Mild Cardiomyopathy Research Articles

Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism and Progression of Chagas’ Cardiomyopathy

Chagas' disease is common in Latin America and is caused by Trypanosoma cruzi. It is usually associated with chronic cardiomyopathy, the progression of which could be related to genetic factors. As alterations in the renin-angiotensin-aldosterone system have been reported in the disease, the aim of this study was to determine whether associated genetic polymorphisms influence the development of myocardial damage. The study involved 125 patients who were divided into two groups according to whether they had mild or severe cardiomyopathy. The insertion/deletion polymorphism of the angiotensin-converting enzyme gene was investigated using standard techniques and results were correlated with disease stage. The genotypes were in Hardy-Weinberg equilibrium. After adjusting for demographic variables, no significant relationship was found between the polymorphism and progression of chronic Chagas' disease. Although our sample was limited, the results suggest that the progression of cardiomyopathy in chronic Chagas' disease is unrelated to the insertion/deletion polymorphism.

Chemotherapy Induced Cardiomyopathy: Pathogenesis, Monitoring and Management

The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side effects associated with the intensive anticancer treatment. The most common adverse effect is cardiotoxicity which may compromise the clinical effectiveness of chemotherapy, affecting the patient's survival and quality of life independently of the oncological prognosis. There are 2 types of cardiac toxicities, type I which is more serious and result in permanent damage to the myocardium and type II which is usually reversible. Chemotherapies varies in their incidence of inducing cardiomyopathy, and the onset which may occur acutely (during or shortly after treatment), sub-acutely (within days or weeks after completion of chemotherapy) or chronically (weeks to months after drug administration). Cardiac events associated with chemotherapy may consist of mild blood pressure changes, thrombosis, Electrocardiographic (ECG) changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure), and congestive heart failure (CHF). The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Serial measurements of LVEF and fractional shortening are the most common indices monitored to assess left ventricular systolic function and cardiotoxicity. This can be achieved by 2-dimensional, M-mode and color Doppler echocardiographic examination; also Cardiac troponins as a biological marker for myocardial damage can be used for monitoring in patients received anthracyclines. Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have been shown to slow the progression of left ventricular dysfunction in several different clinical settings, including anthracycline-induced cardiomyopathy. Carvedilol and probably with anti-oxidants like Probucol and vitamin E benefits also.KeywordsAnthracyclines; Cardiomyopathy; Chemotherapy

Playing Hide and Seek with Adenosine Receptors

Playing Hide and Seek with Adenosine Receptors

Cardiac evaluation in children and adults with Pompe disease sharing the common c.−32-13T>G genotype rarely reveals abnormalities

Background and objectivePompe disease is an inherited metabolic disorder caused by deficiency of acid α-glucosidase. All affected neonates have a severe hypertrophic cardiomyopathy, leading to cardiac failure and death within the first year of life. We investigated the presence and extent of cardiac involvement in children and adults with Pompe disease with the common c.−32-13T>G genotype to determine the usefulness of cardiac screening in these patients with relatively ‘milder’ phenotypes. MethodsCardiac dimensions and function were evaluated through echocardiography, electrocardiography and Holter monitoring. The total group comprised 68 patients with Pompe disease, of whom 22 patients had disease onset before the age of 18. ResultsTwo patients (3%) had cardiac abnormalities possibly related to Pompe disease: Electrocardiography showed a Wolff–Parkinson–White pattern in an 8-year-old girl, and one severely affected adult patient had a mild hypertrophic cardiomyopathy. This hypertrophy did not change during treatment with recombinant human α-glucosidase. In addition, four adult patients showed minor cardiac abnormalities which did not exceed the prevalence in the general population and were attributed to advanced age, hypertension or pre-existing cardiac pathology unrelated to Pompe disease. ConclusionsCardiac involvement is rare in Pompe patients with the common c.−32-13T>G genotype. The younger patients were not more frequently affected than the adults. Electrocardiographic evaluation appears to be appropriate as initial screening tool. Extensive cardiac screening seems indicated only if the electrocardiogram is abnormal or the patient has a history of cardiac disease.

NEW SKELETAL MYOPATHY AND CARDIOMYOPATHY ASSOCIATED WITH A MISSENSE MUTATION IN MYH7

MYH7 encodes slow/β-cardiac myosin heavy chain (MyHC), which is expressed in type 1 fibers of skeletal muscle and in the heart. Pathogenic mutations in MYH7 are common causes of familial hypertrophic cardiomyopathy (FHCM, OMIM 160760) and dilated cardiomyopathy (FDCM, OMIM 160760). These mutations are most frequently located in the globular head of MyHC I but also in the rod. Some mutations in the distal rod region of MyHC 1 cause myosin storage myopathy (OMIM 608358),1 and some mutations in the middle and proximal rod region of MyHC 1 cause Laing early-onset distal myopathy (MPD1, OMIM 160500).2,3 These myopathies are usually not associated with cardiomyopathy. Here we report a mutation in the globular head of slow/β-cardiac myosin associated with distal myopathy and mild cardiomyopathy. See appendix E-1 on the Neurology Web site at www.neurology.org. This boy is the only child of Tanzanian immigrants. The father is healthy. According to the father, the mother has had no obvious muscle weakness, but a maternal aunt in Tanzania has distal muscle …

Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN –42 C>G mutation

Phospholamban is an endogenous sarcoplasmic reticulum calcium ATPase inhibitor with a regulatory effect on cardiac contraction/relaxation coupling. Mutations in the phospholamban gene (PLN) have been associated with primary cardiomyopathies. To screen for PLN mutations in our population of patients with primary cardiomyopathies and to perform functional analysis of the mutations identified. We performed SSCP mutational screening and DNA sequencing of the PLN gene in 186 patients with either hypertrophic or dilated cardiomyopathy. To study promoter strength we constructed reporter plasmids containing the luciferase gene and performed transient transfection analysis in C6 and C2C12 cell lines. The PLN -42 C>G mutation was found in one patient with late onset familial apical hypertrophic cardiomyopathy. This mutation decreased phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines respectively. One son had mild apical hypertrophic cardiomyopathy and carried the mutation, another son with normal ECG and echocardiogram also had the mutation. The PLN -42 C>G mutation is associated with a benign form of apical hypertrophic cardiomyopathy in this family, though the presence of a healthy adult carrier suggests that other genetic and environmental factors could be involved. Otherwise, mutations in the PLN gene are not a frequent cause of cardiomyopathies in our population.

Prognostic value of intra-left ventricular electromechanical asynchrony in patients with mild hypertrophic cardiomyopathy compared with power athletes

Prognostic value of intra-left ventricular electromechanical asynchrony in patients with mild hypertrophic cardiomyopathy compared with power athletes

Regulated Overexpression of the A 1 -Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function

Both the A1- and A3-adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A1-AR and A3-AR is associated with changes in the cardiac phenotype. To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A1-AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter. Constitutive A1-AR overexpression caused the development of cardiac dilatation and death within 6 to 12 weeks. These mice developed diminished ventricular function and decreased heart rate. In contrast, when A1-AR expression was delayed until 3 weeks of age, mice remained phenotypically normal at 6 weeks, and >90% of the mice survived at 30 weeks. However, late induction of A1-AR still caused mild cardiomyopathy at older ages (20 weeks) and accelerated cardiac hypertrophy and the development of dilatation after pressure overload. These changes were accompanied by gene expression changes associated with cardiomyopathy and fibrosis and by decreased Akt phosphorylation. Discontinuation of A1-AR induction mitigated cardiac dysfunction and significantly improved survival rate. These data suggest that robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy, whereas delaying A1-AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A1-AR transgenic mouse model provides novel insights into the role of adenosine signaling in heart failure and illustrates the potentially deleterious consequences of selective versus nonselective activation of adenosine-signaling pathways in the heart.

Phospholamban R14 Deletion Results in Late-Onset, Mild, Hereditary Dilated Cardiomyopathy

The purpose of this research was to determine the phenotypic spectrum associated with phospholamban gene (PLN) mutations. Inheritance contributes to the development of dilated cardiomyopathy. Mutations in the gene encoding PLN have been associated with dilated cardiomyopathy characterized by early onset and the presence of lethal ventricular arrhythmias. We screened a cohort of 260 unrelated dilated cardiomyopathy patients from a tertiary care referral center for mutations in the PLN gene. Family history of cardiomyopathy was present in approximately one-half the individuals in this cohort. We identified 1 family with a deletion of arginine 14 in the PLN. Interestingly, unlike other individuals reported with the identical PLN mutation, these individuals were not diagnosed with dilated cardiomyopathy until their seventh decade when they were only mildly symptomatic with congestive heart failure. The identical PLN mutation can be associated with both mild and severe forms of dilated cardiomyopathy. Additionally, PLN mutations should be considered in late onset cardiomyopathy. (Genetics of Cardiovascular and Neuromuscular Disease; http://www.clinicaltrials.gov/ct/show/NCT00138931?order=1; NCT00138931)

G.P.1 08 Phenotype–genotype correlation in two families with muscle phosphofructokinase deficiency

Muscle phosphofructokinase deficiency (PFK) is a relatively rare glycogenosis characterized by mild proximal myopathy associated with compensated hemolytic anaemia and hyperuricemia. We report 2 unrelated families with PFK deficiency. Family 1: A 45-year-old man (pt1) complained of episodic diffuse myalgias, vomiting and dark urines after mild exercise. He had a mild hypertrophic cardiomyopathy. Neurological examination was unremarkable. Family history was negative but his older 12-year-old son showed elevated CK levels (max 600IU/l).

Human Hantavirus Infection, Brazilian Amazon

Human Hantavirus Infection, Brazilian Amazon

Prognostic value of intra-left ventricular electromechanical asynchrony in patients with mild hypertrophic cardiomyopathy compared with power athletes

Objectives: We sought to assess the indexes of myocardial activation delay, using Doppler myocardial imaging (DMI), as potential diagnostic tools and predictors of cardiac events in patients with hypertrophic cardiomyopathy...

Long-term Effects of Recombinant Human Insulin-like Growth Factor I Treatment on Glucose and Lipid Metabolism and the Growth of a Patient with Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy (CGL) is a disease characterized by generalized lack of body fat, insulin resistance, hypertriglyceridemia, and fatty liver. We studied the long-term effects of recombinant human insulin-like growth factor I (rhIGF-I) treatment on glucose and lipid metabolism and the growth in a patient with CGL. During rhIGF-I treatment, the serum triglyceride level was maintained almost within the normal range, and the plasma glycosylated hemoglobin A1c (HbA1c) levels were maintained under 8.0% (5.8%-7.9%). Thus, rhIGF-I treatment was effective in lowering glucose and triglyceride levels over the long-term in a CGL patient. However, it was difficult to suppress the patient's voracious appetite. Although serum total IGF-I levels were extremely high (1000-1700 ng/ml), growth was not accelerated after the start of rhIGF-I treatment, likely because of normal IGF binding protein 3 (IGFBP-3) levels. During rhIGF-I treatment, the patient developed a recurrence of mild hypertrophic cardiomyopathy and a mild elevation of intraocular pressure.

Myocardial stiffness and the timing difference between tissue Doppler imaging Ea and peak mitral valve opening can distinguish physiological hypertrophy in athletes from hypertrophic cardiomyopathy

To differentiate between physiological and pathological left ventricular hypertrophy in athletes using echocardiography. Eleven patients with mild hypertrophic cardiomyopathy were compared against 17 international rowers with mild left ventricular hypertrophy, and 30 age matched controls. The time difference between peak Ea (Doppler tissue imaging) and peak mitral valve opening (using M-mode) was measured simultaneously. A novel index (E/Ea)/LVEDD, as a measure of left ventricular stiffness was recorded. In athletes the peak Ea preceded peak mitral opening by: median (interquartile range) 20 ms (10,20), control group 15 ms (0,30), compared with HCM where Ea followed peak mitral opening by 10 ms (0,20), P<0.0001. In athletes the index of left ventricular stiffness was lower than controls 1.2 (0.93,1.4) versus 1.5 (1.3,1.6), and HCM 2.2 (2.0,2.3), P<0.0001. Physiological hypertrophy can be differentiated from hypertrophic cardiomyopathy in athletes using the Ea-peak mitral opening difference, and our index of ventricular stiffness.

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.

Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

Targeted deletion of actinin-associated LIM protein (ALP) in mice leads to right ventricular (RV) dysplasia and a mild RV cardiomyopathy. Although the phenotype has been thoroughly characterized, the mechanisms leading from the cytoskeletal defect to the disease are unclear. We hypothesized that ALP deficiency may be associated with (1) changes in regional systolic dysfunction and (2) regional dysregulation of hypertrophic growth, in accordance with the restricted expression of ALP in the outflow tract of the RV. We examined RV regional epicardial systolic strains with respect to end-diastole in ALP knockout (ALPKO) mice and wild-type controls using an open-chest preparation. Strain components were consistently lower in the ALPKO mice than wild-type controls (second principal strain E2: p = 0.05). RV pressure was slightly but not significantly lower in ALPKO mice as well. To assess regional growth, geometric remodeling was analyzed in ALPKO and wild-type mice after 4 weeks of chronic hypoxia (11% oxygen). The average amount of RV wall thickening in response to hypoxia was reduced to 11% in the ALPKO mice compared with 44% in the wild-type controls. In summary, the results are consistent with the view that disruption of ALP is associated with diminished RV contractile function as well as altered hypertrophic remodeling.

Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression

The cardiac-specific tetracycline-regulated gene expression system (tet-system) is a powerful tool using double-transgenic mice. The cardiac alpha-myosin heavy chain promoter (alphaMHC) drives lifetime expression of a tetracycline-inhibited transcription activator (tTA). Crossing alphaMHC-tTA mice with mice containing a tTA-responsive promoter linked to a target gene yields double-transgenic mice having tetracycline-repressed expression of the target gene in the heart. Using the tet-system, some studies use nontransgenic mice for the control group, whereas others use single-transgenic alphaMHC-tTA mice. However, previous studies found that high-level expression of a modified activator protein caused cardiomyopathy. Therefore, we tested whether cardiac expression of tTA was associated with altered function of alphaMHC-tTA mice compared with wild-type (WT) littermates. We monitored in vivo and in vitro function and gene expression profiles for myocardium from WT and alphaMHC-tTA mice. Compared with WT littermates, alphaMHC-tTA mice had a greater heart-to-body weight ratio (approximately 10%), ventricular dilation, and decreased ejection fraction, suggesting mild cardiomyopathy. In vitro, submaximal contractions were greater compared with WT and were associated with greater myofilament Ca2+ sensitivity. Gene expression profiling revealed that the expression of 153 genes was significantly changed by >20% when comparing alphaMHC-tTA with WT myocardium. These findings demonstrate that introduction of the alphaMHC-tTA construct causes significant effects on myocardial gene expression and major functional abnormalities in vivo and in vitro. For studies using the tet-system, these results suggest caution in the use of controls, since alphaMHC-tTA myocardium differs appreciably from WT. Furthermore, the results raise the possibility that the phenotype conferred by a target gene may be influenced by the modified genetic background of alphaMHC-tTA myocardium.

Respiratory Syncytial Virus Prophylaxis

After completing this article, readers should be able to: 1. Identify risk factors for severe respiratory syncytial virus (RSV) lower respiratory tract disease in children. 2. Identify strategies for prevention of severe RSV disease among high-risk infants and children. 3. Know the recommendations for prophylaxis of RSV disease with palivizumab. RSV is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. Preterm infants and children who have bronchopulmonary dysplasia (BPD) (otherwise known as chronic lung disease of prematurity) or congenital heart disease are at increased risk for severe RSV disease that requires hospitalization (Table 1). | | Hospitalization | PICU Admission | Death | |:-----------:| --------------- | -------------- | ----- | | Prematurity | 8% | 3% | 1% | | BPD (CLD) | 13% | 36% | 5% | | CHD | 10% | 4% | 0.6% | * PICU=pediatric intensive care unit, BPD=bronchopulmonary dysplasia, CLD=chronic lung disease of prematurity, CHD=congenital heart disease. Table 1. Clinical Outcomes of Respiratory Syncytial Virus Infection Among Infants and Children Who Have High-risk Conditions Education of parents and other caregivers about methods to decrease the infant’s exposure to RSV and to factors that may contribute to the severity of the RSV infection must form the basis of any RSV prophylaxis program. Because RSV is transmitted by direct or close contact with contaminated secretions and the virus is known to persist for hours on environmental surfaces and for 30 minutes or longer on hands, emphasis on hand hygiene is crucial. High-risk infants and children should not be exposed to individuals who have respiratory infections, and if at all possible, they should not be in settings (eg, child care centers) where such exposures are likely. Exposure to tobacco smoke must be eliminated because it has been associated with more severe RSV disease. These measures have the added benefit of decreasing transmission of other respiratory pathogens. In addition, all high-risk children older than 6 months of age and their contacts must receive influenza vaccine. Passive immunoprophylaxis of high-risk children with RSV immune globulin intravenous (RSV-IGIV) and palivizumab has been …

Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic cardiomyopathy.

Chronic myocarditis is the main pathological finding associated with Chagas disease-related morbidity. Concentrations of CCL2, CCL3, tumor necrosis factor (TNF)-alpha, and brain natriuretic peptide (BNP) were evaluated in plasma samples obtained from patients with different clinical forms of chronic chagasic cardiomyopathy. Patients with more-severe Chagas disease had elevated plasma concentrations of TNF-alpha, CCL2, and BNP, and there was a good correlation between levels of these proteins (especially TNF-alpha ) and the degree of heart dysfunction. Indeed, TNF-alpha level was an excellent predictor of heart failure. Peripheral blood mononuclear cell samples obtained from patients with mild or severe chagasic cardiomyopathy produced greater amounts of TNF-alpha and CCL2 than did those obtained from noninfected individuals. The elevation of TNF-alpha and CCL2 levels in the plasma of patients appears to be secondary to the degree of heart dysfunction, whereas spontaneous production of TNF-alpha and CCL2 by mononuclear cells is secondary not only to heart dysfunction, but also to the underlying inflammation in the heart of chagasic patients. Measurement of the TNF-alpha level could be a useful tool in the identification of patients with heart dysfunction who may benefit from further investigation and treatment.