy as non obstructive. Normal left ventricular outflow tract velocities as detected by the Doppler method were defined as < 2,0 m/s.Doppler echocardiographic measurements were performed after 10 minutes in supine position, within 10 minutes after head-up tilt and again, within 10 minutes in supine position. If systolic blood pressure during this examination exceeded 100 mm Hg 2,5 mg isosorbiddinitrate were sprayed sublingually. Measurements were done after 20 minutes in supine position and within 10 minutes after head-up tilt.Only in 7 of the 11 patients with hypertrophic obstructive cardiomyopathy maximal left ventricular outflow tract velocity in supine position measured > 2,0 m/s (2,2 ± 0,8). During head-up tilt, all patients showed increased values (3,8 ± 1,2 m/s). No differences in maximal left ventricular outflow tract velocity between head-up tilt and nitrate application in supine position (3,5 ± 1,4 m/s) were present. All patients with hypertrophic non obstructive cardiomyopathy showed maximal left ventricular outflow tract velocities < 2,0 m/s in every step of the examination.Consequently, orthostasis testing was able to identify all patients with hypertrophic obstructive cardiomyopathy and demonstrated a diagnostic value similar to nitrate application.     

Apical Hypertrophic Cardiomyopathy: Preliminary Attempt at Palliation with Use of Subselective Alcohol Ablation

We report a case of severe apical hypertrophic cardiomyopathy in order to discuss the nature of this unusual condition and the possibility of using selective alcohol ablation to effectively treat symptomatic hypertrophic cardiomyopathy that presents with apical aneurysm. A 73-year-old woman with severe, progressive dyspnea and intermittent chest pain was found to have localized left ventricular apical dyskinesia distal to an obstructive mid-distal muscular ring. The ring caused total systolic obliteration of the apical left ventricular cavity. Apical cavity pressure was extremely high, up to 330 mmHg—200 mmHg above that in the main left ventricular cavity. Because of the danger of apical rupture and clot formation, we attempted the experimental use of alcohol ablation for effective palliation. We present our pilot experience, offer a novel interpretation of the nature of this obscure entity, and possibly justify a new catheter treatment. In addition, we discuss the developmental, pathophysiologic, and clinical implications of this unusual form of hypertrophic cardiomyopathy. To our knowledge, ours is the first reported use of subselective, modified-protocol alcohol septal ablation to treat an obstructive mid-apical muscular ring in a patient with apical hypertrophic cardiomyopathy.Key words: Cardiomyopathy, hypertrophic/complications/epidemiology/physiopathology/therapy; ethanol/administration & dosage/therapeutic use; heart septum/pathology; hypertrophy, left ventricular/diagnosis; myocardial ischemia/complications; treatment outcomeHypertrophic obstructive cardiomyopathy (HOCM) is a congenital heart condition characterized by ventricular hypertrophy and a progressive worsening of symptoms, as related to the worsening of the subaortic gradient.^1,2 Either traditional surgical septal myomectomy^3,4 or alcohol septal ablation (ASA)^2,4,5 can be used to treat HOCM by effectively reducing the subaortic gradient.^1,2 We describe the case of an elderly woman who had the rarer variant of hypertrophic cardiomyopathy (HCM)—that with apical aneurysm and mid-ventricular obstruction. We describe in detail the experimental use of subselective alcohol ablation to treat the obstructive mid-apical muscular ring in this patient, and we revisit the nature of apical HCM.     

Acute myocardial infarction with diminutive right coronary artery and obstructive hypertrophic cardiomyopathy without significant coronary stenoses

Focal tissue abnormalities consistent with regional ischemia have been reported in patients with hypertrophic cardiomyopathy (HCM). Coronary microvascular dysfunction has been also reported to be present in patients with HCM despite normal epicardial coronary arteries. Moreover, it has been demonstrated that in the case of HCM and idiopathic left ventricular hypertrophy, hypoplastic coronary arteries as diminutive vessels are present and that obstructive hypertrophic cardiomyopathy is associated with enhanced thrombin generation and platelet activation. Previously, it has been described an acute myocardial infarction in a young athlete with non-obstructive hypertrophic cardiomyopathy and normal coronary arteries. We present a case of an acute myocardial infarction with diminutive right coronary artery and obstructive hypertrophic cardiomyopathy without significant coronary stenoses. To our knowledge, this is the first report of an acute myocardial infarction with diminutive right coronary artery and obstructive hypertrophic cardiomyopathy without significant coronary stenoses.     

Mitral valve endocarditis in hypertrophic cardiomyopathy: case report and literature review

Mitral endocarditis complicating hypertrophic cardiomyopathy occurs predominantly on the left ventricular aspect of the anterior mitral valve leaflet in the presence of outflow tract obstruction. It is a rare condition and the estimated cumulative 10 year probability of developing endocarditis in patients with obstruction is < 5%. Combined mitral valve replacement and septal myectomy has been reported in this setting. A case of community acquired Staphylococcus aureus mitral valve endocarditis is reported in a previously asymptomatic young man with hypertrophic obstructive cardiomyopathy. The potential treatment options are discussed.     

Multiple lentiginosis and hypertrophic obstructive cardiomyopathy

Two patients with Multiple Lentiginosis (ML) had hypertrophic cardiomyopathy with severe obstruction of the right and left ventricular outflow tracts. ML is a rare syndrome in which there is a typical skin pigmentation disorder together with various other abnormalities like slight mental retardation, sensorineural deafness, genital and skeletal anomalies and sometimes a characteristic facies. Obstruction of the right ventricular outflow tract is frequent in such patients. The association of ML and obstructive hypertrophic cardiomyopathy has been recently reported. A critical examination of the literature in addition to our clinical observations suggests that the biventricular obstructive hypertrophic cardiomyopathy may play a major role in the clinical feature of ML syndrome.     

The importance of echocardiography for the diagnosis of cardiomyopathies in comparison to cardio-computer tomography and to complex invasive heart diagnostics

112 patients with various forms of cardiomyopathy (typical-subaortic--hypertrophic obstructive; atypical--medioventricular--hypertrophic obstructive; hypertrophic nonobstructive; apical hypertrophic; dilatative) were subjected to echocardiographic examination of the morphological and functional state of the heart. The results were compared with the results of computer heart tomography and comprehensive invasive examination. The high diagnostic reliability of ultrasonic diagnostics has been confirmed. Invasive examination is necessary in hypertrophic nonobstructive and in dilatative cardiomyopathies. Computer heart tomography is suitable for complementing findings and for clarifying contradictory results of examination, especially in apical forms of cardiomyopathy.     

Mechanocardiographic evaluation of left ventricular diastolic function in hypertrophic cardiomyopathy and hypertensive cardiomyopathy

Usefulness of computerized mechanocardiography and echocardiography in the diagnosis of impaired left ventricular diastolic function is shown in a study comparing 17 hypertrophic obstructive cardiomyopathy and 17 hypertensive cardiomyopathy patients to 20 normal subjects. Mechanocardiography allows the evaluation of three different parameters of diastolic function: isovolumic relaxation evaluated by S2a-O or better by t-dr/dt and dr/dt/A2 ratio, left ventricular compliance by the A/H ratio and time of rapid filling. All the parameters are impaired in both pathological populations. Isovolumic relaxation being more depressed in hypertensive cardiomyopathy and duration of rapid filling being prolonged especially in the hypertrophic obstructive cardiomyopathy patients. Although the differences are small indicating only trends computerized mechanocardiography gives some evidence for difference in the alteration of diastolic function in hypertrophic obstructive cardiomyopathy and hypertensive cardiomyopathy.     

HLA-DRW4 antigen linkage in patients with hypertrophic obstructive cardiomyopathy

To determine the association of histocompatibility (HLA) genes in patients with hypertrophic cardiomyopathy, we determined HLA-A, HLA-B, HLA-C, and HLA-DR specificities in 33 Japanese patients (15 with the obstructive type of hypertrophic cardiomyopathy, and 18 with the nonobstructive type). HLA-DRW4 was found in 73% of patients with hypertrophic obstructive cardiomyopathy, as compared to 33% of 144 normal controls (p < 0.005). HLA-DRW4 occurred in 33% of those with hypertrophic nonobstructive cardiomyopathy, and there was no significant difference as compared with controls. Thus, hypertrophic obstructive cardiomyopathy is associated with genes in the HLA-DR region and immunogenetic factors linked to HLA appear to play a role in the pathogenesis. This work is the first attempt at demonstration of HLA-DR antigen in hypertrophic cardiomyopathy.     

Staphylococcus hominis native mitral valve bacterial endocarditis (SBE) in a patient with hypertrophic obstructive cardiomyopathy

There are several species of coagulase-negative Staphylococci (CoNS) that are part of the normal skin flora and are relatively noninvasive/low virulence organisms. CoNS are important pathogens in patients with prosthetic devices and are the most common pathogen associated with prosthetic valve endocarditis. CoNS native valve infective endocarditis (IE) is rare. Patients with hypertrophic obstructive cardiomyopathy and an outflow pressure gradient greater than 30 mm Hg are predisposed to IE. There has been only one reported case of non-mitral valve IE due to CoNS in a patient with hypertrophic obstructive cardiomyopathy. To the best of our knowledge, we report the first case of Staphylococcal hominis mitral valve endocarditis in a patient with hypertrophic obstructive cardiomyopathy.     

Hypertrophic cardiomyopathy in Friedreich's ataxia.

The cardiac findings in two sibs with Friedreich's ataxia are described. The clinical signs were suggestive of hypertrophic obstructive cardiomyopathy. During left heart catheterization a systolic pressure gradient across the left ventricular outflow tract could be provoked by an infusion of isoprenaline. Left ventricular angiocardiograms and echocardiograms showed gross thickening of the interventricular septum. In one patient a systolic anterior movement of the anterior leaflet of the mitral valve was seen. The importance of serial echocardiographic examination for patients with Friedreich's ataxia is emphasized.     

Hypertrophic cardiomyopathy in Friedreich's ataxia.

The cardiac findings in two sibs with Friedreich's ataxia are described. The clinical signs were suggestive of hypertrophic obstructive cardiomyopathy. During left heart catheterization a systolic pressure gradient across the left ventricular outflow tract could be provoked by an infusion of isoprenaline. Left ventricular angiocardiograms and echocardiograms showed gross thickening of the interventricular septum. In one patient a systolic anterior movement of the anterior leaflet of the mitral valve was seen. The importance of serial echocardiographic examination for patients with Friedreich's ataxia is emphasized.     

Analysis of left ventricular pulsus alternans in hypertrophic cardiomyopathy]

We analyzed left ventricular (LV) pulsus alternans in 49 patients with hypertrophic cardiomyopathy during cardiac catheterization. LV pulsus alternans was noted in 6 of 17 patients with hypertrophic obstructive cardiomyopathy, 5 of whom already showed intraventricular pressure gradient at rest. No patient with hypertrophic non-obstructive cardiomyopathy had LV pulsus alternans. Pulsus alternans was neither observed in the right ventricle nor in the pulmonary artery. There was little, if any, pulsus alternans in a low pressure LV chamber (subaortic portion) and peripheral artery during LV pulsus alternans in a high pressure chamber. LV end-diastolic pressure also remained unchanged during LV pulsus alternans, except in one case. It is suggested that LV pulsus alternans in hypertrophic obstructive cardiomyopathy may imply LV dysfunction associated with increased afterload.     

Hypertrophic cardiomyopathy in Friedreich's ataxia

Friedreich's ataxia is an autosomal recessive disorder characterized by spinocerebellar degeneration. It is caused by a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9 (9q13). We reported a case of hypertrophic cardiomyopathy associated with Friedreich's ataxia in a twenty year old patient.