Electrocardiographic Conduction Abnormalities Research Articles

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

Osteogenic circulating endothelial progenitor cells are linked to electrocardiographic conduction abnormalities in rheumatic patients.

Osteogenic circulating endothelial progenitor cells (EPC) play a pathogenic role in cardiovascular system degeneration through promulgating vasculature calcification, but its role in conduction disorders as part of the cardiovascular degenerative continuum remained unknown. To investigate the role of osteocalcin (OCN)-expressing circulating EPCs in cardiac conduction disorders in the unique clinical sample of rheumatoid arthritis (RA) susceptible to both abnormal bone metabolism and cardiac conduction disorders. We performed flow cytometry studies in 134 consecutive asymptomatic patients with rheumatoid arthritis to derive osteogenic circulating OCN-positive (OCN+) CD34+KDR+ vs. CD34+CD133+KDR+ conventional EPC. Study endpoint was the prespecified combined endpoint of electrocardiographic conduction abnormalities. Total prevalence of cardiac conduction abnormality was 9% (n=12). All patients except one had normal sinus rhythm. One patient had atrial fibrillation. No patient had advanced atrioventricular (AV) block. Prevalence of first-degree heart block (>200ms), widened QRS duration (>120ms) and right bundle branch block were 6.7%, 2.1%, and 2.2% respectively. Circulating osteogenic OCN+ CD34+ KDR+ EPCs were significantly higher among patients with cardiac conduction abnormalities (p=0.039). Elevated OCN+ CD34+ KDR+ EPCs> 75th percentile was associated with higher prevalence of cardiac conduction abnormalities (58.3% vs. 20.02%, p=0.003). Adjusted for potential confounders, elevated OCN+ CD34+ KDR+ EPCs> 75th percentile remained independently associated with increased risk of cardiac conduction abnormalities (OR=4.4 [95%CI 1.2-16.4], p=0.028). No significant relation was found between conventional EPCs CD34+CD133+KDR+ and conduction abnormalities (p=0.36). Elevated osteogenic OCN+ CD34+ KDR+ EPCs are independently associated with the presence of electrocardiographic conduction abnormalities in patients with rheumatoid arthritis, unveiling a potential novel pathophysiological mechanism.

Correlation of electrocardiographic conduction abnormalities with myocardial fibrosis and scar in late enhancement

Background Late Gadolinium enhancement represents a widely employed method for detecting myocardial scarring e.g. after myocardial infarction or for myocardial Inflammation. A frequent finding is slight basal septal enhancement as well as intramyocardial enhancement, mostly referred as myocardial fibrosis. Less is known about the impact on myocardial conduction and a possible correlation to ECG findings such as atrioventricular node conduction delay and bundle branch blockations.

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity.

LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.

Global longitudinal strain: a marker of functional and electrical involvement in myotonic dystrophy type 1?

Background: Myotonic dystrophy type 1 (MD1) is the most frequently inherited multisystem neuromuscular disease in adults with major cardiac involvement, including conduction system abnormalities and myocardial dysfunction. Subclinical cardiac involvement has been demonstrated by conventional and tissue echo Doppler parameters and a positive correlation between neuromuscular and cardiac involvement has been reported. There are no data referring to speckle tracking strain analysis in this population. The purpose of this study was to evaluate global longitudinal strain (GLS) in MD1 patients and to assess its relation with the severity of muscle impairment and with electrocardiographic conduction abnormalities. Methods: 25 patients with MD1 and no symptoms or physical signs of heart disease and 13 age and sex matched healthy volunteers were prospectively enrolled. Clinical, electrocardiographic and echocardiographic data were collected. Myocardial deformation evaluation was made through speckle tracking derived strain and strain rate imaging. In patients with MD1, severity of muscle impairment was evaluated through the modified Rankin scale (mRS). Results: Mean age of the study population was 36.7±12.5 years and 50.0% were male. Sinus rhythm was documented in 88.0% of the patients (22) and 16% (4) presented first degree atrioventricular (AV) block. No differences were found between patients and controls regarding atrial and ventricular volumes, left ventricle ejection fraction, right ventricle S' wave velocity or usual diastolic measurements. Patients presented a significantly lower global GLS than controls (-16.6±3.6% vs. -18.7±1.8%, p=0.022). When comparing segmental longitudinal strain, no differences were found between patients and controls. In subjects with MD1, the presence of functional incapacity accessed by the mRS was associated with lower GLS: -15.7±3.3% in patients with some degree of clinical disability (mRS ≥ 1) vs. -18.8±3.1% in those with no muscular symptoms (mRs 0), p=0.046. Furthermore, in sinus rhythm patients, GLS correlated with the duration of PR interval (r=0.52, p=0.017), meaning that patients with absolute lower (worse) GLS presented more delayed atrioventricular conduction. No correlation was found between GLS an QRS duration. Conclusions: Global longitudinal strain is reduced MD1 patients and it seems to correlate with functional disability and electrical involvement. These results might represent a new marker of early and occult cardiac dysfunction in this population.

Myocardial scars correlate with eletrocardiographic changes in chronic Trypanosoma cruzi infection for dogs treated with Benznidazole

The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz-resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. All infected dogs had a high intensity of heart fibrosis (4616.00 ± 1715.82 collagen/74931 μm(2) in dogs infected with Berenice-78 strain, 5839.2 ± 1423.49 collagen/74931 μm(2) in infected by AAS and 6294.40 ± 896.04 collagen/74931 μm(2) in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 ± 607.13 collagen/74931 μm(2) ) and Bz-resistant AAS strains (4024 ± 1272.44 collagen/74931 μm(2) ), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 ± 1596.35 collagen/74931 μm(2) ) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated.

Prospective Cohort Study of Lead Exposure and Electrocardiographic Conduction Disturbances in the Department of Veterans Affairs Normative Aging Study

Background: No studies have examined the association between cumulative low-level lead exposure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points.Objective: We prospectively examined the association between lead exposure and the development of electrocardiographic conduction abnormalities.Methods: We assessed blood lead, bone lead—a biomarker of cumulative lead exposure—measured with K-shell X-ray fluorescence, and electrocardiographic end points among 600 men in the Normative Aging Study who were free of electrocardiographic abnormalities at the time of the baseline ECG. Of these men, we had follow-up data from a second electrocardiogram for 496 men 8.1 (SD = 3.1) years later, on average. We used repeated measures linear regression to analyze change in electrocardiographic conduction timing and logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for developing specific conduction disturbances and adjusted for potential confounders.Results: Mean (± SD) blood (5.8 ± 3.6), patella bone (30.3 ± 17.7), and tibia bone (21.6 ± 12.0) lead concentrations were similar to those found in samples from the general U.S. population and much lower than those reported in occupationally exposed groups. Compared with those in the lowest tertile of tibia lead, those in the highest had a 7.94-ms (95% CI, 1.42–14.45) increase in heart rate–corrected QT (QTc) interval and a 5.94-ms increase in heart rate–corrected QRS (95% CI, 1.66–10.22) duration > 8 years. Those in the highest tertile of tibia lead also had increased odds of QT prolongation (QTc ≥ 440 msec; OR = 2.53; 95% CI, 1.22–5.25) and JT prolongation (heart rate–corrected JT > 360 msec; OR = 2.53; 95% CI, 0.93–6.91). Results were weaker for patella lead. No associations were identified with blood lead.Conclusions: This study suggests that low-level cumulative exposure to lead is associated with worse future cardiac conductivity in the ventricular myocardium, as reflected in QT interval characteristics.

Increased mortality with left ventricular systolic dysfunction and heart failure in adults with myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a neurologic disorder with known cardiac involvement, including left ventricular systolic dysfunction (LVSD), heart failure (HF), atrioventricular and intraventricular conduction system disease, and sudden death. We studied the prevalence of these conditions and associated findings in a large population with DM1. History, physical examination, genetic testing, and electrocardiography were performed on 406 patients with DM1, and cardiac imaging was performed on 180 (44.3%) of these patients. Left ventricular systolic dysfunction and clinical HF were found in 34 (18.9%) of 180 and in 23 (5.7%) of 406 of enrolled subjects, respectively, yielding an overall prevalence of LVSD/HF in 41 (10.1%) of 406. Increasing age, male sex, electrocardiographic conduction abnormalities, presence of atrial and ventricular arrhythmias, and implanted devices were all significantly associated with LVSD/HF, whereas cytosine-thiamine-guanine repeat length and neuromuscular severity score were not. The interval≥240 milliseconds (relative risk 4.1, 95% CI 1.7-9.6, P=.001) and QRS duration≥120 milliseconds (relative risk 4.2, 95% CI 2.0-8.5, P<.001) were significant predictors of LVSD/HF. The presence of LVSD/HF was also significantly associated with all-cause death (relative risk 3.9, 95% CI 2.3-6.4, P<.001) and cardiac death (relative risk 5.7, 95% CI 2.6-12.4, P<.001). A significant prevalence of LVSD/HF exists in patients with DM1. The presence of LVSD/HF in DM1 is significantly associated with all-cause and cardiac death.

Molecular and clinical analysis ofRAF1in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation

Noonan syndrome (NS) and related disorders are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. The dysregulation of the RAS/MAPK pathway appears to be a common molecular pathogenesis of these disorders: mutations in PTPN11, KRAS, and SOS1 have been identified in patients with NS, those in KRAS, BRAF, MAP2K1, and MAP2K2 in patients with CFC syndrome, and those in HRAS mutations in Costello syndrome patients. Recently, mutations in RAF1 have been also identified in patients with NS and two patients with LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In the current study, we identified eight RAF1 mutations in 18 of 119 patients with NS and related conditions without mutations in known genes. We summarized clinical manifestations in patients with RAF1 mutations as well as those in NS patients withPTPN11, SOS1, or KRAS mutations previously reported. Hypertrophic cardiomyopathy and short stature were found to be more frequently observed in patients with RAF1 mutations. Mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (serine at position 259; S259). Functional studies revealed that the RAF1 mutants located in the CR2 domain resulted in the decreased phosphorylation of S259, and that mutant RAF1 then dissociated from 14-3-3, leading to a partial ERK activation. Our results suggest that the dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well as of downstream ERK.

Effect of insulin infusion on electrocardiographic findings following acute myocardial infarction: importance of glycaemic control

To determine the effects of insulin infusion and blood glucose levels during acute myocardial infarction (AMI) on electrocardiographic (ECG) features of myocardial electrical activity. ECGs at admission and 24 h were examined in a randomized study of insulin infusion vs. routine care for AMI patients with diabetes or hyperglycaemia. Results were analysed according to treatment allocation and also according to average blood glucose level. ECG characteristics were similar at admission in both groups. Patients allocated to conventional treatment had prolongation of the QT interval (QTc) after 24 h but those receiving infused insulin did not. In patients with a mean blood glucose in the first 24 h > 8.0 mmol/l, new ECG conduction abnormalities were significantly more common than in patients with mean blood glucose <or= 8.0 mmol/l (15.0% vs. 6.0%, P < 0.05). Prevention of QTc prolongation by administration of insulin may reflect a protective effect on metabolic and electrical activity in threatened myocardial tissue. Abnormalities of cardiac electrical conduction may also be influenced by blood glucose.

The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders

The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).

A Novel A461S Mutation of PTPN11 in a Female with LEOPARD Syndrome

LEOPARD syndrome (LS) is a congenital developmental disorder and is an acronym for multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness (1). These clinical features overlap those of Noonan syndrome (NS), and heterozygous germline PTPN11 mutations have been identified in approximately 45% of NS patients and in >80% of LS patients (1). Herein, we report a novel mutation of PTPN11 in a female with LS.

Non-Invasive Detection of Latent Cardiac Conduction Abnormalities in Patients With Pulmonary Sarcoidosis Application of Signal Averaged Electrocardiogram

Electrocardiographic conduction abnormalities including development of atrioventricular block, bundle branch block or ventricular arrhythmias are characteristic manifestations of cardiac sarcoidosis (CS). The present study seeks to show the minute conduction abnormality by detection of late potentials (LP) on signal averaged electrocardiogram (SAECG). Ten patients with CS, 52 patients with pulmonary sarcoidosis (PS) but no obvious cardiac manifestations and 52 normal controls were studied. All participants underwent SAECG to detect LP. In patients with CS (the CS group), LP were detected in 8 patients (80%). In 52 patients with PS, LP were detected in 25 patients (46.2%, PS-LP(+) group), comparing only 3 (5.8%) of normal controls (p<0.0001). The remaining 27 patients with PS with negative LP were classified in the PS-LP(-) group. In the CS group, premature ventricular contraction frequency on Holter's monitoring and plasma B-type natriuretic peptide concentrations were significantly higher than those in the PS group. However, no significant difference in these parameters between PS-LP(+) and PS-LP(-) groups were found. In the PS patients without obvious cardiac manifestations, LP were detected as high as 46.2%, suggesting latent minute conduction abnormality. The higher incidence of LP in PS might be considered as an expression of latent myocardial fibrosis. Close follow-up is needed in these patients.

LEOPARD syndrome: Clinical diagnosis in the first year of life

LEOPARD syndrome (LS) is an autosomal dominant syndrome characterized by multiple lentigines and café-au-lait spots, electrocardiographic-conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormalities of the genitalia in males, retardation of growth, and deafness. LS shares many features with Noonan syndrome (NS), in which lentigines and deafness are usually not present. Molecular studies have shown that LS and NS are allelic disorders, caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q22-qter. The clinical diagnosis of LS is generally difficult in the first months of life because the distinctive lentigines are generally not present at birth and develop during childhood. From January 2002 to December 2004, we suspected LS clinically in 10 patients admitted to our genetic counseling services in the first 12 months of life. A PTPN11 gene mutation was detected in 8/10 (80%) patients. In one patient without a PTPN11 mutation a subsequent clinical diagnosis of neurofibromatosis type 1 (NF1) was made, following the evaluation of the mother, who had previously undiagnosed classic NF1. The age of LS patients with PTPN11 mutation ranged between 1 and 11 months (mean age +/- SD 7.5 +/- 3.96 months). Review of the clinical characteristics of patients with LS confirmed by molecular study during the first year of life demonstrates that the diagnosis of LS in the first months of age can be clinically suspected in patients presenting with three main features, that is, characteristic facial features (100%), hypertrophic cardiomyopathy (HCM) (87%), and cafe-au-lait spots (75%). Characteristic facial features can be mild or severe, and consist of hypertelorism, downslanting palpebral fissures, ptosis, and dysmorphic ears. The clinical suspicion of LS may be confirmed by molecular screening for PTPN11 mutations. An early diagnosis of the disease is useful for the prospective care of associated medical problems and for precise genetic counseling.

Acute Myelomonocytic Leukemia in a Boy With LEOPARD Syndrome (PTPN11 Gene Mutation Positive)

The LEOPARD syndrome is a complex of multisystemic congenital abnormalities characterized by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (sensorineural). Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q24.1, have been identified in 88% of patients with LEOPARD syndrome. A missense mutation (836-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in this patient and his mother with LEOPARD syndrome. This mutation is one of the two recurrent mutations most often associated with the syndrome. Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4).

Anomalies cardiaques au cours de la dystrophie myotonique de Steinert

Cardiac involvement is described as one of the most frequent multisystemic manifestations of Steinert myotonic dystrophy (DM1). This study was performed to determine the frequency of cardiac abnormalities in Steinert myotonic dystrophy and to decipher the correlation between the severity of cardiac involvement and the degree of neurologic deficit. Thirty-four DM1 patients 23 men and 11 women, aged 13-61 years (mean 37.3+/-13.2 years) underwent neurological and cardiac evaluations. According to the MDRS scale, 32.5 percent were classified in the second stage, 23 percent in stage 3; 32.5 percent in stage 4 and 12 percent in stage 5. There was a positive correlation between neurological symptoms duration and the MRDS scale. Cardiac involvement was detected in 77.4 percent of patients. Electrocardiographic conduction abnormalities were the most frequent, represented by first-degree atrioventicular block in 64 percent of patients and bundle-branch block in 32 percent. From 5 patients having an invasive electrophysiology testing, subhisien block was observed in 3 patients. We respectively found alterations in systolic and diastolic left ventricular function in 22 percent and 30 percent of patients and a cardiac pacemaker was implanted in 3 patients. The frequency of cardiac manifestations was correlated to the degree of the neurological involvement assisted by MDRS scale, but it seam that the severity of cardiac abnormalities is not correlated to the degree of neurological deficit. We recommend that patients with DM1 undergo 24-h electrocardiogram monitoring and echocardiography at least yearly. Long-term prospective follow-up is required to determine the prognostic value of the observed abnormalities.

Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11

LEOPARD syndrome (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) is an autosomal dominant condition. The main clinical features include multiple lentigines, cardiovascular defects, and facial anomalies, some of which are shared with Noonan syndrome (NS). Recent reports have shown that LEOPARD syndrome can be caused by mutations in PTPN11, the gene in which mutations can produce NS. Here we report the findings of mutation screening and linkage analysis of PTPN11 in three families with LEOPARD syndrome. We identified a novel mutation in one family. The mutation (1529A>C) substitutes proline for glutamine at amino acid 510 (Gln510Pro). No variations in sequence were observed in the other two families, and negative LOD scores excluded linkage to the PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.

Prevalence of electrocardiographic conduction abnormalities among 475 patients with ejection fraction ≤0.35 and congestive heart failure

Prevalence of electrocardiographic conduction abnormalities among 475 patients with ejection fraction ≤0.35 and congestive heart failure

Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 Gene

Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and café au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple café au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS.

Intraventricular conduction delay and functional mitral regurgitation

Despite recent improvements in medical management of advanced congestive heart failure, morbidity and mortality rates remain high. New nonpharmacologic therapies of congestive heart failure including biventricular pacing are being actively explored. Several studies have investigated the role of biventricular pacing in patients with congestive heart failure. Preliminary data indicate that biventricular pacing improves hemodynamics, exercise duration, functional class, and quality of life. 1 Saxon L.A Boehmer J.P Hummel J Kacet S De Marco T Naccarelli G Daoud E Biventricular pacing in patients with congestive heart failure two prospective randomized trials. Am J Cardiol. 1999; 83: 120D-123D Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar , 2 Auricchio A Stellbrink C Sack S Block M Vogt J Bakker P Mortensen P Klein H The pacing therapies for congestive heart failure (PATH -CHF) study rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol. 1999; 83: 130D-135D Abstract Full Text Full Text PDF PubMed Google Scholar , 3 Cazeau S Ritter P Bacdach S Lazarus A Limousin N Henao N Mundler O Dauber J.C Mugica J Four-chamber pacing in dilated cardiomyopathy. PACE. 1994; 17: 1974-1979 Crossref Scopus (386) Google Scholar , 4 Auricchio A Salo R.W Acute hemodynamic improvement by pacing in patients with severe congestive heart failure. PACE. 1997; 20: 313-324 Crossref Scopus (90) Google Scholar , 5 Bakker P Sen K.C.A de Jonge N Klopping C Algra A Robles de Medina E Bredee J Biventricular pacing improves functional capacity in patients with end-stage congestive heart failure. PACE. 1995; 18 (abstr): 825 Google Scholar It has been proposed that the mechanisms of benefit of biventricular pacing are resynchronization of left ventricular function and amelioration of mitral regurgitation (MR). If biventricular pacing improves functional MR via shortening of the QRS duration, we hypothesized that intraventricular delay could be a determinant of functional MR. To test this hypothesis, we correlated Doppler echocardiographic parameters with electrocardiographic conduction abnormalities in a retrospective analysis.