Multigene phylogenetics of euglenids based on single-cell transcriptomics of diverse phagotrophs.

Euglenids are a well-known group of single-celled eukaryotes, with phototrophic, osmotrophic and phagotrophic members. Phagotrophs represent most of the phylogenetic diversity of euglenids, and gave rise to the phototrophs and osmotrophs, but their evolutionary relationships are poorly understood. Symbiontids, in contrast, are anaerobes that are alternatively inferred to be derived euglenids, or a separate euglenozoan group. Most phylogenetic studies of euglenids have examined the SSU rDNA only, which is often highly divergent. Also, many phagotrophic euglenids (and symbiontids) are uncultured, restricting collection of other molecular data. We generated transcriptome data for 28 taxa, mostly using a single-cell approach, and conducted the first multigene phylogenetic analyses of euglenids to include phagotrophs and symbiontids. Euglenids are recovered as monophyletic, with symbiontids forming an independent branch within Euglenozoa. Spirocuta, the clade of flexible euglenids that contains both the phototrophs (Euglenophyceae) and osmotrophs (Aphagea), is robustly resolved, with the ploeotid Olkasia as its sister group, forming the new taxon Olkaspira. Ploeotids are paraphyletic, although Ploeotiidae (represented by Ploeotia spp.), Lentomonas, and Keelungia form a robust clade (new taxon Alistosa). Petalomonadida branches robustly as sister to other euglenids in outgroup-rooted analyses. Within Spirocuta, Euglenophyceae is a robust clade that includes Rapaza, and Anisonemia is a well-supported monophyletic group containing Anisonemidae (Anisonema and Dinema spp.), 'Heteronema II' (represented by H. vittatum), and a clade of Neometanema plus Aphagea. Among 'peranemid' phagotrophs, Chasmostoma branches with included Urceolus, and Peranema with the undescribed 'Jenningsia II', while other relationships are weakly supported and consequently the closest sister group to Euglenophyceae remains unresolved. Our results are inconsistent with recent inferences that Entosiphon is the evolutionarily pivotal sister either to other euglenids, or to Spirocuta. At least three transitions between posterior and anterior flagellar gliding occurred in euglenids, with the phylogenetic positions and directions of those transitions remaining ambiguous.

The origins of malaria: there are more things in heaven and earth .

SUMMARY Malaria remains one of the most significant global public health burdens, with nearly half of the world's population at risk of infection. Malaria is not however a monolithic disease - it can be caused by multiple different parasite species of the Plasmodium genus, each of which can induce different symptoms and pathology, and which pose quite different challenges for control. Furthermore, malaria is in no way restricted to humans. There are Plasmodium species that have adapted to infect most warm-blooded vertebrate species, and the genus as a whole is both highly successful and highly diverse. How, where and when human malaria parasites originated from within this diversity has long been a subject of fascination and sometimes also controversy. The past decade has seen the publication of a number of important discoveries about malaria parasite origins, all based on the application of molecular diagnostic tools to new sources of samples. This review summarizes some of those recent discoveries and discusses their implication for our current understanding of the origin and evolution of the Plasmodium genus. The nature of these discoveries and the manner in which they are made are then used to lay out a series of opportunities and challenges for the next wave of parasite hunters.

Microbiomes of microscopic marine invertebrates do not reveal signatures of phylosymbiosis.

Animals and microorganisms often establish close ecological relationships. However, much of our knowledge about animal microbiomes comes from two deeply studied groups: vertebrates and arthropods. To understand interactions on a broader scale of diversity, we characterized the bacterial microbiomes of close to 1,000 microscopic marine invertebrates from 21 phyla, spanning most of the remaining tree of metazoans. Samples were collected from five temperate and tropical locations covering three marine habitats (sediment, water column and intertidal macroalgae) and bacterial microbiomes were characterized using 16S ribosomal RNA gene sequencing. Our data show that, despite their size, these animals harbour bacterial communities that differ from those in the surrounding environment. Distantly related but coexisting invertebrates tend to share many of the same bacteria, suggesting that guilds of microorganisms preferentially associated with animals, but not tied to any specific host lineage, are the main drivers of the ecological relationship. Host identity is a minor factor shaping these microbiomes, which do not show the same correlation with host phylogeny, or 'phylosymbiosis', observed in many large animals. Hence, the current debate on the varying strength of phylosymbiosis within selected lineages should be reframed to account for the possibility that such a pattern might be the exception rather than the rule.

Archaebacterial genomes: eubacterial form and eukaryotic content.

Since the recognition of the uniqueness and coherence of the archaebacteria (sometimes called Archaea), our perception of their role in early evolution has been modified repeatedly. The deluge of sequence data and rapidly improving molecular systematic methods have combined with a better understanding of archaebacterial molecular biology to describe a group that in some ways appears to be very similar to the eubacteria, though in others is more like the eukaryotes. The structure and contents of archaebacterial genomes are examined here, with an eye to their meaning in terms of the evolution of cell structure and function.

Microsporidia - Emergent Pathogens in the Global Food Chain.

Intensification of food production has the potential to drive increased disease prevalence in food plants and animals. Microsporidia are diversely distributed, opportunistic, and density-dependent parasites infecting hosts from almost all known animal taxa. They are frequent in highly managed aquatic and terrestrial hosts, many of which are vulnerable to epizootics, and all of which are crucial for the stability of the animal-human food chain. Mass rearing and changes in global climate may exacerbate disease and more efficient transmission of parasites in stressed or immune-deficient hosts. Further, human microsporidiosis appears to be adventitious and primarily associated with an increasing community of immune-deficient individuals. Taken together, strong evidence exists for an increasing prevalence of microsporidiosis in animals and humans, and for sharing of pathogens across hosts and biomes.

Origins of microsporidia.

Microsporidia are obligate intracellular parasites that infect a wide range of eukaryotes, causing severe diseases in immunocompromised humans and losses to apiaries, fisheries and silk farms. They have often been considered to be primitive eukaryotes; however, more recent evidence suggests they are more closely related to fungi.

Lack of association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and idiopathic dilated cardiomyopathy.

OBJECTIVES: We sought to investigate the role of polymorphisms of the gene for angiotensin-converting enzyme in the development and progression of idiopathic dilated cardiomyopathy. BACKGROUND: Cardiovascular renin-angiotensin systems may be involved in cardiac remodeling and fibrosis. The absence (deletion [D]) of a 287-base pair marker in the angiotensin-converting enzyme gene (introm 16) is associated with increased serum angiotensin-converting enzyme levels. The DD genotype may be a risk factor for the development of end-stage heart failure due to cardiomyopathy. We therefore examined the relation of the angiotensin-converting enzyme genotype to idiopathic dilated cardiomyopathy and to markers of disease severity. METHODS: We studied 364 control subjects and 99 consecutive patients with idiopathic dilated cardiomyopathy. When the incidence of the DD genotype in our control group was assumed to be similar to that previously reported (27%), this study had a power of 0.9 to detect a different incidence in the patient group, if the true incidence in patients was 42%. Deoxyribonucleic acid (DNA) was isolated from blood samples, and angiotensin-converting enzyme genotype was determined by specific polymerase chain reaction and separation of amplified fragments by agarose gel electrophoresis. We also compared genotype distribution with that in previously reported European control subjects. Functional status, clinical course over a mean +/- SD of 28 +/- 33 months and outcome were documented. Cardiac morphology and function and evidence of rhythm disturbance were noninvasively determined. RESULTS: Angiotensin-converting enzyme genotype distribution and allele frequencies were similar in patients and control subjects to within 10% (with 95% confidence) and were also similar between patients and European control subjects. No markers of disease severity or progression other than duration of symptoms before diagnosis and the number of ventricular ectopic beats/h were significantly associated with the presence of the DD alleles. CONCLUSIONS: We find no evidence to support an association between angiotensin-converting enzyme genotype and either the diagnosis of idiopathic dilated cardiomyopathy itself or progression of the disease.

A prospective case-control study of antibodies to coxsackie B virus in idiopathic dilated cardiomyopathy.

OBJECTIVES: This study was conducted to determine the frequency and significance of Coxsackie B virus-specific immunoglobulin-M (IgM) in patients with idiopathic dilated cardiomyopathy and compare them with the frequency in both unmatched and matched control subjects. BACKGROUND: The principal evidence supporting a pathoetiologic role for Coxsackie B viruses in human dilated cardiomyopathy is derived from retrospective serologic studies. These studies have evaluated patients with end-stage disease and have failed to recognize the importance of assessing both matched and unmatched control subjects. METHODS: In this prospective case-control study, we assessed sera for Coxsackie B virus-specific IgM (serotypes B1 to B5) from 114 patients with dilated cardiomyopathy at diagnosis or referral to our center, 94 healthy unmatched control subjects, 41 healthy matched control subjects from the same general practitioner and 32 members of the patients' own households. RESULTS: A higher frequency of positive Coxsackie B virus IgM was observed in patients with dilated cardiomyopathy than in unmatched control subjects (33% vs. 5%; p = 3 x 10(-7)). In patients with dilated cardiomyopathy, the response was monotypic (84%), commonly against serotypes B2 and B5, and was not associated with any clinical or histologic feature. The frequency of positive virus-specific IgM was similar in patients with dilated cardiomyopathy and their 41 matched community control subjects (46% vs. 27%; p = 0.11) and 32 household contacts (37% vs. 28%; p = 0.59). Control subjects who tested positive for virus-specific IgM tended more commonly to be seropositive than did control seronegative subjects (community control subjects 37% vs. 18%, p = 0.32; household contacts 42% vs. 20%; p = 0.36) and had an identical serotypic response in 4 (33%) of 12 cases. CONCLUSIONS: The frequency of Coxsackie B virus IgM was higher in patients with dilated cardiomyopathy than in unmatched control subjects but was similar in patients and control subjects who shared the same environment, indicating local spread of infection. The reason for the association between Coxsackie B virus IgM and dilated cardiomyopathy and its relevance to pathogenesis remain to be established.

Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease.

OBJECTIVES: This study sought to determine whether early disease is identifiable in asymptomatic relatives of patients with dilated cardiomyopathy (DCM) by means of noninvasive cardiologic assessment. BACKGROUND: DCM is diagnosed on the basis of advanced heart failure, where cardiac dilation and impaired contractility are recognized in the absence of a recognized etiology (World Health Organization criteria). However, initial clinical presentation may be with severe complications: thromboembolism, arrhythmia or sudden death. DCM has recently been recognized to be familial, with autosomal dominant inheritance in many cases. Familial disease is present in 9% to 20% of patients with DCM, and the ability to identify early disease in such people may improve patient management and aid in the understanding of pathogenesis. METHOD: We prospectively assessed 408 asymptomatic relatives (mean [+/-SD] age 35 +/- 15 years, 193 men) of 110 consecutive patients with DCM by means of history and physical examination, two-dimensional echocardiography, 12-lead and signal-averaged electrocardiography and metabolic exercise testing. We hypothesized that signs of lesser cardiac dysfunction in such relatives might indicate early disease. RESULTS: Twenty-nine percent of relatives had abnormal results on the echocardiogram. Twenty percent (n = 45) had left ventricular enlargement (LVE), defined as LV end-diastolic diameter (LVEDD) > or = 112% predicted; 6% (n = 13) had depressed fractional shortening (dFS), defined as FS < or = 25%; and 3% (n = 7) had frank DCM, defined as LV dilation, impaired contractile performance and LVEDD > or = 112% plus FS < or = 25%. Other abnormalities of cardiac function were identified in relatives with LVE or dFS: A greater number with LVE had an abnormal metabolic exercise test result than normal relatives (9% vs. 1%, p < 0.05). Relatives with LVE and abnormal maximal oxygen consumption (VO2max) (defined as VO2max < 80% predicted) had a lower absolute VO2max than normal relatives (30 +/- 8 vs. 43 +/- 9 ml/min per kg, p = 0.01). The QRS duration (at the 25-Hz filter) on the signal-averaged electrocardiogram was prolonged in relatives with LVE (103 +/- 13 ms) and dFS (102 +/- 12 ms) compared with that of normal relatives (97 +/- 12 ms, p < 0.05). Over a mean 39-month follow-up period, 12 relatives with LVE (27%) and none with dFS developed symptomatic DCM (p < 0.0001). One relative with LVE died suddenly, and another underwent heart transplantation. CONCLUSIONS: Nearly one-third of asymptomatic relatives (29%) have echocardiographic abnormalities, and 27% of such relatives progress to development of overt DCM. Early identification of such people would permit appropriate intervention that might influence the serious complications and mortality of this disease.

Alpha and beta subunits of pyruvate dehydrogenase E1 from the microsporidian Nosema locustae: mitochondrion-derived carbon metabolism in microsporidia.

Microsporidia are highly adapted eukaryotic intracellular parasites that infect a variety of animals. Microsporidia contain no recognisable mitochondrion, but recently have been shown to have evolved from fungi and to possess heat shock protein genes derived from mitochondria. These findings make it clear that microsporidian ancestors were mitochondrial, yet it remains unknown whether they still contain the organelle, and if so what its role in microsporidian metabolism might be. Here we have characterised genes encoding the alpha and beta subunits of pyruvate dehydrogenase complex E1 (PDH, EC 1.2.4.1) from the microsporidian Nosema locustae. All other amitochondriate eukaryotes studied to date have lost the PDH complex and replaced it with pyruvate:ferredoxin oxidoreductase (PFOR). Nevertheless, molecular phylogeny shows that these Nosema enzymes are most closely related to mitochondrial PDH from other eukaryotes, demonstrating that elements of mitochondrial metabolism have been retained in microsporidia, and that PDH has not been wholly lost. However, there is still no evidence for a mitochondrion in microsporidia, and neither PDH subunit is predicted to encode an amino terminal leader sequence that could function as a mitochondrion-targeting transit peptide, raising questions as to whether these proteins function in a relic organelle or in the cytosol. Moreover, it is also unclear whether these proteins remain part of the PDH complex, or whether they have been retained for another purpose. We propose that microsporidia may utilise a unique pyruvate decarboxylation pathway involving PDH, demonstrating once again the diversity of core metabolism in amitochondriate eukaryotes.

Prognostic significance of spectral turbulence analysis of the signal-averaged electrocardiogram in patients with idiopathic dilated cardiomyopathy.

The aim of this study was to assess whether spectral turbulence analysis (STA) of the signal-averaged electrocardiogram (SAECG) is of prognostic use in patients with idiopathic dilated cardiomyopathy. SAECGs were recorded at presentation in 84 patients with idiopathic dilated cardiomyopathy and STA was performed using 183 Del Mar software. STA was abnormal (> or = 3 of the 4 standard parameters beyond the normal range) in 31 patients (37%). Patients were followed for a mean duration of 24 +/- 18 months (range 1 to 59) during which time 24 (29%) developed progressive heart failure (14 underwent cardiac transplantation), 4 died suddenly or had aborted sudden death, and the others remained clinically stable. Progressive heart failure occurred more often in patients who had an abnormal versus a normal STA result (15 [48%] vs 9 [17%]; p < 0.002). Actuarial survival revealed a 1-year survival of 90% in patients with a normal STA result, and 63% in patients with an abnormal STA result (p < 0.01). The predictive ability of STA to identify patients with progressive heart failure was sensitivity 63%, specificity 77%, positive predictive value 54%, and negative predictive value 83%. Univariate analysis identified peak oxygen consumption as having the largest relative risk for the development of progressive heart failure (9.55, 95% confidence interval [CI] 2.1 to 43.9). Left ventricular end-diastolic dimension (relative risk 4.18, 95% CI 1.5 to 11.4) and STA (relative risk 3.81, 95% CI 1.7 to 8.8) were also significantly associated with the development of progressive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of signal-averaged electrocardiography in evaluation of idiopathic-dilated cardiomyopathy in families.

Family studies have confirmed that familial dilated cardiomyopathy is common and that a large proportion of relatives have mild left ventricular enlargement and therefore potentially early disease. Previous studies have shown that patients with idiopathic dilated cardiomyopathy have abnormalities of the signal-averaged electrocardiogram (ECG). We assessed the usefulness of analysis of the signal-averaged ECG in the evaluation of familial dilated cardiomyopathy. Signal-averaged electrocardiographic recordings were obtained from 58 patients with idiopathic dilated cardiomyopathy, from 161 of their relatives (35 of whom had left ventricular enlargement), and from 59 healthy subjects. Signal-averaged ECGs were analyzed using both time domain and spectral turbulence analysis techniques. The time domain and spectral turbulence analysis variables were markedly abnormal in patients with idiopathic dilated cardiomyopathy compared with relatives considered normal and healthy controls (p <0.05). Late potentials were more common in patients with idiopathic dilated cardiomyopathy (17%) and in relatives with left ventricular enlargement (20%) than in normal relatives (5%) or healthy controls (5%) (p = 0.003). Spectral turbulence analysis was abnormal in 24% of patients with idiopathic dilated cardiomyopathy, 14% of relatives with left ventricular enlargement, 6% of normal relatives, and 5% of healthy controls (p = 0.0006). The sensitivity, specificity, and positive predictive accuracy for identification of relatives with left ventricular enlargement were 20%, 95%, and 54% for time domain analysis and 14%, 94%, and 42% for spectral turbulence analysis. Similar positive predictive accuracy was achievable with spectral turbulence analysis and with time domain analysis. In conclusion, the signal-averaged ECG is frequently abnormal in patients with idiopathic dilated cardiomyopathy and relatives with left ventricular enlargement.

Usefulness of signal-averaged electrocardiogram in idiopathic dilated cardiomyopathy for identifying patients with ventricular arrhythmias.

In idiopathic dilated cardiomyopathy (IDC), the relation between the signal-averaged electrocardiogram and ventricular tachycardia (VT) remains unclear. In this study, conventional time domain and frequency domain analyses (2-dimensional, spectral temporal mapping and spectral turbulence analysis) of the signal-averaged electrocardiogram were performed in 64 patients with IDC. Eight patients had a history of symptomatic sustained VT and an additional 24 had nonsustained VT recorded during ambulatory electrocardiography. Conventional time domain analysis, using the 25 and 40 Hz filter, and spectral temporal mapping, detected late potentials within the terminal QRS in 8 (13%), 14 (22%) and 18 (28%) patients, respectively. Late potentials were seen more often in patients with than without VT, and in patients with sustained versus nonsustained VT, but these differences were not significant. The predictive accuracy of these techniques in detecting either form of VT were: sensitivity, 22, 25 and 31%; specificity, 97, 81 and 75%; and overall predictive value, 59, 53 and 50%, respectively. Two-dimensional frequency domain analysis of the signal-averaged electrocardiogram revealed a higher energy and area ratio in patients with than without VT (entire QRS), and in patients with sustained versus nonsustained VT (entire QRS and terminal QRS). Spectral turbulence analysis was abnormal in 24 patients (39%), but no differences were observed between patients with and without VT. During follow-up (mean duration 18 +/- 14 months), 5 patients had arrhythmic events (3 died suddenly, 1 had aborted sudden death and 1 developed sustained VT).(ABSTRACT TRUNCATED AT 250 WORDS)

Diplonemid glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and prokaryote-to-eukaryote lateral gene transfer.

Lateral gene transfer refers to the movement of genetic information from one genome to another, and the integration of that foreign DNA into its new genetic environment. There are currently only a few well-supported cases of prokaryote-to-eukaryote transfer known that do not involve mitochondria or plastids, but it is not clear whether this reflects a lack of such transfer events, or poor sampling of diverse eukaryotes. One gene where this process is apparently active is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), where lateral transfer has been implicated in the origin of euglenoid and kinetoplastid genes. We have characterised GAPDH genes from diplonemids, heterotrophic flagellates that are closely related to kinetoplastids and euglenoids. Two distinct classes of diplonemid GAPDH genes were found in diplonemids, however, neither class is closely related to any other euglenozoan GAPDH. One diplonemid GAPDH is related to the cytosolic gapC of eukaryotes, although not to either euglenoids or kinetoplastids, and the second is related to cyanobacterial and proteobacterial gap3. The bacterial gap3 gene in diplonemids provides one of the most well-supported examples of lateral gene transfer from a bacterium to a eukaryote characterised to date, and may indicate that diplonemids have acquired a novel biochemical capacity through lateral transfer.

Heart rate variability in idiopathic dilated cardiomyopathy: relation to disease severity and prognosis.

OBJECTIVE: To assess the clinical importance of heart rate variability (HRV) in patients with idiopathic dilated cardiomyopathy (DCM). PATIENTS AND METHODS: Time domain analysis of 24 hour HRV was performed in 64 patients with DCM, 19 of their relatives with left ventricular enlargement (possible early DCM), and 33 healthy control subjects. RESULTS: Measures of HRV were reduced in patients with DCM compared with controls (P < 0.05). HRV parameters were similar in relatives and controls. Measures of HRV were lower in DCM patients in whom progressive heart failure developed (n = 28) than in those who remained clinically stable (n = 36) during a follow up of 24 (20) months (P = 0.0001). Reduced HRV was associated with NYHA functional class, left ventricular end diastolic dimension, reduced left ventricular ejection fraction, and peak exercise oxygen consumption (P < 0.05) in all patients. DCM patients with standard deviation of normal to normal RR intervals calculated over the 24 hour period (SDNN) < 50 ms had a significantly lower survival rate free of progressive heart failure than those with SDNN > 50 ms (P = 0.0002, at 12 months; P = 0.0001, during overall follow up). Stepwise multiple regression analysis showed that SDNN < 50 ms identified, independently of other clinical variables, patients who were at increased risk of developing progressive heart failure (P = 0.0004). CONCLUSIONS: HRV is reduced in patients with DCM and related to disease severity. HRV is clinically useful as an early non-invasive marker of DCM deterioration.

Abnormal cytokine profiles in patients with idiopathic dilated cardiomyopathy and their asymptomatic relatives.

OBJECTIVES: Immunological abnormalities in idiopathic dilated cardiomyopathy (DCM) include an increase in soluble interleukin (IL)-2 receptor, disease specific cardiac autoantibodies, an HLA-DR4 association, and familial aggregation of disease; however, cytokine profiles have not been defined. Serum concentrations of IL-2, IL-4, IL-10, and IL-12 were measured in patients with DCM (WHO criteria), relatives with asymptomatic left ventricular enlargement (LVE), patients with ischaemic heart failure (IHD), and healthy controls. DESIGN: Serum from 20 individuals from each of the four groups was assayed for cytokine concentrations by a commercial enzyme linked immunosorbent assay. RESULTS: IL-2 concentrations were abnormally increased in DCM patients and relatives with LVE. Concentrations of IL-10 were increased in DCM patients. Concentrations of IL-4 and IL-12 were not increased in any of the groups. CONCLUSION: These abnormalities may reflect defective/inappropriate T cell function in patients with DCM and in their relatives with LVE.

Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression.

OBJECTIVE: To determine the relation of cardiac autoantibody and disease status in a consecutive series of patients with dilated cardiomyopathy by prospective antibody testing at diagnosis and at follow up. METHODS: Antibody status was assessed by indirect immunofluorescence in 110 patients with dilated cardiomyopathy (85 male, mean (SD) age 44 (13) years) at diagnosis and at follow up (mean (SD) 14 (12) months); in 57 of them cardiac specific anti-alpha myosin antibody titres were also measured by an enzyme-linked immunosorbent assay (ELISA). Patients underwent complete evaluation at diagnosis and clinical and non-invasive assessment at follow up, including exercise testing with maximal oxygen consumption measurements. RESULTS: The frequency of cardiac specific antibodies by immunofluorescence was lower at follow up than at diagnosis (28 (25%) v 11 (10%), P = 0.002). Mean (SEM) anti-alpha myosin antibody titres at follow up were also lower than at diagnosis (0.24 (0.02) v 0.30 (0.02), P = 0.038); 24% of patients at diagnosis and 14% at follow up had an abnormal ELISA result. None of the patients who were negative by immunofluorescence or ELISA at diagnosis became positive at follow up. Presence of antibody at diagnosis was associated with milder symptoms and greater exercise capacity at follow up and persistence of antibody at follow up was associated with stable disease and milder symptoms at diagnosis. CONCLUSIONS: Cardiac specific autoantibodies in dilated cardiomyopathy become undetectable with disease progression; this is a recognised feature of other autoimmune conditions, such as type 1 diabetes. Detection of these antibodies at diagnosis and at follow up may provide a non-invasive marker of early dilated cardiomyopathy.

Comparison of time domain and spectral turbulence analysis of the signal-averaged electrocardiogram for the prediction of prognosis in idiopathic dilated cardiomyopathy.

BACKGROUND: Despite significant advances in the treatment of heart failure, the prognosis of patients with idiopathic dilated cardiomyopathy remains poor. Although several of prognostic variables have been shown to be useful in risk stratification of patients with idiopathic dilated cardiomyopathy, their predictive accuracy is low and clinical usefulness uncertain. HYPOTHESIS: This study was undertaken to assess the signal-averaged electrocardiogram (SAECG) in patients with idiopathic dilated cardiomyopathy and to compare the ability of time domain and spectral turbulence analytic techniques to predict clinical outcome. METHODS: SAECG analysis was performed in 80 patients with idiopathic dilated cardiomyopathy. Nineteen patients had left bundle-branch block and eight were taking low-dose amiodarone for life-threatening arrhythmias. Conventional time domain and spectral turbulence analyses of the SAECG were performed using Del Mar 183 software. RESULTS: During a follow-up of 27 +/- 19 months, 24 patients developed progressive heart failure, while the others remained clinically stable. Late potentials were detected in 28% of patients and were equally frequent in patients with and without progressive heart failure (38 vs. 23%, p = 0.20). Spectral turbulence analysis was abnormal in 34% of patients, and patients with abnormal results developed progressive heart failure more frequently than those with normal results (50 vs. 17%, p = 0.01). All spectral turbulence analysis parameters were significantly different in patients with progressive heart failure compared with those who remained clinically stable (p < or = 0.01). Furthermore, progressive heart failure-free survival at 2 years was significantly lower in patients with abnormal compared with normal results (63 vs. 87%; p < 0.05), but was similar in patients with and without late potentials (72 vs. 83%; p = 0.30). The relative risk for developing progressive heart failure using spectral turbulence analysis was 3.4 (95% confidence interval 1.2-9.7) and 2.8 (95% confidence interval 1.1-8.7) using time domain analysis. The sensitivity, specificity, and the positive and negative predictive accuracy for identifying patients who developed progressive heart failure were 50, 83, 50, and 83%, respectively, (p = 0.01) for spectral turbulence analysis, and 36, 85, 45 and 80%, respectively, (p = 0.09) for time domain analysis. CONCLUSION: Abnormalities in the SAECG of patients with idiopathic dilated cardiomyopathy are common and appear to provide a noninvasive marker for development of progressive heart failure.

Creatine kinase isoforms as circulating markers of deterioration in idiopathic dilated cardiomyopathy.

BACKGROUND: A proportion of patients with dilated cardiomyopathy (DCM) may have ongoing myocardial damage secondary to viral or immune mediated myocardial inflammation. HYPOTHESIS: The prognostic determinants identify patients with decreased survival but do not provide a measure of myocardial damage. To obtain an objective assessment of myocardial damage in DCM, we measured plasma levels of creatine kinase (CK), its isoenzymes (CK-MM and CK-MB), and separated the isoforms of CK-MM and CK-MB. METHODS: The cohort consisted of 77 consecutive patients (61 men, 16 women) with DCM (World Health Organization criteria), aged 49 +/- 14 years (range 19-60). Patients had been symptomatic for 29 +/- 38 months (range 0.5-200 months) with 48 in New York Heart Association class I/II and 29 in class III/IV at the time of diagnosis. During median follow-up of 27 months from diagnosis (range 0.6-165), 50 patients remained clinically stable and 27 had deteriorated. RESULTS: A significantly higher proportion of patients with DCM had abnormal MB2/MB1 ratio compared with normal volunteers (11, 14% vs. 1,1%, p = 0.003). Patients who deteriorated had higher MB2/MB1 ratio, (1.22 +/- 0.62 vs. 0.85 +/- 0.56; p = 0.01), and more frequently had abnormal MB2/ MB1 ratio (8, 30% vs. 3, 6%; p = 0.004) and CK and CK-MM activities (5, 19% vs. 2, 4%; p = 0.03) than those who remained stable. Patients with DCM with high CK-MB activity had 3.13-fold increased odds of sudden death or need for cardiac transplantation (95% confidence interval 1.53-6.40, p = 0.008). Thus, CK measurements, in particular CK-MB isoforms, are markers of myocardial damage in a subset of patients with DCM and could be useful in investigating the possibility of persistent myocardial damage in these patients.