Mild Dilated Cardiomyopathy Research Articles

Cardiovascular magnetic resonance to differentiate veteran athlete's heart with cavity dilatation and mild dilated cardiomyopathy

Abstract Introduction Endurance athletic training may lead to left ventricular (LV) dilatation and mildly reduced resting LV function which can be difficult to differentiate from dilated cardiomyopathy (DCM). Myocardial fibrosis is increasingly recognised in lifelong athletes and is also prevalent in DCM where it confers adverse prognosis.(1,2) However, it is unknown whether the pattern and prevalence of fibrosis in athletes with cavity dilatation differs from DCM. In this study, we compared the CMR fibrosis distribution and tissue characteristics between athletic LV dilatation and mild DCM patients. Methods We prospectively recruited 113 males; 64 endurance athletes and 49 mild DCM patients. Inclusion criteria Age 50-80 years, LVEF 45-54% and LV end-diastolic volume indexed to body surface area (LVEDVi)≥110ml/m2. Athletes trained≥10 weekly hrs for≥15 yrs. Exclusion criteria; Chest pain, prior coronary revascularisation, severe valvular disease, myocarditis, hypertrophic cardiomyopathy, inducible ischaemia or myocardial infarction on CMR. CMR protocol included volumetric assessment, T1 mapping, quantitative stress perfusion and quantitative late gadolinium enhancement. Statistical analysis between groups was performed using unpaired t-test and receiver-operator curve (ROC) analysis. Results LVEDVi was not significantly different between athletes and mild DCM patients (123.3±12.6 vs 129.8±23.1ml/m2, P=0.057). However, LVEF (52.0±6.1 vs 47.6±5.2%, P<0.001) and right ventricular (RV) EDVi (121.0±14.3 vs 97.6±25.2ml/m2, P<0.001) were both greater in athletes. There was no difference in non-ischaemic fibrosis prevalence between both groups (50.0 vs 49.0%, P=0.915) nor the burden of fibrosis (3.5±2.9 vs 7.4±12.0g, P=0.087). However, the distribution of fibrosis varied with a significantly greater prevalence of basal mid-myocardial inferolateral fibrosis amongst athletes (87.5 vs 50.0%, P=0.002) whereas basal mid-myocardial inferoseptal fibrosis was significantly more common in mild DCM (45.8 vs 9.4%, P=0.002). Native T1 (1249.0±38.1 vs 1308.3±47.1ms, P<0.001) and extracellular volume (ECV) (22.0±2.1 vs 25.9±3.5%, P<0.001) were both lower in athletes than mild DCM patients. Furthermore, athletes had higher myocardial perfusion reserve (MPR) (3.65±1.30 vs 2.76±0.92, P<0.001) and stress myocardial blood flow (MBF) (2.09±0.70 vs 1.62±0.66, P<0.001). On ROC analysis, native T1 (area under curve (AUC) 0.89, P<0.001), ECV (AUC 0.85, P<0.001) and stress MBF (AUC 0.68, P<0.001) were able to differentiate athletes and mild DCM. Native T1 and ECV were significantly better at discriminating than MPR (P<0.001). Conclusion Myocardial fibrosis was highly prevalent in both veteran endurance athlete's heart and mild DCM whilst its distribution was distinctive between the groups. Native T1 and ECV were the best discriminators. Recognition of fibrosis patterns and associated tissue characteristics may be clinically useful to differentiate these two overlapping phenotypes.Figure 1; LGE distribution in athletes cFigure 2; CMR tissue characteristics to

Abstract We147: The Utility of Cardiopulmonary Exercise Testing (CPET) Amongst Male and Female athletes to Differentiate Between Physiological Left Ventricular Enlargement and Mildly Depressed Resting Systolic Function and Athletic Individuals with Dilated Cardiomyopathy.

Background: Athletes frequently reveal a dilated left ventricle (LV),some also demonstrate a co-existent mildly depressed LV ejection fraction, raising the possibility of mild dilated cardiomyopathy (DCM). The maximal oxygen consumption(VO2max) is a valuable tool for assessing fitness, largely determined by cardiac output. References ranges derived from the general population, may have limitations when assessing athletes with primary myocardial disease. This study investigated the role of VO2max and VO2max predicted (V02pred) to differentiate between physiological LV dilatation and athletic individuals with DCM in male and female athletes. Methods: 147 male and 35 female athletes with dilated LV(mean age 35.4years, 34.5 years respectively) underwent a 25watt cycle ergometer continuous ramp protocol. 75% males and 67% females participated in endurance sports, remaining participating in mixed sports. 52 had mild DCM, 62 defined as healthy control athletes(dilated LV) and 68 were Grey zone (dilated LV and mildly depressed LVEF) Results: DCM males (N=39) revealed a lower mean VO2max than male control (N=46), 34.9ml/kg/min and 48ml/kg/min respectively (p value <0.001). DCM females(N=13) showed lower VO2max of 29.9ml/min/kg than female control (N=16) who revealed similar values to male controls (48 ml/kg/min)(p value <0.001). 62 male Grey zones and 6 female Grey zone revealed lower VO2max than controls 43.1ml/min/kg and 34.1ml/min/kg respectively. DCM females had lower VO2pred than control females 119% and 161% respectively but significantly higher than their male counterparts, means of 106% and 123% respectively (p value <0.001). Male and female grey zones had lower mean VO2pred than controls, 121% and 106% respectively. Higher VO2max of ≥38ml/kg/min and VO2pred of ≥120% gave a sensitivity, specificity of 84.7% and 77%respectively to differentiate healthy athletes and athletic DCMs in males and females. Only41.1% Grey zone athletes were able to achieve above these thresholds. Conclusion: Female athletes with dilated LV may reveal supranormal VO2max which can equal their male counterparts. Furthermore, athletic females with physiological or pathological LV dilatation can reveal higher VO2pred than male athletes. Most athletic DCM individuals show lower CPET parameters than controls athletes but can still achieve greater than normal measurements seen in healthy general population. VO2 may have a role in assisting in differentiating healthy athletes from athletic DCM.

Sudden Death in Pediatric Patient With Dilated Cardiomyopathy Due to Founder Variant in NKX2-5: Case Report.

Background: The NKX2-5 gene encodes a transcription factor that plays a role in atrioventricular nodal and myocardial development. Pathogenic variants of NKX2-5 are associated with congenital heart disease and sudden cardiac death. The missense variant in this case is one of the more common ones in Northern Europe and has high penetrance in familial cases. To our knowledge, this is the youngest person who died due to this variant. Case summary: This was a healthy, asymptomatic 14-year-old male with well-managed mild congenital dilated cardiomyopathy who died unexpectedly in his home. Postmortem examination revealed the NKX2-5 pathogenic missense variant, p.Phe145Leu, as the only explicable cause of death. Discussion: We propose that immediate family members of those who die suddenly due to NKX2-5 disease undergo genetic counseling and longitudinal screening to include this gene, as pathogenic variants in the NKX2-5 gene may manifest in a time-dependent manner.

Therapeutic potential of living donor liver transplantation from heterozygous carrier donors in children with propionic acidemia

BackgroundCurrent world experience regarding living donor liver transplantation (LDLT) in the treatment of propionic acidemia (PA) is limited, especially in terms of using obligate heterozygous carriers as donors. This study aimed to evaluate the clinical outcomes of LDLT in children with PA.MethodsFrom November 2017 to January 2020, 7 of the 192 children who underwent LDLT at our institution had been diagnosed with PA (median age, 2.1 years; range, 1.1–5.8 years). The primary indication for transplantation was frequent metabolic decompensations in 6 patients and preventative treatment in 1 patient. Of the seven parental living donors, six were genetically proven obligate heterozygous carriers.ResultsDuring a median follow-up of 23.9 months (range, 13.9–40.2 months), all patients were alive with 100% allograft survival, and no severe transplant-related complications occurred. In the case of liberalized protein intake, they did not suffer metabolic decompensation or disease-related complications and made progress in neurodevelopmental delay and body growth, as well as blood and urinary metabolite levels. In one patient with pre-existing mild dilated cardiomyopathy, her echocardiogram results completely normalized 13.8 months post-transplant. All living donors recovered well after surgery, with no metabolic decompensations or procedure-related complications. Western blotting revealed that the hepatic expressions of PCCA and PCCB in one of the heterozygous donors were comparable to those of the normal healthy control at the protein level.ConclusionsLDLT using partial liver grafts from asymptomatic obligate heterozygous carrier donors is a viable therapeutic option for selected PA patients, with no negative impact on donors’ and recipients' clinical courses.

N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue.

We investigated N471D WASH complex subunit strumpellin (Washc5) knock-in and Washc5 knock-out mice as models for hereditary spastic paraplegia type 8 (SPG8). We generated heterozygous and homozygous N471D Washc5 knock-in mice and subjected them to a comprehensive clinical, morphological and laboratory parameter screen, and gait analyses. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous Washc5 knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting. Homozygous N471D Washc5 knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline phosphatase and potassium levels and increased white blood cell counts. Gait analyses revealed multiple aberrations indicative of locomotor instability. Similarly, the clinical chemistry, haematology and gait parameters of heterozygous mice also deviated from the values expected for healthy animals, albeit to a lesser extent. Proteomic analysis of brain tissue depicted consistent upregulation of BPTF and downregulation of KLHL11 in heterozygous and homozygous knock-in mice. WASHC5-related protein interaction partners and complexes showed no change in abundancies. Heterozygous Washc5 knock-out mice showing normal WASHC5 levels could not be bred to homozygosity. While biallelic ablation of Washc5 was prenatally lethal, expression of N471D mutated WASHC5 led to several mild clinical and laboratory parameter abnormalities, but not to a typical SPG8 phenotype. The consistent upregulation of BPTF and downregulation of KLHL11 suggest mechanistic links between the expression of N471D mutated WASHC5 and the roles of both proteins in neurodegeneration and protein quality control, respectively.

Heartbeat: Early cardiomyopathy or physiological left ventricular dilation in athletes?

Athletic physical conditioning results in changes in cardiac anatomy and function that make it challenging to distinguish normal physiological changes from a pathological process in athletes with left ventricular (LV) dilation or a reduced ejection fraction. Millar and colleagues1 propose an approach for identifying athletes with dilated cardiomyopathy (DCM) based on sequential evaluation using N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement, resting ECG, ambulatory ECG monitoring, exercise echocardiography and cardiac magnetic resonance (CMR) imaging. In 25 male athletes with LV dilation and an ejection fraction 11% compared with baseline on exercise echocardiography had the highest sensitivity, with a high specificity, for prediction of DCM. (figure 1) Figure 1 The figure demonstrates the utility of the stepwise clinical algorithm for differentiating between physiological adaptation and morphologically mild DCM in apparently healthy individuals with LV dilatation and LVEF <55%. The number and percentages of both cohorts with abnormal investigations is shown with the cumulative TN and TP results on the extreme right and left, respectively. The overall sensitivity of the algorithm is 94.1% with a specificity of 83.3%. The PPV is 90.3% with an NPV of …

582 Clinical and Genetic Characterisation of Long QT Syndrome in Indigenous Australians

There is little data on the clinical and genetic characteristics of long QT syndrome (LQTS) in Indigenous Australians. Here, three Indigenous Australian patients from Central Australia with LQTS are described. Patient 1 is a 38-year-old female who presented feeling generally unwell, with a background of alcohol abuse. No electrolyte abnormalities were detected. Her QTc measurements were 580–625ms. Genetic testing subsequently revealed heterogenicity for a likely pathogenetic variant in KCNQ1, c.1018T>C p.Phe340Leu. Patient 2 is a 21-year-old female who presented with loss of consciousness following seizure-like activity, with a background of suspected seizures and alcohol abuse. QTc remained intermittently above 500ms despite electrolyte correction. On monitoring, she developed torsades de pointes. Echocardiogram showed a mild dilated cardiomyopathy thought to be alcoholic in aetiology. Genetic testing revealed a variant of uncertain significance in ANK2. Patient 3 is a 39-year-old female who presented with a second episode of polymorphic ventricular tachycardia following excess alcohol consumption, with a background of mild rheumatic valvular disease and alcohol abuse. No family history was suggestive of LQTS. QTc remained elevated above 500ms despite electrolyte correction. Genetic testing is pending. All 3 patients received an implantable cardioverter-defibrillator without complications. This series on LQTS adds significantly to the paucity of data on arrhythmic disorders in Indigenous Australians and highlights the potential importance of exacerbating factors in this population.

002 Sudden cardiac death risk stratification in patients with mild dilated cardiomyopathy

Background The DANISH trial emphasised that the selection of patients with dilated cardiomyopathy (DCM) for implantable cardioverter defibrillators (ICD) needs to be improved. Registries demonstrate that the major burden of sudden cardiac death (SCD) occurs in those with a left ventricular ejection fraction (LVEF) >35%. Those at high-risk of SCD with milder reductions in LVEF may gain greater quality-adjusted life years from successful ICD therapy compared to those with more severe reductions, due to a lower risk of death from competing non-sudden causes. Variables that identify patients with milder reductions in LVEF at high-risk of SCD are required. Methods We prospectively investigated the utility of mid-wall late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to predict SCD and aborted SCD in consecutive patients with DCM and LVEF >40% seen in our cardiomyopathy service or referred for CMR between 2000 and 2011. Those with potential pre-existing indications for ICD implantation were excluded. The presence of LGE was determined by a specialist blinded to clinical data. A panel blinded to CMR data adjudicated end-point occurrences. Results Of 399 patients (145 women, median age 50 years, median LVEF 50%) followed for a median of 4.6 years, 18 of 101 (17.8%) with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9–21.8; p 5% compared to those without LGE were 10.6 (95%CI 3.9–29.4), 4.9 (95% CI 1.3–18.9) and 11.8 (95% CI 4.3–32.3). Conclusion Mid-wall LGE identifies patients with DCM and a LVEF >40% with an 8-fold increased risk of SCD and aborted SCD, who may benefit from ICD implantation. Acknowledgements BPH is supported by a British Heart Foundation Clinical Research Training Fellowship. The study has also been supported by the Alexander Jansons Foundation and CORDA.

Dynamics of cerebral blood flow in patients with mild non-ischaemic heart failure.

Heart failure (HF) is associated with tissue hypoperfusion and congestion leading to organ dysfunction. Although cerebral blood flow (CBF) is preserved over a wide range of perfusion pressures in healthy subjects, it is impaired in end-stage HF. We aimed to compare CBF, autoregulation, and cognitive function in patients with mild non-ischaemic HF with healthy controls. Fifteen patients with mild idiopathic dilated cardiomyopathy and 15 matched healthy controls were studied. Co-existing cerebrovascular disease was excluded. All subjects, except five patients with an implantable cardioverter defibrillator, underwent magnetic resonance imaging for measurements of both CBF by arterial spin labelling and quantitative volume flow entering the brain. Cardiocerebral vascular function was assessed with Doppler techniques testing cerebral dynamic autoregulation and vasomotor reactivity. Cognitive analysis was performed by neuropsychological testing. Global and regional CBF did not differ between HF patients (44.3 mL/100 g.min) and controls (42.1 mL/100 g.min). Basilar but not carotid artery inflow was reduced in patients (1.95 mL/s vs. 2.51 mL/s, P = 0.009). Testing autoregulation revealed fewer dampened blood flow fluctuations in HF patients vs. controls (0.96% vs. 0.67%, P < 0.001). Vasomotor reactivity in HF patients showed a reduced CBF velocity (48.4% vs. 61.0%, P = 0.05) and regional cerebral oxygen saturation (18.3% vs. 23.8%, P = 0.02). Cognitive function overall was not affected. Although global CBF was unaffected in patients with mild HF, significant changes in basilar inflow volume, cerebral autoregulation and vasomotor reactivity were observed. We describe a model of dynamic cerebral mechanisms required to compensate for the impaired haemodynamics in early-stage HF.

Potential genetic predisposition for anthracycline-associated cardiomyopathy in families with dilated cardiomyopathy

ObjectiveAnthracyclines are successfully used in cancer treatment, but their use is limited by their cardiotoxic side effects. Several risk factors for anthracycline-associated cardiomyopathy (AACM) are known, yet the occurrence of...

Cardiovascular magnetic resonance T2 mapping can detect myocardial edema in idiopathic dilated cardiomyopathy

Myocardial edema and inflammation play an important role in dilated cardiomyopathy (DCM). This pathologic condition can be identified noninvasively using cardiovascular magnetic resonance imaging (CMR). The purpose of this study was to determine the effectiveness of T2 values obtained with T2 mapping in the detection of edema in DCM patients, compared with that of conventional T2-weighted imaging (T2WI). CMR was used for 15 normal controls (NML) and 26 DCM patients. The DCM patients were classified as having either mild dysfunction with a left ventricular ejection fraction (EF) >35% or severe dysfunction with an EF ≤35%. Myocardial edema was assessed by both T2 mapping and T2WI. The differences between the T2 values determined from T2 mapping and the T2 ratios that were calculated from the T2WI were compared among the NML, mild DCM, and severe DCM patients. The T2 values for the NML, mild DCM, and severe DCM patients were 51.2 ± 1.6, 61.2 ± 0.37, and 67.4 ± 6.8, respectively (P < 0.05 for each pair), and the corresponding T2 ratios were 1.88 ± 0.09, 2.12 ± 0.37, and 2.04 ± 0.34, respectively (P > 0.05). T2 mapping clearly showed that the myocardial water content was larger in DCM patients than in NML controls and that the myocardial water content increased as the disease progressed. Thus, T2 mapping is a useful technique for the diagnosis and quantitation of diffuse myocardial edema.

Abstract 280: Deficiency of FKBP12 in the Heart Leads to Impaired Contractility and Pregnancy Induced Cardiomyopathy

FK506 Binding Proteins (FKBPs) are a family of cis-trans prolyl isomerases that bind rapamycin and FK506. FKBP12 and 12.6 interact with ryanodine receptors (RyR), homotetrameric transmembrane ion channels that regulate Ca2+ release from the sarcoplasmic reticulum (SR). FKBP12 interacts with RyR1 in skeletal muscle and FKBP12.6 interacts with RyR2 in cardiac muscle to regulate the Ca2+ leak properties of these channels. Recently it has been suggested that FKBP12 also plays a role in regulating RyR2 activity. Using mice with a cardiac specific deficiency in FKBP12, we analyzed the role of FKBP12 in cardiac function. We found that both male and female mice with a α-MyHC Cre/Lox mediated deficiency in FKBP12 in the heart (FKBP12 KD) developed a mild dilated cardiomyopathy, with enlarged left ventricular diameter both during systole and diastole, decreased ejection fraction and decreased fractional shortening. To elucidate the mechanism for these effects we assessed Ca2+ sparks in isolated cardiomyocytes. We found an increase in both Ca2+ spark frequency and spark amplitude in FKBP12 cardiac deficient mice without a change in spark duration. Despite a mild phenotype in adult mice, we found that approximately 25% of all pregnancies (26/106) in the FKBP12 deficient mice resulted in the mothers dying following the birth. Autopsies show that these cardiac specific FKBP12 deficient mice had increased heart weight and significantly dilated ventricles compared to female Cre mice. Our data suggest that a cardiac specific deficiency in FKBP12 leads to the development of pregnancy induced cardiomyopathy. Echocardiography on FKBP12 deficient mice one day after giving birth found that there was no significant difference in ejection fraction or fractional shortening compared to α-MyHC Cre control mice. FKBP12 deficient females, however, had larger hearts and 50% (2/4) displayed heart failure and died. In conclusion, we show that FKBP12 does indeed alter Ca2+ handling in the heart and that a loss of FKBP12 leads to the development of pregnancy induced cardiomyopathies in females.

POEMS Syndrome Presenting with Acute Demyelinating Polyneuropathy: Increased Terminal Latency Indices and Uniform Demyelination

We herein report a case of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome presenting with acute Guillain-Barré syndrome (GBS)-like features. The patient was healthy, except for mild dilated cardiomyopathy. She was unable to walk within ten days of the onset of weakness. A nerve conduction study (NCS) showed length-dependent, symmetric and non-focal demyelinating features with increased terminal latency indices (TLIs) in the lower limbs. Following the administration of intravenous immunoglobulin infusion, the proximal weakness of the lower extremities improved; however, the pleural effusion was aggravated and ascites newly developed. On further work-ups, splenomegaly, M-protein and sclerotic bone changes were observed. This case suggests that, although rare, POEMS syndrome can present with acute demyelinating polyneuropathy resembling GBS and that characteristic NCS features such as increased TLI and uniform demyelination are helpful for the early diagnosis of POEMS syndrome.

Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support

Myocarditis that develops because of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening disease. We report a case of DRESS-associated myocarditis with cardiac failure that required extracorporeal membrane oxygenation (ECMO) for cardiovascular support. A 14-year-old boy experienced DRESS-associated myocarditis after anticonvulsive therapy with carbamazepine, clonazepam and phenytoin. The clinical signs included hypotension, cardiac arrhythmia and poor left ventricular (LV) performance. Laboratory investigations showed elevated levels of cardiac enzymes. Systemic corticosteroid pulse therapy for 3days was administered for treating the DRESS syndrome. The patient required inotropic drugs including dopamine, dobutamine and milrinone because of refractory hypotension and poor LV function. He was placed on ECMO support, and intra-aortic balloon pumping was initiated because of poor response to inotropic drugs and stasis of blood flow in the ventricle on hospital day 17. Plasma exchanges for four separate times over 8days were also performed during ECMO support on day 22. His condition stabilized 13days after ECMO support was initiated. The patient was discharged on hospital day 50, and the seizure was controlled by the oral form clonazepam, phenobarbital, topiramate and levetiracetam. Three months later, an echocardiogram showed mild dilated cardiomyopathy. Drug reaction with eosinophilia and systemic symptoms-associated fulminant myocarditis is a life-threatening disease. Traditionally, systemic corticosteroid administration, plasmapheresis, intravenous immunoglobulin infusion and ventricular assist device implantation have been used for the treatment of this disease. To our knowledge, this is the first case of DRESS-associated fulminant myocarditis treated successfully with ECMO support. However, echocardiogram should be followed regularly because dilated cardiomyopathy may be the late sequela.

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.

Identification of a new lamin A/C mutation in a chinese family affected with atrioventricular block as the prominent phenotype

Even though mutations in LMNA have been reported in patients with typical dilated cardiomyopathy (DCM) and atrioventricular block (AVB) previously, the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval. Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2, where the LMNA gene was located. Direct DNA sequence analysis revealed a heterozygous G to A transition at nucleotide 244 in exon 1 of LMNA, which resulted in an E82K mutation. The E82K mutation co-segregated with all affected individuals in the family, and was not present in 200 normal controls. Further clinical evaluation of mutation carriers showed that 5 of 6 AVB patients exhibited mild DCM with a late onset of age in the fourth and fifth decades. Ejection fractions were documented in 5 patients with DCM, but 4 showed a normal value of > or = 50%. Echocardiography showed that atrial dilatation occurred earlier than ventricular dilatation in the patients. This study suggests that progressive AVB with normal QRS interval and accompanying DCM at later stages may represent a distinct type of DCM. The molecular mechanism by which the E82K mutation causes AVB as the prominent phenotype in DCM may be a focus of future studies.

A case of intraneural perineurioma presenting with monomelic atrophy in a child

We report the case of an 11-year-old girl who developed slowly progressive atrophy of the left lower extremity. She suffered from mild dilated cardiomyopathy of unknown cause since 4 years of age. When she was 7 years old, her family noticed that her left extremity was thinner compared to the right one. Computed tomography showed atrophy and areas of low density in the left gluteus maximus, thigh, and calf muscles. The left sciatic nerve showed gadolinium enhancement on magnetic resonance imaging. A biopsy of the left sural nerve revealed pseudo-onion bulbs. Immunohistochemical staining was positive for epithelial membrane antigen and negative for S100 protein. Electron microscopy demonstrated myelinated or unmyelinated nerve fibers surrounded by concentric layers of perineurial cells. These results indicated intraneural perineurioma. The tumor was estimated at least from the nerve root to the ankle joint. The length of nerve involvement in this patient was the highest recorded in the literatures. Intraneural perineurioma is a very rare disorder, but is tend to be found in youth. This disorder should be considered when we see children with monomelic weakness and/or atrophy.

A novel X‐linked form of congenital fiber‐type disproportion

We describe a four-generation family with a previously unreported form of congenital fiber-type disproportion that follows an X-linked inheritance pattern. Affected male family members have a striking pattern of weakness. From birth there is marked ptosis, facial weakness, poor sucking, hypotonia, respiratory weakness, and relatively preserved limb strength. Most affected male individuals die of respiratory failure within the first months of life. A mild dilated cardiomyopathy developed in infancy in the sole surviving affected male member of this family. Some carrier female individuals manifest milder signs. We have demonstrated linkage to two regions of the X chromosome, Xp22.13 to Xp11.4 and Xq13.1 to Xq22.1, with a maximum logarithm of odds score of 3.25 in the latter region. We propose that clinical clues can differentiate this disorder from other forms of congenital fiber-type disproportion so that affected families can receive appropriate genetic counseling.

Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: The Prospective P 2C 2 HIV Multicenter Study

Many HIV-infected children die with cardiac abnormalities. We sought to understand the course of these HIV-associated abnormalities and their impact on all-cause mortality. We describe longitudinal changes in left ventricular (LV) structure and function and mortality in 185 children vertically infected with HIV. Serial cardiac data were obtained from 0.1 to 10 years of age. Age- or body surface area-adjusted z scores were calculated for 10 echocardiographic outcomes. Median age at first echocardiogram was 2 years (range 0.2-9.4 years); median follow-up was 3.6 years (range 0-6.3 years). The 5-year cumulative incidence of congestive heart failure was 12.3%. Mean fractional shortening z scores declined from -0.65 at 1 year of age to -1.47 at 3 years of age without further decline between 3 and 10 years of age. Among children with 2 echocardiograms performed in the first year of follow-up, mild LV dysfunction (fractional shortening of < -2 SD on both echocardiograms) was present in 29 (18%) of 158 children. For these 29 children, the 5-year mortality was 55.4%. Left ventricular mass z scores were elevated at 1 year (mean z score 0.68, P < .001) and remained elevated throughout follow-up. In the 8 children with LV mass z score of > 2 SD on both initial and follow-up echocardiograms, the 5-year mortality was 75%. In HIV-infected children, LV structure and function progressively deteriorated in the first 3 years of life, resulting in subsequent persistent mild LV dysfunction and increased LV mass. Chronic mild depression of LV function and elevated LV mass were associated with higher all-cause mortality.

Suppressed enhancement of the force-frequency relation to adrenergic stimulation is an indicator of poor prognosis in patients with dilated cardiomyopathy

Objectives: To investigate the relation between the response of force-frequency relation (FFR) to adrenergic stimulation, and gene expression of Ca 2+-handlin proteins in patients with dilated cardiomyopathy (DCM). Methods and Results: We measured the maximum first derivative of left ventricular (LV) pressure (LV dP/dt max) during pacing and dobutamine infusion in 10 patients with mild DCM (NYHA I-II). Endomyocardial biopsy was performed, and mRNA levels of SR Ca 2+-ATPase(SERCA2a), ryanodine receptor-2, phospholamban (PLB), calsequestrin, and Na +/ Ca2 + exchanger were quantified by a real-time quantitative reverse transcription-polymerase chain reaction method. In 6 patients (group A), the increase in LV dP/dt max during dobutamine infusion was greater than pacing alone, whereas in 4 patients (group B), the increase in LV dP/dt max during dobutamine infusion was significantly attenuated compaired with group A. The ratio of SERCA2a to PLB mRNA expression was significantly higher in group B than group A. In group B, one patient has died, and two has hospitalized for congestive heart failure during follow-up period (25 ± 18months). Conversely, there were no death and hospitalization in group A. Conclusions: In this study, the LV contractile reserve to adrenergic stimulation was impaired in some patients with mild DCM, and those showed poor prognosis, although the ratio of SERCA2a to PLB mRNA expression was in normal range.