Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmd mdx /J Mouse.

Duchenne muscular dystrophy involves an absence of dystrophin, a cytoskeletal protein which supports cell structural integrity and scaffolding for signalling molecules in myocytes. Affected individuals experience progressive muscle degeneration that leads to irreversible loss of ambulation and respiratory diaphragm function. Although clinical management has greatly advanced, heart failure due to myocardial cell loss and fibrosis remains the major cause of death. We examined cardiac morphology and function in D2.B10-Dmd mdx /J (D2-mdx) mice, a relatively new mouse model of muscular dystrophy, which we compared to their wild-type background DBA/2J mice (DBA/2). We also tested whether drug treatment with a specific blocker of mitochondrial permeability transition pore opening (Debio-025), or ACE inhibition (Perindopril), had any effect on dystrophy-related cardiomyopathy. D2-mdx mice were treated for six weeks with Vehicle control, Debio-025 (20 mg/kg/day), Perindopril (2 mg/kg/day), or a combination (n = 8/group). At 18 weeks, compared to DBA/2, D2-mdx hearts displayed greater ventricular collagen, lower cell density, greater cell diameter, and greater protein expression levels of IL-6, TLR4, BAX/Bcl2, caspase-3, PGC-1α, and notably monoamine oxidases A and B. Remarkably, these adaptations in D2-mdx mice were associated with preserved resting left ventricular function similar to DBA/2 mice. Compared to vehicle, although Perindopril partly attenuated the increase in heart weight and collagen at 18 weeks, the drug treatments had no marked impact on dystrophic cardiomyopathy.

A Cross-Sectional Study of the Prevalence of Exercise-Induced Hypertension in Childhood Following Repair of Coarctation of the Aorta.

BACKGROUND: Exercise-testing may be a more tolerable method of detecting hypertension in children after coarctation repair compared to gold-standard 24-hour ambulatory blood pressure (BP) monitoring (ABPM). This study aims to determine the prevalence of exercise-induced hypertension and end-organ damage in children after coarctation repair, and the effectiveness of exercise-testing compared to 24-hour ABPM in this population. METHODS: Exercise-testing (Bruce protocol), transthoracic echocardiogram, 24-hour ABPM, and pulse wave velocity were performed in 41 patients aged 8 to 18 years with previous coarctation repair. Median age at repair was 13 days. Exercise-testing data were compared to healthy paediatric controls. Hypertension was defined as BP >95th percentile on 24-hour ABPM compared to normalised data, and systolic BP (SBP) arbitrarily >200mmHg on exercise-testing. RESULTS: After 13±3years, 39% (14/36) were hypertensive on 24-hour ABPM and 12% (5/41) on exercise-testing. Coarctation patients had a higher peak exercise SBP and reduced endurance compared to controls (164±26mmHg vs. 148±19mmHg, p=0.003; and 13.0±1.7mins vs. 14.2±2.4mins, p=0.007; respectively). All patients with a peak exercise SBP >190mmHg were hypertensive on 24-hour ABPM. Pulse wave velocity was higher in hypertensive patients on exercise-testing and 24-hour ABPM compared to normotensive patients (p=0.004 and p=0.06; respectively). CONCLUSIONS: Exercise-testing may be a useful tool to detect hypertension in children and young adults after coarctation repair, particularly in those who do not tolerate 24-hour ABPM. Normative peak exercise BP data for age should be obtained to improve the accuracy of exercise-testing in detecting hypertension.

Impact of arch reobstruction and early hypertension on late hypertension after coarctation repair.

OBJECTIVES: Late hypertension after coarctation repair is associated with high mortality, but its risk factors remain unclear. This study aims to determine early and late postoperative risk factors for late hypertension after coarctation repair. METHODS: A cross-sectional study including transthoracic echocardiogram and 24-h blood pressure (BP) monitoring was performed in 144 patients aged ≥10 years with previous coarctation repair. Median age at repair was 39 days (interquartile range 0-3 years). Early postoperative hypertension was evaluated by calculating the mean of BP measurements taken on the same day before hospital discharge or the need for antihypertensives prior to discharge. Multivariable analyses were performed to adjust for gender, surgical age, and follow-up age. RESULTS: After a mean follow-up period of 22 ± 7 years, 59% (84/142) of patients were hypertensive: 58% (82/142) on 24-h BP monitoring and 1% (2/142) on antihypertensives. Early postoperative hypertension was present in 58% (73/126): 39% (49/126) on BP measurements and 19% (24/126) on antihypertensives. Early and late arch reobstruction (transthoracic echocardiogram peak gradient ≥25 mmHg) was present in 37% (23/62) and 23% (33/144), respectively. On multivariable logistic analysis, early postoperative hypertension and maximum descending arch velocity on echocardiography were associated with late hypertension on 24-h BP monitoring (odds ratio 2.21, 95% confidence interval 1.05-4.66, P = 0.04; and odds ratio 2.28, 95% confidence interval 1.08-4.81, P = 0.03; respectively). CONCLUSIONS: There is a high prevalence of late hypertension after coarctation repair. Arch reobstruction may be a major determinant of late hypertension. Early postoperative hypertension may identify very early in life those at risk of developing late hypertension.

High Prevalence of Hypertension and End-Organ Damage Late After Coarctation Repair in Normal Arches.

BACKGROUND: To (1) determine the prevalence of hypertension late after coarctation repair in patients with normal-sized transverse arches, and (2) evaluate the potential for end-organ damage related to hypertension after coarctation repair. There are no studies specifically investigating end-organ damage and hypertension after coarctation repair using noninvasive techniques. METHODS: Eighty-two patients aged 10 years or greater with a coarctation repair and a normal-sized arch operated on between 1978 and 2010, underwent a transthoracic echocardiogram, 24-hour blood pressure (BP) monitoring, and retinal imaging. Median age at repair was 1 year (interquartile range, 0 to 6); 45% (37 of 82) were operated in the first year of life. RESULTS: After a follow-up of 24 ± 7 years, 27% (22 of 82) and 50% (41 of 82) suffered resting hypertension and resting prehypertension, respectively. On 24-hour BP monitoring, 61% (49 of 80) and 21% (17 of 80) suffered hypertension and prehypertension, respectively. Arch reobstruction (echo gradient > 25 mm Hg) was present in only 15% (12 of 82), and in only 15% (7 of 47) with 24-hour hypertension. Resting hypertension was associated with a smaller central retinal artery equivalent (average width of arterioles) and central retinal vein equivalent (average width of venules) (p = 0.0006 and p = 0.003, respectively). Left ventricular hypertrophy on echocardiography was present in 63% (31 of 49) with 24-hour hypertension compared with only 42% (13 of 31) with normal 24-hour BP (p = 0.06). CONCLUSIONS: There is a high rate of hypertension late after coarctation repair, even in patients with unobstructed arches. The presence of retinal imaging abnormalities and left ventricular hypertrophy signals the presence of end-organ damage in this young adult population. Regular follow-up with 24-hour BP monitoring is warranted.

Reproducibility of aortic intima-media thickness in infants using edge-detection software and manual caliper measurements.

BACKGROUND: Aortic intima-media thickness measured by transabdominal ultrasound (aIMT) is an intermediate phenotype of cardiovascular risk. We aimed to (1) investigate the reproducibility of aIMT in a population-derived cohort of infants; (2) establish the distribution of aIMT in early infancy; (3) compare measurement by edge-detection software to that by manual sonographic calipers; and (4) assess the effect of individual and environmental variables on image quality. METHODS: Participants were term infants recruited to a population-derived birth cohort study. Transabdominal ultrasound was performed at six weeks of age by one of two trained operators. Thirty participants had ultrasounds performed by both operators on the same day. Data were collected on environmental (infant sleeping, presence of a sibling, use of sucrose, timing during study visit) and individual (post-conception age, weight, gender) variables. Two readers assessed image quality and measured aIMT by edge-detection software and a subset by manual sonographic calipers. Measurements were repeated by the same reader and between readers to obtain intra-observer and inter-observer reliability. RESULTS: Aortic IMT was measured successfully using edge-detection in 814 infants, and 290 of these infants also had aIMT measured using manual sonographic calipers. The intra-reader intra-class correlation (ICC) (n = 20) was 0.90 (95% CI 0.76, 0.96), mean difference 1.5 µm (95% LOA -39, 59). The between reader ICC using edge-detection (n = 20) was 0.92 (95% CI 0.82, 0.97) mean difference 2 µm (95% LOA -45.0, 49.0) and with manual caliper measurement (n = 290) the ICC was 0.84 (95% CI 0.80, 0.87) mean difference 5 µm (95% LOA -51.8, 61.8). Edge-detection measurements were greater than those from manual sonographic calipers (mean aIMT 618 µm (50) versus mean aIMT 563 µm (49) respectively; p < 0.001, mean difference 44 µm, 95% LOA -54, 142). With the exception of infant crying (p = 0.001), no associations were observed between individual and environmental variables and image quality. CONCLUSION: In a population-derived cohort of term infants, aIMT measurement has a high level of intra and inter-reader reproducibility. Measurement of aIMT using edge-detection software gives higher inter-reader ICC than manual sonographic calipers. Image quality is not substantially affected by individual and environmental factors.

Favourable anatomy after end-to-side repair of interrupted aortic arch.

OBJECTIVE: To evaluate cardiovascular outcomes in patients with aortic arch repair and their possible correlation with arch geometry. METHODS: Ten patients who underwent end-to-side repair for aortic arch interruption (IAA), older than 10 years were compared to a cohort of 10 post coarctation (CoA) repair patients matched for age, sex and age at repair. Mean age at operation was 9.7±6.5 days. Patients underwent a resting and 24 h blood pressure measurements, exercise study, MRI, transthoracic echocardiography and vascular studies. RESULTS: Seven patients developed hypertension, two from IAA group and five from CoA group. Nine patients (45%) had gothic arch geometry, three from IAA group and six from CoA group. Despite differences in arch geometry, both groups had normal LV mass, LV function and vascular function. CONCLUSION: No differences in functional or morphologic outcomes could be demonstrated between the end-to-side repair of the arch by sternotomy and the conventional coarctation repair by thoracotomy. A favourable arch geometry can be achieved after the end-to-side repair of the aortic arch. In the present study, we could not correlate adverse arch geometry with any adverse cardio-vascular outcomes. After neonatal arch repair, the contributive role of aortic arch geometry to late hypertension remains uncertain.

Twenty-four-hour ambulatory blood pressure monitoring detects a high prevalence of hypertension late after coarctation repair in patients with hypoplastic arches.

OBJECTIVES: To determine by 24-hour blood pressure monitoring the risk of hypertension late after coarctation repair in patients with arch hypoplasia. METHODS: Sixty-two of 116 consecutive patients (age, ≥10 years) who had coarctation repair and were quoted subjectively by the surgeon or the cardiologist to have arch hypoplasia at the time of the repair underwent a transthoracic echocardiogram and 24-hour blood pressure monitoring. Median age at repair was 11 days (range, 6-48 days). Mean preoperative z score of the proximal transverse arch was -2.43 ± 0.46. Eight patients had a repair via sternotomy (6 end-to-side anastomoses, 2 patch repairs) and 54 had a conventional repair via thoracotomy. RESULTS: After a follow-up of 18 ± 5 years, 27% of the patients (17/62) had resting hypertension and 60% (37/62) had abnormal ambulatory blood pressure. Sensitivity of high resting blood pressure in detecting an abnormal 24-hour ambulatory blood pressure was 41%. Twenty patients had arch obstruction at last follow-up. Eighteen of them (90%) had abnormal ambulatory blood pressure. None of the patients operated on with end-to-side repair via sternotomy had reobstruction compared with 33% (18/54) of those repaired via thoracotomy. CONCLUSIONS: Patients with a hypoplastic arch operated via thoracotomy have an alarming prevalence of hypertension. Regular follow-up with 24-hour ambulatory blood pressure monitoring is warranted, especially in patients who have had a smaller aortic arch at the time of the initial operation.

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy.

Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6(gt/gt) mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects. Ndufs6(gt/gt) mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females, Ndufs6(gt/gt) mice are at increased risk of cardiac failure and death. Before overt heart failure, Ndufs6(gt/gt) hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS). Ndufs6(gt/gt) mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure. Ndufs6(gt/gt) isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches.