The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation.

Aberrant regulation of myocardial force production represents an early biomechanical defect associated with sarcomeric cardiomyopathies, but the molecular mechanisms remain poorly defined. Here, we evaluated the pathogenicity of a previously unreported sarcomeric gene variant identified in a pediatric patient with sporadic dilated cardiomyopathy, and we determined a molecular mechanism. Trio whole-exome sequencing revealed a de novo missense variant in TNNC1 that encodes a p.I4M substitution in the N-terminal helix of cardiac troponin C (cTnC). Reconstitution of this human cTnC variant into permeabilized porcine cardiac muscle preparations significantly decreases the magnitude and rate of isometric force generation at physiological Ca2+-activation levels. Computational modeling suggests that this inhibitory effect can be explained by a decrease in the rates of cross-bridge attachment and detachment. For the first time, we show that cardiac troponin T (cTnT), in part through its intrinsically disordered C terminus, directly binds to WT cTnC, and we find that this cardiomyopathic variant displays tighter binding to cTnT. Steady-state fluorescence and NMR spectroscopy studies suggest that this variant propagates perturbations in cTnC structural dynamics to distal regions of the molecule. We propose that the intrinsically disordered C terminus of cTnT directly interacts with the regulatory N-domain of cTnC to allosterically modulate Ca2+ activation of force, perhaps by controlling the troponin I switching mechanism of striated muscle contraction. Alterations in cTnC-cTnT binding may compromise contractile performance and trigger pathological remodeling of the myocardium.

Clinical diversity of MYH7-related cardiomyopathies: Insights into genotype-phenotype correlations.

MYH7-related disease (MRD) is the most common hereditary primary cardiomyopathy (CM), with pathogenic MYH7 variants accounting for approximately 40% of familial hypertrophic CMs. MRDs may also present as skeletal myopathies, with or without CM. Since pathogenic MYH7 variants result in highly variable clinical phenotypes, from mild to fatal forms of cardiac and skeletal myopathies, genotype-phenotype correlations are not always apparent, and translation of the genetic findings to clinical practice can be complicated. Data on genotype-phenotype correlations can help facilitate more specific and personalized decisions on treatment strategies, surveillance, and genetic counseling. We present a series of six MRD pedigrees with rare genotypes, encompassing various clinical presentations and inheritance patterns. This study provides new insights into the spectrum of MRD that is directly translatable to clinical practice.

The importance of early bedside echocardiography in children with scorpion envenomation.

Scorpion sting may cause myocardial injury and heart failure (HF). Clinical signs of failure may develop several hours or even days after the sting, while electrocardiography (ECG) and blood examination soon after the sting may be normal. We sought to examine whether normal echocardiographic (echo) examination performed shortly after hospital arrival would exclude subsequent HF. We also sought to check if blood troponin and natriuretic peptide values measured shortly after arrival may predict or exclude subsequent HF. Natriuretic peptide activities have not been measured in scorpion sting victims. We also wanted to check if HF occurs in envenomated young infants. In a 3-year prospective study we looked at the demographic, clinical, laboratory, ECG, and echo data of all patients with general envenomation who arrived at the emergency department (ED) after scorpion sting. Clinical, laboratory, ECG, and echo results on arrival and 24 h after arrival were checked and compared between groups of patients with normal and abnormal echo on arrival. We then looked for differences in clinical course, therapy, and outcome between groups. The study included 98 children aged 80 days to 19 years (median 53.1 months), 25 were below the age of 2 years. Envenomation by the "yellow scorpion"Leiurus quinquestriatus was suspected in 74 cases. Median time between sting and ED arrival was 80 min. Echo was performed on arrival in 93 of the 98 patients, (in 5 occasions it was not performed or not recorded) 74 were normal and 19 were abnormal. Abnormal echo included hypokinesia and low fractional shortening and ejection fraction of the left ventricle. Clinical signs, abnormal ECG, and laboratory results were not discriminative between groups on arrival. Mean troponin T was higher in patients with abnormal echo, but within normal range in 13 of the 19 patients with abnormal echo and above normal in 2 of the 74 patients with normal echo-missing sensitivity and specificity. Mean N-terminal pro B-type natriuretic peptide was above normal in both groups but within normal range in 5 patients with abnormal echo and above normal range in 24 patients with normal echo-missing sensitivity and specificity. None of the patients with normal echo had subsequent HF and none of the children younger than 2 years of age had HF. All patients survived the intoxication and were discharged home without sequel. We conclude that early echo examination is an important procedure. In our study, normal examination excluded subsequent HF. Abnormal examination accelerated cardiac therapy which might have contributed to our favorable outcome. HF did not occur in infants younger than two years of age.

From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG).

Congenital disorders of glycosylation are a growing group of inborn errors of protein glycosylation. Cardiac involvement is frequently observed in the most common form, PMM2-CDG, especially hypertrophic cardiomyopathy. Dilated cardiomyopathy, however, has been only observed in a few CDG subtypes, usually with a lethal outcome. We report on cardiac pathology in nine patients from three unrelated Israeli families, diagnosed with dolichol kinase deficiency, due to novel, homozygous DK1 gene mutations. The cardiac symptoms varied from discrete, mild dilation to overt heart failure with death. Two children died unexpectedly with acute symptoms of heart failure before the diagnosis of DK1-CDG and heart transplantation could take place. Three other affected children with mild dilated cardiomyopathy at the time of the diagnosis deteriorated rapidly, two of them within days after an acute infection. They all went through successful heart transplantation; one died unexpectedly and 2 others are currently (after 1-5 years) clinically stable. The other 4 children diagnosed with mild dilated cardiomyopathy are doing well on supportive heart failure therapy. In most cases, the cardiac findings dominated the clinical picture, without central nervous system or multisystem involvement, which is unique in CDG syndrome. We suggest to test for DK1-CDG in patients with dilated cardiomyopathy. Patients with discrete cardiomyopathy may remain stable on supportive treatment while others deteriorate rapidly. Our paper is the first comprehensive study on the phenotype of DK1-CDG and the first successful organ transplantation in CDG syndrome.

Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

Cardiac manifestations following electrocution in children.

BACKGROUND: Electrical injury can result in a variety of cardiac abnormalities. We evaluate the cardiac effects in patients injured by electric shock and treated in our medical centre. METHODS: We reviewed retrospectively the findings in 52 children, aged from 7 months to 17 years, with a mean age of 10.1 +/- 5.1 years, all evaluated and treated for accidental electric shock from January, 1992, through July, 2004. Relevant data regarding clinical presentation, electrocardiogram recording and cardiac enzymes was compiled. We also evaluated the echocardiographic findings, clinical course, treatment, and outcome. RESULTS: Syncope had been the presenting symptom in 17 children (33%), asystole in 1 patient, and ventricular fibrillation or tachycardia in 2 patients. Characteristic changes of acute ischaemia of the anterior wall on the basis of changes in the ST segments were noted in 2 patients. Total creatine phosphokinase was measured in 33 children (63%), and was elevated in 20. Creatine phosphokinase-MB was measured in 11 patients, and was abnormal in six (54%). Troponin was measured in three children, and was significantly high in one (33%). Cardiopulmonary resuscitation and mechanical ventilation for a significant period was necessary in 5 patients, of whom 4 (80%) survived. None of the survivors was left with any cardiac disability following the acute event. CONCLUSIONS: Significant cardiac damage and complications are rare in children and young adults who survive incidental electrocution. Most of the cardiac events are observed during the acute phase and immediately subsequent to electrocution. No delayed complications are anticipated.

Early blood pressure-independent cardiac changes in diabetic rats.

Cardiac remodeling is a key event in both diabetic and hypertensive heart diseases. In the present study, we investigated early myocardial changes in an animal model, the male Sabra rat model (SBH/y) of salt-induced hypertension-rendered diabetic with streptozotocin. Control non-diabetic (C), diabetic (D), and D or C rats made hypertensive by salt loading (DS or CS) were studied after 6 weeks. M-mode echocardiography revealed that left ventricular internal dimension during diastole and systole were significantly increased in D and DS, but not in C or CS. Concurrently, we found in D and DS an increase in cardiac beta-myosin heavy chain, atrial natriuretic peptide, skeletal alpha-actin mRNA, type III collagen, and transforming growth factor-beta. Myocardial angiotensin-converting enzyme (ACE) mRNA levels were increased while ACE2 mRNA levels were decreased in both D and DS groups. Cardiac angiotensin-1 (AT1) receptor protein levels were unchanged but the levels of phosphorylated (p) ERK and Jun-NH(2)-protein kinase (JNK) were increased in D and DS. In conclusion, we detected early cardiac changes in diabetic rats that were unrelated to hypertension. The increase in ACE, the decrease in ACE2, and the increase in cardiac pERK and pJNK suggest an increase in free angiotensin II and AT1R signaling in the diabetic myocardium as a possible mechanism contributing to cardiac remodeling in diabetes.

Positional cyanosis in infants: an unusual presentation of right-sided cardiac masses.

Positional cyanosis is an uncommon finding in young patients. We report three infants who presented with positional cyanosis due to a pedunculated tumour in the right heart. Arterial desaturation was the result of right-to-left shunting at the level of the oval foramen caused by obstruction and/or insufficiency of the tricuspid valve. The obstruction at the level of the tricuspid valve was variable because of the pedunculated nature of the tumours, which gave them considerable mobility. Hence, the degree of right-to-left shunting was dependent on the position of the patient. In all the patients, surgical resection of the tumours resolved the cyanosis.

Presentation, natural history, and outcome in children and adolescents with double orifice mitral valve.

Forty-six children, aged 2 days to 16 years (median 2.4 years) with double orifice mitral valve (DOMV), were studied. Partial atrioventricular septal defect was the most commonly associated cardiac lesion. Symptoms were related to the degree of mitral insufficiency and/or stenosis when present. Surgical intervention directed at DOMV was required in the minority of patients who underwent repair of associated cardiac lesions. The long-term morbidity attributable to DOMV was low.

Clinical presentation, natural history, and outcome of patients with the absent pulmonary valve syndrome.

So-called 'absent pulmonary valve syndrome' is a rare cardiac malformation, usually associated with tetralogy of Fallot. Congenital absence of the leaflets of the pulmonary valve is less common when the ventricular septum is intact. Characteristic features of the syndrome include dysplasia or absence of the pulmonary valvar leaflets, permitting severe pulmonary regurgitation, and aneurysmal dilation of the pulmonary arteries. The purpose of our study was to review our experience with patients diagnosed as having the absent pulmonary valve syndrome, and to describe their clinical presentation, natural history, and outcome. We reviewed retrospectively data from 18 patients with absent pulmonary valve syndrome, 10 boys and eight girls, treated between March 1983 and May 2003. We identified two groups of patients, one made up of 11 patients with a ventricular septal defect, in whom the morphology of the subpulmonary outflow tract was phenotypic for tetralogy of Fallot, and another group, with seven patients, having an intact ventricular septum. Family history of congenital heart disease was common only in patients with ventricular septal defect, being found in 73%, all of whom were diagnosed during infancy with variable respiratory distress. Diagnosis was delayed in 43% of the patients with an intact ventricular septum. Cardiac surgery was performed in eight patients with ventricular septal defect (73%), compared to only two patients (28%) with an intact ventricular septum. Overall mortality was 28%, with five patients dying. Although our sample was small, two clinical patterns emerged depending on the presence or absence of a ventricular septal defect. Patients with a ventricular septal defect and phenotypic features of tetralogy of Fallot have a strong family history of congenital cardiac disease, develop respiratory symptoms during infancy and exhibit a variable prognosis, despite cardiac surgery. Patients with an intact ventricular septum are usually asymptomatic, present later in life, and show a relatively benign prognosis.

Aortic dissection in children and young adults: diagnosis, patients at risk, and outcomes.

OBJECTIVE: To heighten the awareness of pediatricians and pediatric cardiologists to aortic dissection, a potentially dangerous medical condition. METHODS: We reviewed the charts of 13 patients, seen in four medical centers, who suffered acute or chronic aortic dissection over the period 1970 through 2000 whilst under the age of 25 years. RESULTS: There were seven male and six female patients, with the mean age at diagnosis being 12.1 years, with a range from one day to 25 years. Congenital cardiac defects were present in five patients, and Marfan syndrome in four. In three of the patients with congenital cardiac defects, aortic dissection developed as a complication of medical procedures. In three patients, dissection followed blunt trauma to the chest. We could not identify any risk factors in one patient. The presenting symptoms included chest pain in four patients, abdominal pain and signs of ischemic bowel in two, non-palpable femoral pulses in one, and obstruction of the superior caval vein in one. Angiography and magnetic resonance imaging were the main diagnostic tools. Overall mortality was 38%. Only six patients had successful surgical outcomes. CONCLUSION: Due to the rarity of aortic dissection a high index of suspicion is required to reach the diagnosis in a timely manner. It should be considered in young patients complaining of chest pain in association with Marfan syndrome, anomalies of the aortic valve and arch, and chest trauma.

Successful treatment of infective endocarditis with recombinant tissue plasminogen activator.

OBJECTIVES: In a prospective study, we examined the effect of treatment with recombinant tissue plasminogen activator (r-TPA) on survival and morbidity in a series of high-risk children with infectious endocarditis (IE) after prolonged treatment with indwelling catheters. We hypothesized that r-TPA is an adjunctive therapy for dissolution of infected thrombi in drug-resistant IE. STUDY DESIGN: In the prospective 3-year study (1998-2001), we identified high-risk children with chronic illness and prolonged treatment with indwelling catheters who developed IE and overwhelming sepsis. Patients were allocated to receive r-TPA after persistent and enlarging intracardiac vegetations and failure to respond to conventional medical management. Complications associated with treatment, survival, and cardiac morbidity were observed. RESULTS: Seven infants were treated prospectively with r-TPA. All infants responded promptly to treatment, with resolution of the intracardiac vegetations within 3 to 4 days of commencement and without any adverse complications. All patients survived without long-term cardiac morbidity. CONCLUSION: Recombinant tissue plasminogen activator may offer a safe alternative to surgical intervention in the high-risk infant with IE.

Methotrexate in recurrent postpericardiotomy syndrome.

The postpericardiotomy syndrome occurs in up to one-third of children undergoing cardiac surgery. Its treatment includes anti-inflammatory agents, diuresis, and drainage of effusions. Administration of steroids can have a dramatic effect, but is limited by adverse effects. Usually the syndrome lasts weeks only, and persistence beyond six months is exceptional. We describe a rare case of chronic postpericardiotomy syndrome, with recurrent pericardial effusions and steroid dependency, that was treated successfully with a low weekly dose of methotrexate.

Digoxin concentration in saliva and plasma in infants, children, and adolescents with heart disease.

BACKGROUND: Because of its narrow therapeutic index, therapeutic monitoring of digoxin is important in the management of infants and children receiving the drug for cardiac failure or arrhythmias, or following accidental ingestion. Whether saliva can replace plasma in the therapeutic monitoring of digoxin therapy in children is unclear. OBJECTIVE: This study assessed the value of determining saliva digoxin concentration in infants, children, and adolescents. METHODS: Infants, children, and adolescents receiving digoxin for various indications, whose digoxin dosage had remained unchanged for ≥10 days, and whose compliance was good according to the parents were enrolled. Digoxin concentration was measured in paired specimens of citric acid-stimulated mixed saliva and plasma obtained simultaneously. RESULTS: Eighteen children (10 boys, 8 girls; mean [SD] age, 42.3 [53.1] months [range, 2 months-14 years]) were included in the study. Digoxin therapy was administered for cardiac failure due to dilated cardiomyopathy in 9 patients (50.0%), ventricular septal defect in 4 (22.2%), supraventricular tachycardia in 3 (16.7%), and after cardiac surgery in 2 (11.1%). Digoxin concentration in the 20 paired specimens obtained varied from 0.0 to 0.92 ng/mL (mean [SD], 0.25 [0.26] ng/mL) in saliva and from 0.27 to 1.54 ng/mL (mean [SD], 0.77 [0.40] ng/mL) in plasma. The mean plasma/saliva digoxin concentration ratio was 2.8. CONCLUSIONS: This study of infants, children, and adolescents receiving digoxin for a variety of indications and whose dose was unchanged for ≥10 days showed that marked individual variability in the saliva/plasma concentration ratio precludes the use of saliva in predicting the plasma digoxin concentration. The value of saliva digoxin (as opposed to plasma digoxin) measurements in the assessment of the cardiac effects of the drug in children remains to be determined.

Advanced atrioventricular conduction block in acute rheumatic fever.

We carried out a retrospective case control analysis to evaluate the outcome, and the need for treatment, of problems with atrioventricular conduction occurring during an acute attack of rheumatic fever, assessing the occurrence of second and third atrioventricular block versus first degree block. We reviewed and analysed the clinical, electrocardiographic and echocardiographic records of all children diagnosed in a single institute as having acute rheumatic fever during a period of seven consecutive years. During the period from October, 1994, through October, 2001, 65 children meeting the modified Jones criterions for acute rheumatic fever were hospitalized in the Soroka University Medical Center, Israel. First-degree atrioventricular block was identified in 72.3% of the children, and resolved with no specific treatment other than non-steroidal anti-inflammatory medications. Second-degree atrioventricular block of Mobitz type I, was observed in one child (1.5%), which progressed from first-degree block, and subsequently resolved. Complete atrioventricuar block was found in 3 children (4.6%), one progressing from Mobitz type I second-degree block, and two being seen as the first presentation. Of the three children with complete atrioventricular block, one patient was not treated, the second was treated with aspirin, and the final one with combined aspirin and steroids. The disturbances of conduction resolved in all three. We conclude that advanced atrioventricular block is rare during acute rheumatic fever. If occurring, block appears to be temporary, and resolves with conventional anti-inflammatory treatment. Specific treatment, such as insertion of a temporary pacemaker, should be considered only when syncope or clinical symptoms persist.

Infective endocarditis successfully treated in extremely low birth weight infants with recombinant tissue plasminogen activator.

Increased survival of extremely low birth weight infants depends on the use of indwelling catheters. These catheters expose the infant to the risk of thrombus formation and line infection. When intracardiac thromboses become infected, the entity is indistinguishable from infective endocarditis and exposes the infant to prolonged sepsis and risk of disseminated infected emboli. Despite prolonged antiinfective therapy and removal of the infected line, resolution of the sepsis and dissolution of the vegetations is frequently not achieved. We describe 2 cases of infective endocarditis in extremely low birth weight infants successfully treated with recombinant tissue plasminogen activator in addition to prolonged antiinfective therapy. Blood cultures became sterile and vegetations disappeared within days of commencing treatment, and there were no systemic complications. A literature search detailed in the article confirms the poor outcome associated with infectious endocarditis in preterm infants. Tissue plasminogen activator may play an important role when standard care has failed.