Usefulness of Urinary N-Terminal Fragment of Titin to Predict Mortality in Dilated Cardiomyopathy.

Titin is associated with myocardial stiffness and hypertrophy, and mutations in its gene have been identified in cardiac myopathies such as dilated cardiomyopathy (DC). It has recently been reported that in damaged muscle, the N-terminal fragment of titin (Titin-N) is cleaved by calpain-3, and urinary Titin-N (U-TN) could be a marker of sarcomere damage. We aimed to investigate the impact of U-TN on prognosis of DC. We measured urinary levels of Titin-N/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 102 patients with DC, and followed up all the patients (mean 1,167 days). The patients were divided into 3 groups based on the U-TN/Cr: first (U-TN/Cr <3.35, n = 34), second (3.35 ≤ U-TN/Cr <7.26, n = 34), and third (7.26 ≤ U-TN/Cr, n = 34) tertiles. In the Kaplan-Meier analysis, cardiac and all-cause mortality progressively increased from the first to the second and third groups (p <0.05, respectively). In the Cox proportional hazard analyses, U-TN/Cr was a predictor of cardiac and all-cause mortality in patients with DC (p <0.05, respectively). U-TN, a possible marker of sarcomere damage, can identify high-risk patients with DC.

Propionic acidemia as a cause of adult-onset dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Measurement of propionyl-CoA carboxylase (PCC) activity was done in fibroblasts. Whole exome sequencing (WES) data of 157 additional DCM patients were analyzed for genetic defects. We found a metabolic profile characteristic for propionic acidemia in a patient with severe DCM from 55 years of age. Genetic analysis demonstrated compound heterozygous variants in PCCA. Enzymatic activity of PCC in fibroblasts was markedly reduced. A targeted analysis of the PCCA and PCCB genes using available WES data from 157 further DCM patients subsequently identified another patient with propionic acidemia. This patient had compound heterozygous variants in PCCB, and developed severe DCM from 42 years of age. Adult-onset DCM can be caused by propionic acidemia, an autosomal recessive inheritable metabolic disorder usually presenting as neonatal or childhood disease. Current guidelines advise a low-protein diet to ameliorate or prevent detrimental aspects of the disease. Long-term follow-up of a larger group of patients may show whether this diet would also ameliorate DCM. Our results suggest that diagnostic metabolic screening to identify propionic acidemia and related disorders in DCM patients is justified.

Dilated cardiomyopathy secondary to chronic cocaine abuse: a case report.

BACKGROUND: Cocaine is a potent sympathomimetic agent associated with the development of possible fatal cardiovascular complications. Dysrhythmias, acute myocardial infarction, hypertension and dilated cardiomyopathy are just some of many cardiovascular effects related to the abuse of cocaine. CASE PRESENTATION: A 38-year-old Hispanic male with a past medical history of hypertension presented with a chief complaint of progressive shortness of breath. The patient confessed to the use of cocaine for almost 18 years once per week. On examination he was hypertensive and tachycardic with a systolic murmur over the 5th intercostal space at the level of the left mid-clavicular line. Laboratory workup revealed an elevated Brain natriuretic peptide; urine toxicology was positive for cocaine. 2D-echocardiogram showed dilated cardiomyopathy. Cardiac catheterization excluded angioischemic cause. He was managed medically and subsequently discharged with drug rehabilitation. On follow-up diagnostic evaluation after 5 months of cocaine cessation, his ejection function improved significantly. CONCLUSION: The exact incidence of cocaine related cardiomyopathy is unknown and likely underreported. The clinical course is abrupt and comparatively similar to other types of cardiomyopathy. The management is like other forms of cardiomyopathy; however ß-blockers should be avoided. The myocardial dysfunction is reversible with abstaining from additional cocaine ingestion. Non-invasive testing should be performed after several months to re-evaluate the treatment response.

Occupational exposure to cobalt is not associated with incipient signs of dilated cardiomyopathy in a Belgian refinery.

BACKGROUND: Excessive absorption of cobalt has been associated with cases of dilated cardiomyopathy in the past, but it is unclear whether occupationally exposed populations are at risk. OBJECTIVE: To assess the possible relationship between occupational exposure to cobalt and incipient signs of dilated cardiomyopathy. METHODS: A cross-sectional survey was conducted in a cobalt production facility in Belgium constituting one of the largest occupational populations worldwide (n=256 male workers). Exposure to cobalt was assessed by measuring urinary cobalt concentration (µg/gcreat), reflecting recent exposure, and by computing an integrated exposure index (µg/gcreat×years), reflecting long-term exposure. The effect on the myocardium was investigated by echocardiography and electrocardiography, and dose-effect relations with cobalt exposure were traced by multiple regression analysis. RESULTS: No dose-effect relationship between exposure to cobalt and parameters reflecting dilated cardiomyopathy was found in a population of workers characterised by a median recent cobalturia of 4 µg/gcreat and a median long-term cobalturia of 100 µg/gcreat×years. A reduction in the dimensions of the left ventricular internal cavity was associated with recent exposure to cobalt. CONCLUSIONS: Occupational exposure to cobalt does not appear associated with incipient signs of dilated cardiomyopathy within the gradient of exposure recorded in this population.

Usefulness of albuminuria as a prognostic indicator in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Albuminuria is an established risk factor for mortality and cardiovascular events in the general population. Albuminuria might be a marker of the various pathophysiologic changes, such as diffuse vascular injury and systemic inflammation, that arise in patients with chronic heart failure (CHF). However, the relation between albuminuria and CHF has not yet been fully elucidated. Therefore, the purpose of the present study was to assess the prevalence and prognostic significance of albuminuria in patients with CHF secondary to ischemic or idiopathic dilated cardiomyopathy. Of the 712 patients with CHF, 311 had normoalbuminuria, 304 had microalbuminuria, and 97 had macroalbuminuria. The patients with albuminuria had more cardiovascular co-morbidity and worse renal function than those with normoalbuminuria. A total of 152 cardiac events occurred during the follow-up period. Kaplan-Meier analysis demonstrated that patients with albuminuria had a greater incidence of cardiac events than those without albuminuria. Furthermore, albuminuria was significantly associated with an increased risk of cardiac events, even after adjustment for other prognostic variables. In conclusion, albuminuria is a powerful and independent predictor of adverse prognosis in patients with CHF and could be useful for risk stratification of patients with CHF.

Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.

Increased urinary 3-methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I-V) in the order of discovery regardless of pathomechanism. Especially, the so called "unspecified" 3-methylglutaconic aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these "inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature". One should distinguish between "primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the--currently known--three groups of "secondary 3-methylglutaconic aciduria". The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-methylglutaconic aciduria in whom the above mentioned syndromes have been excluded, should be referred to as "not otherwise specified (NOS) 3-MGA-uria" until elucidation of the underlying pathomechanism enables proper (possibly extended) classification.

Dilated cardiomyopathy and adipic aciduria in nutritional rickets.

Hypocalcemia secondary to nutritional rickets is a rare cause of dilated cardiomyopathy. It is also not a recognized cause of dicarboxylic aciduria. We report the first case of adipic aciduria, presenting with dilated cardiomyopathy, secondary to hypocalcemia.

Vasopressin, cortisol, and catecholamine concentrations in dogs with dilated cardiomyopathy.

OBJECTIVE: To evaluate plasma concentrations and urinary excretion of vasopressin and cortisol and urinary excretion of catecholamines in dogs with dilated cardiomyopathy (DCM). ANIMALS: 15 dogs with clinical signs of DCM, 15 dogs with preclinical DCM, and 15 control dogs. PROCEDURE: Physical examinations, thoracic radiography, ECG, and echocardiography were performed on all dogs. Blood and urine samples were collected. RESULTS: Plasma concentration of vasopressin and the urine cortisol-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM and dogs with preclinical DCM, compared with control dogs. Plasma vasopressin concentration was significantly higher in dogs with clinical signs of DCM, compared with dogs with preclinical DCM. Urine vasopressin-to-urine creatinine ratio was significantly increased in dogs with clinical signs of DCM, compared with dogs with preclinical DCM and control dogs. Urine epinephrine-to-urine creatinine ratio and urine norepinephrine-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM, compared with control dogs. Plasma concentration of cortisol and urine dopamine-to-urine creatinine ratio did not differ significantly among groups. CONCLUSIONS AND CLINICAL RELEVANCE: According to this study, the neuroendocrine pattern is changed in dogs with preclinical DCM. These changes are even more pronounced in dogs with clinical signs of DCM. Analysis of concentrations of vasopressin, cortisol, and catecholamines may aid in identification of the clinical stages of DCM. These findings may also provide a basis for additional studies of the possible beneficial effects of vasopressin antagonists and beta-adrenergic receptor antagonists in the treatment of dogs with congestive heart failure and DCM.

[Cardiomyopathy associated with uncontrolled self medication of anabolic steroids]. / Kardiomyopathie assoziiert mit unkontrollierter Selbstmedikation anaboler Steroide.

Though doping has become increasingly ostracized in the context of professional sports, an enormous number of unrecorded cases must be assumed in semi-professional competitive sports as well as in popular sports. This holds especially true for those forms of sports which are done in order to obtain a well-proportioned, athletic, healthy looking body. This case report describes a formerly healthy young man who had to be urgently admitted to an intensive care unit due to severe myocardial pump failure. As anamnestic information was insufficient and inadequate, the taking of anabolic steroids in high doses was proven, as their metabolites could be detected by urine analysis. Until now, myocardial contractile dysfunction has persisted for more than twelve months after the initial admission. Though other diagnoses which might have led to this impaired myocardial contractile performance have been excluded, cardiomyopathy associated with the taking of anabolic steroids must be assumed. Even in non-professional and public sports, a widespread abuse of doping substances exists. Hence, cardiomyopathy associated with the misuse of anabolic steroids has to be considered especially in young, formerly healthy patients.

Plasma nitrate accumulation during the development of pacing-induced dilated cardiac myopathy in conscious dogs is due to renal impairment.

Heart failure is associated with an increase in plasma nitrate and nitrite (NOx). To date there is still some controversy regarding the causes of nitrate accumulation during the development of heart failure. The goal of this study was to analyze the underlying mechanisms that cause accumulation of plasma nitrates during the development of heart failure in dogs. Dogs were chronically instrumented for measurement of hemodynamics and renal function. Hearts were paced initially at 210 bpm for 3 weeks and then at 240 until the development of heart failure. Hemodynamics, renal function, renal blood flow, arterial blood gases, hemoglobin, plasma and urine NOx levels, and creatinine levels were measured weekly. Heart failure was assessed by hemodynamic alterations, physical signs such as lethargy, ascites, cachexia, and postmortem evidence of cardiac hypertrophy. LVSP (from 127 +/- 3 to 106 +/- 3 mmHg), LV dP/dt (from 2658 +/- 173 to 1439 +/- 217 mmHg/s), MAP (from 101 +/- 1.9 to 83 +/- 1.8 mmHg) fell, whereas LVEDP tripled (from 6.4 +/- 0.9 to 20 +/- 2.6 mmHg), and heart rate rose (from 101 +/- 4.2 to 117 +/- 6.3 bpm), all changes P < 0.05. RBF (from 146 +/- 10 to 96 +/- 9.9 ml/min), urine output (V) (from 0.26 +/- 0.02 to 0.16 +/- 0.02 ml/min), GFR (from 63 +/- 1.8 to 49 +/- 2 ml/min), and Na excretion (from 45 +/- 4.5 to 14 +/- 4.6 microEq/min) all decreased (P < 0.05), whereas RVR increased (from 0.68 +/- 0.05 to 0.94 +/- 0.1 mmHg/ml/min). These changes took place during a rise in plasma NOx (from 3.7 +/- 0.5 to 16+/-3.3 microM), a decrease in urine NOx (from 33 +/- 9.9 to 8.1 +/- 4.9 microM), and a concurrent increase in NOx reabsorption (from 221 +/- 31 to 818 +/- 166 nmol/min). There was a direct correlation between the increase in plasma NOx levels and an increase in filtered load (r(2) = 0.97, P = 0.02), a negative correlation between NOx levels and NOx excretion (r(2) = 0.65 P < 0.09), and a direct correlation between plasma NOx levels and NOx reabsorption (r(2) = 0.97, P = 0.02). These results indicate that elevated plasma NOx during heart failure are most likely the result of an impairment of the renal function and not increased NOx production. Furthermore, without knowing changes in renal function the measurement of plasma NOx in and of itself is a meaningless index of NO formation.

Detection of exogenous growth hormone (GH) administration by monitoring ratio of 20kDa- and 22kDa-GH in serum and urine.

We previously demonstrated that individual subjects have fairly constant ratios of serum concentrations of 20 kDa- (20K) and 22 kDa-GH (22K). The aim of this study is to demonstrate the possibility of utilizing the changes in the ratio of 20K/22K for detecting the exogenous administration of 22K. A male patient with idiopathic dilated cardiomyopathy (age 51) received 22K (4U, s.c.) every other day. The concentrations of 20K and 22K in serum and urine were measured using enzyme-linked immunosorbent assays before and after administration. The administration of 22K increased total GH concentration, and markedly decreased the ratio of 20K/22K in serum, especially 2-10 h after the administration. From calculations, it became clear that the concentration of exogenous 22K reached a peak between 2-4 h after the administration and decreased to a negligible level after 24 h. The ratio of 20K/22K in the 0-24 h urine was 5 times lower than that in the 24-48 h urine. These data suggest that, by monitoring the ratio of 20K/22K in serum or urine, it is possible to determine whether or not GH has been externally administered and to calculate the serum GH that has been administered.

Plasma and urinary selenium in Saudi Arabian patients with dilated cardiomyopathy.

We measured selenium (Se) levels in the urine and blood plasma samples of 72 Saudi Arabian patients with dilated cardiomyopathy (DCM) and 70 control subjects of the same origin. To correct for differences in the hydration state of the subjects, the selenium concentration for each urine sample was normalized by dividing it by the concentration of creatinine (CREAT) in the same sample. The median (and range) of the values found for the concentration of Se in plasma, urine, and normalized concentration in urine for the control subjects was 1.306 (0.66-2.50) microM, 0.478 (0.05-2.00) microM, and 56.7 (10.6-426.5) microM Se/M CREAT, respectively, whereas, for the patients, it was 1.246 (0.53-2.45) microM, 0.39 (0.05-1.90) microM, and 75.1 (4.9-656.2) microM Se/M CREAT, respectively. Additionally, the patients were separated into three subgroups according to the severity of their disease state as judged by NYHA procedure, and were then compared to the control group. Only group 4 (the most severe state of the disease) had a significantly lower concentration of urinary Se than the control group. However, the difference became nonsignificant when normalized for CREAT levels. There was no significant difference in the plasma Se levels between the controls and any of the patient groups. As the plasma Se in the control group and in the DCM patients both fell on the low end of the "normal" range, with the patients being marginally lower than the controls, there is no firm evidence from this study to suggest that Se is related to the high incidence rate of DCM found in Saudi Arabia.

Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts.

We report on 2 children, brother and sister, who presented with cardiomyopathy and muscular hypotonia at the age of B months. They both excreted significant amounts of 3-hydroxy-3-methylglutaric acid (3-HMG) and 3-methylglutaconic acid (3-MGC) but no 3-methylglutaric acid (3-MG). Enzyme analysis in fibroblasts revealed normal activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase and of 3-methylglutaconyl hydratase and other enzymes of 3-HMG metabolism. Loading tests with leucine did not affect the excretion of 3-HMG and 3-MGC. The girl died as a result of her cardiomyopathy, while the boy recovered and was treated with cardiac supportive therapy. He showed a steady improvement during his clinical course with biochemical normalization of the urinary excretion of 3-HMG, concomitant with marked improvement in the hypertrophic cardiomyopathy. In cultured fibroblasts from both patients a reduced activity of complex II/III of the respiratory chain was measured which may be the cause of this new type of 3-HMG uria. Analysis of mitochondrial DNA heart muscle, liver and fibroblast culture of the patient did not reveal any major mitochondrial DNA rearrangements (deletion, duplication) or any point mutation that had been described in association with mitochondrial cardiomyopathy.

Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid.

A case of dilated cardiomyopathy in a young boy secondary to type II 3-methylglutaconic aciduria is described. A metabolic cause for his dilated cardiomyopathy was suspected because of the development on the electrocardiogram of an unusual "camel's hump" shape of the T waves, and of progressive thickening with increasing echogenicity of the left ventricular wall. He initially improved on digoxin treatment, but did not maintain the response with conventional dietary treatment for this condition. Supplementation with L-carnitine was associated with rapid deterioration in cardiac state, and may be contraindicated in this condition. At a point when the patient was moribund, large doses of pantothenic acid, a precursor of coenzyme A, produced a dramatic and sustained improvement in myocardial function and in growth, neutrophil cell count, hypocholesterolaemia, and hyperuricaemia, which suggests that limitation of availability of coenzyme A is a fundamental pathological process in this condition. The clinical improvement has been maintained for 13 months, and myocardial function is now nearly normal. Oral pantothenol, unlike pantothenic acid, is not efficacious.

Dilated cardiomyopathy with 3-methylglutaconic aciduria.

The case of an infant with both dilated cardiomyopathy and 3-methylglutaconic aciduria is presented. The literature on this subject is reviewed.

[Hypertension, heart failure and angina pectoris. Diurnal rhythm of urinary excretion of catecholamines]. / Nadcisnienie tetnicze, niewydolnosc krazenia, angina pectoris. Dobowy rytm wydalania katecholamin.

Adrenaline, noradrenaline and dopamine excretion was investigated in essential hypertension (n = 20), atherosclerotic heart failure (n = 20, NYHA class II and III), chronic angina (n = 10) and in healthy controls, in four time intervals: between 600-1200, 1200-1800, 1800-2400, 2400-600. Fluorimetric method of Anton and Sayre was employed. In patients with essential hypertension the circadian rhythm of adrenaline, noradrenaline and dopamine excretion was maintained but in all time intervals excretion of dopamine was decreased. In individuals with congestive heart failure due to atherosclerosis and in patients with ischemic heart disease, physiological circadian rhythm of adrenaline and noradrenaline excretion was found to be abolished. This was not the case with dopamine excretion which was undisturbed.

[Metolazone in the treatment of advanced therapy-resistant dilated cardiomyopathy]. / Metolazone in der Behandlung fortgeschrittener therapieresistenter dilatativer Kardiomyopathie.

Ten patients (eight male/two female) with advanced dilated cardiomyopathy (NYHA III/IV) and a mean fractional shortening in two-dimensional echocardiogram of 20% (9 to 30%) and a mean sodium excretion of 21 mmol (8 to 40 mmol) per day, pretreated with digoxin, captopril and a mean frusemide-dose of 147 mg (80 to 500 mg) without an effective diuresis, were additional treated with 2.5 to 5 mg oral metolazone daily. All patients had a brisk diuresis within 24 hours and a mean weight loss of 8.9 kg (3 to 20 kg) until discharge. All patients improved considerably by additional metolazone-therapy. Seven patients developed a mild hyponatraemia (122 to 132 mmol/l), seven showed mild (greater than or equal to 3.2 mmol/l) and one had a serious hypokalaemia (2.8 mmol/l); spironolactone-pretreated patients developed no hypokalaemia. Notably none of the patients had serious blood pressure fluctuation or a deterioration of renal function. To avoid severe electrolyte-disturbances, additional metolazone-therapy should be practised in hospital, preferring low-dose metolazone and reducing frusemide-dose under careful biochemical monitoring after diuresis is started.

Emetine identified in urine by HPLC, with fluorescence and ultraviolet/diode array detection, in a patient with cardiomyopathy.

A 15-year-old girl with a four-month history of cardiac failure from undetermined cause was admitted to the hospital with weakness, fatigue, and weight loss. During her hospitalization she was found to have abused diet aids, laxatives, and cathartics. Although an electrocardiogram revealed nonspecific T-wave abnormalities and laboratory studies showed supranormal enzyme test results for creatine kinase and lactate dehydrogenase, no definite explanation of the cardiomyopathy was forthcoming. Ipecac abuse leading to cardiomyopathy was suspected early in the hospitalization. HPLC analysis of a urine sample showed emetine, a principle component of ipecac, the presence of which was later confirmed by more-specific HPLC analysis with photodiode array detection.

Digoxin toxicity associated with amiodarone therapy in children.

The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations (68% to 800%) in the presence of preserved serum creatinine and BUN concentrations. Digoxin half-life was prolonged. Digoxin accumulation could be attributed in part to the decrease in the renal clearance of digoxin resulting from inhibited tubular secretion of the drug and to the reduction in the distribution volume of digoxin caused by amiodarone. Creatinine clearance was not affected by amiodarone. This interaction appears to be more acute in children than in adults, presumably because of the more important role of the renal tubular secretion of digoxin in children. Whenever digoxin and amiodarone therapy are combined, the digoxin serum concentration should be monitored carefully, with appropriate reduction of the digoxin dose.