Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism

Skeletal Muscle Pump Drives Control of Cardiovascular and Postural Systems

The causal interaction between cardio-postural-musculoskeletal systems is critical in maintaining postural stability under orthostatic challenge. The absence or reduction of such interactions could lead to fainting and falls often experienced by elderly individuals. The causal relationship between systolic blood pressure (SBP), calf electromyography (EMG), and resultant center of pressure (COPr) can quantify the behavior of cardio-postural control loop. Convergent cross mapping (CCM) is a non-linear approach to establish causality, thus, expected to decipher nonlinear causal cardio-postural-musculoskeletal interactions. Data were acquired simultaneously from young participants (25 ± 2 years, n = 18) during a 10-minute sit-to-stand test. In the young population, skeletal muscle pump was found to drive blood pressure control (EMG → SBP) as well as control the postural sway (EMG → COPr) through the significantly higher causal drive in the direction towards SBP and COPr. Furthermore, the effect of aging on muscle pump activation associated with blood pressure regulation was explored. Simultaneous EMG and SBP were acquired from elderly group (69 ± 4 years, n = 14). A significant (p = 0.002) decline in EMG → SBP causality was observed in the elderly group, compared to the young group. The results highlight the potential of causality to detect alteration in blood pressure regulation with age, thus, a potential clinical utility towards detection of fall proneness

Maturation of the Cardiac Autonomic Nervous System Activity in Children and Adolescents

Background Despite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic‐(SNS) and parasympathetic nervous system (PNS) activity parameters in healthy patients aged 0.5 to 20 years. A second aim was to determine potential sex differences. Methods and Results Five studies covering the 0.5‐ to 20‐year age range provided impedance‐ and electrocardiography recordings from which heart rate, different PNS‐parameters (eg, respiratory sinus arrhythmia) and an SNS‐parameter (pre‐ejection period) were collected. Age trends were computed in the mean values across 12 age‐bins and in the age‐specific variances. Age was associated with changes in mean and variance of all parameters. PNS‐activity followed a cubic trend, with an exponential increase from infancy, a plateau phase during middle childhood, followed by a decrease to adolescence. SNS‐activity showed a more linear trend, with a gradual decrease from infancy to adolescence. Boys had higher SNS‐activity at ages 11 to 15 years, while PNS‐activity was higher at 5 and 11 to 12 years with the plateau level reached earlier in girls. Interindividual variation was high at all ages. Variance was reasonably stable for SNS‐ and the log‐transformed PNS‐parameters. Conclusions Cardiac PNS‐ and SNS‐activity in childhood follows different maturational trajectories. Whereas PNS‐activity shows a cubic trend with a plateau phase during middle childhood, SNS‐activity shows a linear decrease from 0.5 to 20 years. Despite the large samples used, clinical use of the sex‐specific centile and percentile normative values is modest in view of the large individual differences, even within narrow age bands.National Institute of Diabetes and Digestive and Kidney Diseases; the Netherlands Organization for Scientific Research; National Initiative for Brain and Cognition Research; European Commission under the 7th Framework Health Program with Grant; The Netherlands Organization for Health Research and Development (ZonMw); The Dutch Heart Foundatio

Fetal dilated cardiomyopathy caused by persistent junctional reciprocating tachycardia

Ultrasound examination of a fetus at 32 weeks' gestation revealed dilated cardiomyopathy and a heart rate of 170 beats per minute. Prenatally, this mild tachycardia was not primarily suspected to be the cause of the myocardial changes. Postnatal electrocardiography revealed a persistent junctional reciprocating tachycardia (PJRT) and the diagnosis of tachycardia-induced cardiomyopathy (TICM) became apparent. After conversion to a sinus rhythm under digoxin and amiodarone, the cardiac changes regressed. PJRT is a rare form of supraventricular tachycardia. The prenatal findings in the condition have previously been described retrospectively, but it can only be diagnosed postnatally by its characteristic electrocardiographic properties. This case indicates that TICM can occur at lower heart rates than previously assumed. Even severe prenatal cardiomyopathy may be reversible once sinus rhythm has been restored. Copyright (C) 2009 ISUOG. Published by John Wiley & Sons, Ltd