ubiquinone and Hypertrophy--Left-Ventricular

Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012.. To assess the effects of pharmacological treatments for Friedreich ataxia.. On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies.. We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months.. Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane.. We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion.In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence).The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low.There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis.. Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.

Topics: Antioxidants; Friedreich Ataxia; Heart; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Rare Diseases; Ubiquinone; Ultrasonography; Vitamin E

Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis and pes cavus. Heart abnormalities cause premature death in 60% to 80% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the first update of a review published in 2009.. To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia.. We searched The Cochrane Neuromuscular Disease Group Specialized Register (11 July 2011), CENTRAL (2011, Issue 3), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011), AMED (January 1985 to July 2011), CINAHL Plus (January 1937 to July 2011), LILACS (January 1982 to July 2011), ORPHANET (1990 to July 2011), TRIP (1998 to July 2011) and PEDRO (October 1999 to July 2011).. Randomised controlled trials (RCTs) or quasi-RCTs of drug treatment in people with genetically confirmed Friedreich ataxia. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography. We excluded trials of shorter duration than 12 months.. Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria. We planned to collect adverse event data from included studies.. More than 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants, using the synthetic antioxidant idebenone 5 mg/kg, fulfilled the selection criteria for this review. Other RCTs were of insufficient duration. We identified no additional RCT when the searches were updated in 2011. In the included study, the primary outcome specified for this review, change in ICARS scale, did not reveal any significant differences with idebenone treatment compared to placebo. The secondary outcome of change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not assessed. The second secondary outcome, change in left ventricular mass as measured by echocardiography, did improve significantly; there was a 10.7% worsening after 12 months of treatment in the placebo group and a 5.6% improvement in the idebenone group. The mean difference was 16.37% (95% CI 95% 2% to 31%). There were no adverse events. We considered the included study at low risk of bias in five of the seven domains assessed. A larger trial using idebenone published an interm report in May 2010 stating that the study had failed to reach its primary endpoint, which was change in the ICARS scale.. No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but the clinical relevance of this change was not assessed in the included study.

Topics: Antioxidants; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Rare Diseases; Ubiquinone; Ultrasonography

Friedreich ataxia (FRDA) is commonly associated with hypertrophic cardiomyopathy, but little is known about its frequency, severity, or treatment. In this 6-month randomized, double-blind, controlled study, we sought to determine whether idebenone improves cardiac measures in FRDA.. Seventy pediatric subjects were treated either with idebenone (450/900 mg/d or 1,350/2,250 mg/d) or with placebo. Electrocardiograms (ECGs) were assessed at each visit, and echocardiograms, at baseline and week 24.. We found ECG abnormalities in 90% of the subjects. On echocardiogram, 81.4% of the total cohort had left ventricular (LV) hypertrophy, as measured by increased LV mass index-Dubois, and the mean ejection fraction (EF) was 56.9%. In linear regression models, longer PR intervals at baseline were marginally associated with longer GAA repeat length (P = .011). Similarly, GAA repeat length did not clearly predict baseline EF (P = .086) and LV mass by M-mode (P = .045). Left ventricular mass index, posterior wall thickness, EF, and ECG parameters were not significantly improved by treatment with idebenone. Some changes in echocardiographic parameters during the treatment phase correlated with baseline status but not with treatment group.. Idebenone did not decrease LV hypertrophy or improve cardiac function in subjects with FRDA. The present study does not provide evidence of benefit in this cohort over a 6-month treatment period.

Topics: Adolescent; Antioxidants; Cardiomyopathy, Hypertrophic; Child; Clinical Trials, Phase III as Topic; Double-Blind Method; Echocardiography, Doppler; Electrocardiography; Female; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Male; Ubiquinone; Ventricular Function

The authors carried out a 1-year, randomized, placebo-controlled trial of idebenone in 29 patients with Friedreich ataxia. They found significant reductions of interventricular septal thickness and left ventricular mass in the idebenone group vs the placebo group, with no improvement in other heart ultrasound measures or neurologic condition. The absolute cardiac changes were modest, but the findings suggest that larger trials should assess whether idebenone reduces ventricular hypertrophy in patients with Friedreich ataxia.

Topics: Adolescent; Adult; Benzoquinones; Cardiomyopathy, Hypertrophic; Child; Erythrocytes; Female; Frataxin; Free Radical Scavengers; Free Radicals; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Iron-Binding Proteins; Male; Mitochondria; Oxidative Stress; Prospective Studies; Protoporphyrins; Ubiquinone

The authors report 1-year prospective data on eight patients with Friedreich ataxia. Idebenone did not halt the progression of ataxia. At the end of therapy, cardiac ultrasound demonstrated significant reduction of cardiac hypertrophy in six of eight patients. Cardiac strain and strain rate imaging showed that the reduction of hypertrophy is preceded by an early and linear improvement in cardiac function. Idebenone reduced erythrocyte protoporphyrin IX levels in five of six patients with elevated baseline levels; however, changes did not consistently relate to cardiac improvement.

Topics: Adolescent; Adult; Benzoquinones; Cardiomyopathy, Hypertrophic; Child; Erythrocytes; Female; Frataxin; Free Radical Scavengers; Free Radicals; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Iron-Binding Proteins; Male; Mitochondria; Oxidative Stress; Prospective Studies; Protoporphyrins; Stroke Volume; Ubiquinone

Mitochondria-derived reactive oxygen species (ROS) play important roles in the development of cardiovascular disease highlighting the need for novel targeted therapies. This study assessed the potential therapeutic benefit of combining the mitochondria-specific antioxidant, MitoQ10, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ10 on cardiac hypertrophy in a neonatal cardiomyocyte cell line.. Eight-week-old male stroke-prone spontaneously hypertensive rats (SHRSPs, n=8-11) were treated with low-dose losartan (2.5 mg/kg per day); MitoQ10 (500 μmol/l); a combination of MitoQ10 and losartan (M+L); or vehicle for 8 weeks. Systolic pressure and pulse pressure were significantly lower in M+L rats (167.1 ± 2.9 mmHg; 50.2 ± 2.05 mmHg) than in untreated SHRSP (206.6 ± 9 mmHg, P<0.001; 63.7 ± 2.7 mmHg, P=0.001) and demonstrated greater improvement than MitoQ10 or low-dose losartan alone, as measured by radiotelemetry. Left ventricular mass index was significantly reduced from 22.8 ± 0.74 to 20.1 ± 0.61 mg/mm in the combination group (P<0.05). Picrosirius red staining showed significantly reduced cardiac fibrosis in M+L rats (0.82 ± 0.22 A.U.) compared with control (5.94 ± 1.35 A.U., P<0.01). In H9c2 neonatal rat cardiomyocytes, MitoQ10 significantly inhibited angiotensin II mediated hypertrophy in a dose-dependent manner (500  nmol/l MitoQ10 153.7 ± 3.1 microns vs. angiotensin II 200.1 ± 3.6 microns, P<0.001).. Combining MitoQ10 and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension and reducing left ventricular hypertrophy. In addition, MitoQ10 mediates a direct antihypertrophic effect on rat cardiomyocytes in vitro. MitoQ10 has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Antioxidants; Cell Enlargement; Cell Line; Drug Synergism; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Myocytes, Cardiac; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Ubiquinone

Left ventricular hypertrophy (LVH) is a frequent finding in Friedreich's ataxia (FRDA). In previous studies treatment with idebenone, a synthetic analogue of coenzyme Q10, has been associated with a substantial decrease in myocardial hypertrophy, despite great variability in cardiac responsiveness among patients. Here we present the results of a retrospective analysis of a cohort of 35 patients (20 with LVH, 15 without LVH) with confirmed molecular diagnosis of FRDA, treated with idebenone 5 mg/kg/day for up to five years. At the end of the study, we found an increase of interventricular septum and posterior wall thickness in the group without LVH before treatment and no change in the group with LVH before treatment. The neurological picture of the disease significantly deteriorated with time in both groups.

Topics: Adult; Analysis of Variance; Antioxidants; Cohort Studies; Echocardiography; Female; Follow-Up Studies; Friedreich Ataxia; Heart; Heart Septum; Humans; Hypertrophy, Left Ventricular; Male; Myocardium; Retrospective Studies; Severity of Illness Index; Ubiquinone

Untreated or poorly controlled arterial hypertension induced development of pathologic left ventricular hypertrophy (LVH), a common finding in hypertensive patients and a strong predictor of cardiovascular morbidity and mortality. The proteomic approach is a powerful technique to analyze a complex mixture of proteins in various settings. An experimental model of hypertension-induced early LVH was performed in spontaneously hypertensive rats, and the cardiac protein pattern compared with the normotensive Wistar Kyoto counterpart was analyzed. Fifteen altered protein spots were shown in the early stage of LVH. Compared with a previous animal model of established and regressed LVH, three protein spots were common in both models. These three altered protein spots corresponded to two unique proteins that were identified as Calsarcin-1 (CS-1) and ubiquinone biosynthesis protein COQ7 homolog. CS-1 is a negative regulator of the calcineurin/NF-AT pathway. Because upregulation in the expression levels of this protein was observed, the activation level of NF-kappaB by oxidative stress as an alternative pathway was investigated. It was found that antihypertensive therapies partially decreased oxidative stress and normalized the activation of NF-kappaB in the kidneys and aorta NF-kappaB activation but just moderately in the heart. This could be due to the interaction of any specific cardiac protein with any component of the NF-kappaB pathway. In this sense, CS-1 could be a good candidate because it is expressed preferentially in heart, to a lesser extent in smooth muscle cells, but not in kidney. Further investigations are necessary to elucidate the exact role of CS-1 and ubiquinone biosynthesis protein COQ7 in the setting of hypertension-induced LVH.

Topics: Animals; Antihypertensive Agents; Aorta; Carrier Proteins; Disease Models, Animal; Gene Expression Profiling; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Microfilament Proteins; Muscle Proteins; Myocardium; NF-kappa B; Oxidative Stress; Proteomics; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Ubiquinone

We investigated whether the substrate for nitric oxide synthesis L-arginine is able to modify hypertension and left ventricular hypertrophy development induced by chronic blockade of nitric oxide synthase activity by NG-nitro-L-arginine-methyl ester (L-NAME).. Four groups of rats were investigated: control, L-arginine 1.5 g kg-1, L-NAME 40 mg kg-1, and L-NAME +L-arginine in corresponding doses. Systolic blood pressure was measured by non-invasive tail-cuff plethysmography each week. After 4 weeks, the animals were sacrificed and hydroxyproline and coenzyme Q9 and Q10 concentrations in the left ventricle, and nitric oxide synthase activity in the left ventricle, kidney and brain were investigated.. In the L-NAME group, nitric oxide synthase activity was decreased in the left ventricle, kidney and brain, and hypertension, left ventricular hypertrophy and fibrosis developed. Heart remodelling was associated with the decrease of coenzyme Q9 and Q10 concentrations in the left ventricle. Simultaneous treatment with L-NAME and L-arginine prevented nitric oxide synthase activity diminution in the left ventricle but not in the kidney and brain, and completely failed to prevent hypertension, left ventricular hypertrophy and fibrosis. Nevertheless, l-arginine prevented the diminution of coenzyme Q9 and Q10 concentrations in the left ventricle.. We conclude that L-arginine failed to prevent hypertension, left ventricular hypertrophy and fibrosis development despite restoration of nitric oxide synthase activity in the left ventricle. However, L-arginine prevented the diminution of coenzyme Q levels in the left ventricle.

Topics: Animals; Antihypertensive Agents; Arginine; Brain; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Ubiquinone

Topics: Antioxidants; Benzoquinones; Cardiotonic Agents; Clinical Trials as Topic; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Mitochondria, Heart; Oxidative Stress; Ubiquinone; Ultrasonography

Topics: Benzoquinones; Double-Blind Method; Free Radical Scavengers; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Research Design; Ubiquinone