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Biomedical subjects

D L Mann

Publications and source records attributed to D L Mann.

At least 37 records · Page 2Linked to original sources
PubMed2001

Brief murine myocardial I/R induces chemokines in a TNF-alpha-independent manner: role of oxygen radicals.

Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-alpha, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-alpha-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-alpha double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1 alpha, -1 beta, and -2 at both the mRNA and protein levels. This induction was independent of TNF-alpha, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-kappa B and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.

Animals↗
PubMed2001

A novel bile duct cannulation method with tail cuff exteriorization allowing continuous intravenous infusion and enterohepatic recirculation in the unrestrained rat.

A variety of bile duct cannulation methods have been used in the study of biliary excretion in the rat. We now report the validation and use of one such method. In this method, the common bile duct and duodenum were cannulated, the free ends of the cannulae tunnelled through the abdominal wall, passed through a trochar and exteriorized at the ventral aspect of the tail. A purpose-designed stainless steel tail cuff was then attached, to protect the cannulae from the rat. The cannulae were passed through the top of a metabolism cage and attached to a dual swivel that allows the rat freedom of movement within the metabolism cage. Where necessary an additional cannula could be placed in the femoral vein to allow infusion of test material or blood sampling. The results demonstrate that the method is robust and that its use allows a reliable correlation between surgically prepared and intact animals, as physiological parameters are allowed to return to normal prior to inclusion of the animals in the study. The technique allows the animals a great deal of freedom and, as such, is considered to minimize stress associated with the procedure. This fact is reflected in the reliability and reproducibility of the data obtained over the wide range of studies that have been conducted using this method. This method has been in use for over 4 years at Inveresk and this paper describes the authors' experience with the method to date.

Animals↗
PubMed2001

Effects of vesnarinone on peripheral circulating levels of cytokines and cytokine receptors in patients with heart failure: a report from the Vesnarinone Trial.

STUDY OBJECTIVES: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST). METHODS: Circulating levels of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327). RESULTS: Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period. CONCLUSIONS: In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure.

Cardiotonic Agents↗
PubMed2001

Experimental options in the treatment of heart failure: the role of cytokine antagonism.

Recent studies have identified the importance of biologically active molecules, such as neurohormones, as mediators of disease progression in heart failure. More recently, it has become apparent that, in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article will review recent clinical material that suggests that tumor necrosis factor, a pro-inflammatory cytokine, may contribute to disease progression in heart failure by virtue of the direct toxic effects that this molecule exerts on the heart and circulation. In addition, this article reviews the existing clinical literature, which suggests that cytokine antagonism is safe and potentially effective in patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed2000

Cardiac-specific overexpression of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm.

BACKGROUND: We have developed a transgenic mouse with cardiac-restricted overexpression of tumor necrosis factor-alpha (TNF-alpha). These mice develop a heart failure phenotype characterized by left ventricular dysfunction and remodeling, pulmonary edema, and elevated levels of TNF-alpha in the peripheral circulation from cardiac spillover. Given that TNF-alpha causes atrophy and loss of function in respiratory muscle, we asked whether transgenic mice developed diaphragm dysfunction and whether contractile losses were caused by oxidative stress or tissue remodeling. METHODS AND RESULTS: muscles excised from transgenic mice and littermate controls were studied in vitro with direct electrical stimulation. Cytosolic oxidant levels were measured with 2', 7'-dichlorofluorescin diacetate; emissions of the oxidized product were detected by fluorescence microscopy. Force generation by the diaphragm of transgenic animals was 47% less than control (13.2+/-0. 8 [+/-SEM] versus 25.1+/-0.6 N/cm(2); P:<0.001); this weakness was associated with greater intracellular oxidant levels (P:<0.025) and was partially reversed by 30-minute incubation with the antioxidant N:-acetylcysteine 10 mmol/L (P:<0.01). Exogenous TNF-alpha 500 micromol/L increased oxidant production in diaphragm of wild-type mice and caused weakness that was inhibited by N:-acetylcysteine, suggesting that changes observed in the diaphragm of transgenic animals were mediated by TNF-alpha. There were no differences in body or diaphragm weights between transgenic and control animals, nor was there evidence of muscle injury or apoptosis. CONCLUSIONS: Elevated circulating levels of TNF-alpha provoke contractile dysfunction in the diaphragm through an endocrine mechanism thought to be mediated by oxidative stress.

Animals↗
PubMed2000

Nitric oxide provokes tumor necrosis factor-alpha expression in adult feline myocardium through a cGMP-dependent pathway.

BACKGROUND: The mechanism(s) responsible for the persistent coexpression of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in the failing heart is unknown. METHODS AND RESULTS: To determine whether NO was sufficient to provoke TNF-alpha biosynthesis, we examined the effects of an NO donor, S-nitroso-N-acetyl penicillamine (SNAP), in buffer-perfused Langendorff hearts. SNAP (1 micromol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF-alpha mRNA and protein biosynthesis in adult cat hearts. The effects of SNAP were completely abrogated by a NO quenching agent, 2-(4-carboxyphenyl)-4, 4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (C-PTIO), and mimicked by sodium nitroprusside. Electrophoretic mobility shift assays demonstrated that SNAP treatment led to the rapid induction of nuclear factor kappa-beta (NF-kappaB) but not AP-1. The importance of the cGMP pathway in terms of mediating NO-induced TNF-alpha biosynthesis was shown by studies that demonstrated that 8-bromo-cGMP mimicked the effects of SNAP and that the effects of SNAP could be completely abrogated using a cGMP antagonist, 1H-(1,2, 4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or protein kinase G antagonist (Rp-8-Br-cGMPS). SNAP and 8-Br-cGMP were both sufficient to lead to the site-specific phosphorylation (serine 32) and degradation of IkappaBalpha in isolated cardiac myocytes. Finally, protein kinase G was sufficient to directly phosphorylate IkappaBalpha on serine 32, a critical step in the activation of NF-kappaB. CONCLUSIONS: These studies show that NO provokes TNF-alpha biosynthesis through a cGMP-dependent pathway, which suggests that the coincident expression of TNF-alpha and NO may foster self-sustaining positive autocrine/paracrine feedback inflammatory circuits within the failing heart.

Animals↗
PubMed2000

Group B Streptococcus induces TNF-alpha gene expression and activation of the transcription factors NF-kappa B and activator protein-1 in human cord blood monocytes.

It has been postulated that production of TNF-alpha is central to the pathogenesis of septic shock induced by group B Streptococcus (GBS). In vitro studies using human cord blood monocytes have demonstrated that GBS induces TNF-alpha secretion, but little is known about the intracellular signaling pathways of TNF-alpha induction. In this report we show that heat-killed serotype III GBS induces host cell signal transduction pathways that lead to activation of the transcription factors NF-kappaB and AP-1. Using adenoviral transfer of IkappaBalpha (IkappaBalpha overexpression), the production of TNF-alpha induced by whole GBS was inhibited by only 20%. We also show that the p38 mitogen-activated protein kinase (MAPK) pathway is involved in GBS-induced TNF-alpha secretion, because TNF-alpha protein and mRNA levels in the presence of a specific inhibitor of p38 MAPK, SB 202190, were dramatically diminished. EMSAs showed that SB 202190 inhibited GBS-induced AP-1 activation, but had no effect on NF-kappaB-DNA binding activity. These results indicate that both NF-kappaB and AP-1 (via p38 MAPK) are involved in the regulation of TNF-alpha production in GBS-stimulated neonatal monocytes. Therefore, disrupting the signal transduction pathways induced by GBS has the potential to attenuate the production of immune response mediators, thereby halting or possibly reversing the course of this potentially fatal disease.

Enzyme Activation↗
PubMed2000

Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction.

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%) when compared with either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.

Acute Disease↗
PubMed2000

Is inflammation good for the ischemic heart--perspectives beyond the ordinary.

In recent years, early reperfusion of the myocardial infarct has become the mainstay of optimal therapeutic management since it limits ventricular injury and infarct expansion and improves patient survival [14]. It has become clear that reperfusion promotes effective tissue repair and decreases ventricular remodeling even under circumstances where reperfusion is effected at too late a time to limit myocardial necrosis [4]. One of the striking differences between reperfused and non-reperfused myocardial infarctions is that the early intense inflammatory reaction which ensues immediately upon reperfusion has been demonstrated to potentially extend myocardial injury [9]. Substantial evidence suggests that this inflammatory reaction is important in tissue repair, leading to an obvious paradox with regard to the role of the inflammatory reaction. This communication takes the position that inflammatory injury occurring upon reperfusion of the infarcted myocardium results from the overwhelming of tissue defenses against inflammation resulting from the sudden entry of large amounts of neutrophils to an area of infarction where chemotactic factors have built up to high concentration. However, we hypothesize that inflammation fundamentally evolved as a protective mechanism to promote tissue healing and protect jeopardized myocardium. In this presentation, we will discuss our approach and data designed to evaluate potential protective roles of the inflammatory reaction after reperfusion.

Animals↗
PubMed2000

Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload.

OBJECTIVES: We sought to determine whether serum tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with hemodynamically significant pressure and volume overload. BACKGROUND: It has been previously shown that TNF-alpha messenger ribonucleic acid (mRNA) and protein are rapidly expressed in the hearts of animal models subjected to abrupt hemodynamic overloading. The clinical significance of these experimental findings has not been tested in pathophysiologically relevant clinical models in human subjects. METHODS: We prospectively measured serum TNF-alpha levels and serum TNF receptor 1 and 2 levels in 21 patients with severe aortic stenosis (AS), in 26 patients with 3+ to 4+ mitral regurgitation (MR) and in normal age- and gender-matched control subjects. Patients with AS and MR were either in New York Heart Association (NYHA) functional class I or II and had no significant coronary disease. We compared the cytokine levels among the groups using analysis of variance. We related cytokine levels to the severity of AS using simple regression analysis. RESULTS: Serum TNF-alpha levels in patients with AS (2.1 +/- 1.6 pg/ml, n = 21) and MR (1.3 +/-0.7 pg/ml, n = 26) were significantly higher than those in the control subjects (0.7 +/-0.2 pg/ml, n = 28). Serum TNF receptor 1 and 2 levels were also higher in patients with AS and MR than in control subjects. Cytokine levels were higher in patients in NYHA class II than in those in class I. In patients with a normal ejection fraction (>50%, n = 16), there was a mild positive correlation (r = 0.56, p = 0.025) between serum TNF-alpha levels and the mean gradient across the aortic valve. CONCLUSIONS: This study demonstrates that serum TNF-alpha is elevated in patients with chronic hemodynamic overloading and early cardiac decompensation. Furthermore, these findings suggest not only that peripheral TNF-alpha levels correlate with the severity of the hemodynamic pressure overload, but also that peripheral TNF-alpha and TNF receptor levels increase in direct relation to deteriorating NYHA functional class.

Aged↗
PubMed2000

The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors.

OBJECTIVES: The object of the study was to assess the relationship between erythrocyte sedimentation rate (ESR) and inflammatory cytokine production in chronic heart failure (CHF). Our findings lead us to re-evaluate the prognostic value of the ESR in assessing patients with CHF. BACKGROUND: The search for simple prognostic markers in CHF that can be assessed anywhere at low cost is important. Increases in ESR are related to the acute phase response in states of inflammation and infection. METHODS: Initially, we studied ESR in relation to plasma levels of inflammatory cytokines in 58 CHF patients. The findings prompted us to analyze the mortality predictive power of ESR compared with established risk factors in these patients and (retrospectively) in a second group of 101 clinically stable CHF patients who had ESR measured. RESULTS: In all 159 CHF patients (age 62+/-2 years, New York Heart Association [NYHA] class 2.7+/-0.1), ESR ranged from 1 to 96 mm/h (median 14 mm/h). The ESR was correlated with tumor necrosis factor (TNF)-alpha (r = 0.31, p<0.05), soluble TNF receptor-1 (r = 0.48, p<0.0005), soluble TNF receptor-2 (r = 0.39, p<0.005) and interleukin 6 (r = 0.45, p<0.005) levels. High ESR levels indicated a poor prognosis (p<0.0001), and this was independent of age, NYHA class, ejection fraction and peak oxygen consumption (p < 0.005). Patients with ESR above median (> or =15 mm/h) compared with patients with ESR <15 mm/h had an impaired survival (hazard ratio 2.62, 95% confidence interval 1.58-4.36, p<0.0001). CONCLUSIONS: Our study demonstrates that in CHF a high ESR is an unfavorable prognostic sign, independent of patients' symptomatology and ventricular function. These results are in diametrical contrast to previous results. This may reflect a change in the underlying pathophysiology due to today's treatment with angiotensin-converting enzyme inhibitors.

Adult↗
PubMed2000

Cytokines as emerging targets in the treatment of heart failure.

Recent studies have identified the importance of biologically active molecules such as neurohormones in disease progression in heart failure. More recently it has become apparent that in addition to neurohormones another portfolio of biologically active molecules termed cytokines are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material which suggest that the cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) may represent another class of biologically active molecules that are responsible for the development and progression of heart failure. In addition, we also review the early results from clinical trials that have utilized various targeted anti-cytokine strategies in patients with heart failure.

Cytokines↗
PubMed2000

Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure.

BACKGROUND: Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, are elevated in patients with congestive heart failure (CHF). Recent studies suggest that the failing human heart is a source of proinflammatory cytokines in the end-stage failing heart. However, the relevance of plasma levels to those of the myocardium remains undefined. We sought to compare cytokine expression in early and end-stage CHF, and to evaluate the correlation of tissue expression to plasma levels. METHODS: Two patient populations were studied: patients with recent-onset CHF, all with symptoms less than 6 months (n = 17, duration of symptoms 2.1 +/- 1.6 months, range of New York Heart Association (NYHA) 1 to 3), and end-stage heart-failure patients (n = 7) who underwent left-ventricular assist-device (LVAD) implantation (Duration of symptoms 47.1 +/- 28.0 months, all NYHA class 4). Plasma levels of TNF-alpha and IL-6 proteins were evaluated by an Enzyme-Linked Immuno-Sorbent Assay (ELISA), while myocardial levels of cytokine transcripts were assessed by ribonuclease (Rnase) protection assay. RESULTS: In patients with end-stage heart failure, TNF-alpha and IL-6 were increased in the plasma as well as in the myocardium (plasma: TNF-alpha = 7.7 +/- 2.3 pg/ml, IL-6 = 45.0 +/- 47.1 pg/ml; myocardium: TNF-alpha = 0.31 +/- 0.15% of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, IL-6 = 1.56 +/- 1.54% ). In contrast, despite elevated plasma levels of TNF-alpha and IL-6, the myocardium of patients with the recent onset of symptoms demonstrated minimal expression of TNF-alpha and IL-6 messenger ribonucleic acid (mRNA) (plasma: TNF-alpha = 4.3 +/- 1.7 pg/ml, IL-6 = 3.3 +/- 1.8 pg/ml; myocardium: TNF-alpha = 0.13 +/- 0. 04%, IL-6 = 0.02 +/- 0.04%). Plasma levels of TNF-alpha were significantly correlated with those in the myocardium when both populations were combined. (r = 0.69, p < 0.001). CONCLUSIONS: Cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent-onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF. Furthermore, plasma levels of TNF-alpha correlates with mRNA expression in the myocardium and thus may serve as an appropriate marker of myocardial cytokine activation. Whether the production of cytokines in the failing human heart precedes the elevation of cytokines in the plasma remains undefined. Therefore, we studied expression of TNF-alpha and IL-6 in the myocardium as well as in the plasma in patients with early and end-stage CHF. The results have demonstrated that cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF.

Adult↗
PubMed2000

Veterans Affairs Quality Enhancement Research Initiative in chronic heart failure.

Chronic heart failure (CHF) is a highly prevalent condition associated with serious morbidity, intense levels of health services use, and shortened survival. It is also a condition for which ameliorative therapies exist. The evidence indicates that there is substantial need to change clinical practice and health care delivery for people with CHF and thereby improve their outcomes. The goal of the Veterans Affairs (VA) Quality Enhancement Research Initiative in CHF (CHF QUERI) is to create measurable, rapid, and sustainable improvements in quality of care and health outcomes of veterans with heart failure. This article describes the current state of knowledge and practice in care for people with CHF. Using the framework of the 5 steps of the QUERI process, we point out the gaps in research and practice that must be filled if the CHF QUERI is to achieve its goal. We relate our recommendations for how the VA can put its research and administrative infrastructure to work to fill the gaps. Lessons learned about CHF in the course of the CHF QUERI will be applicable to all people with heart failure and to all health care systems--VA as well as non-VA--that care for them.

Benchmarking↗
PubMed1999

Developing dendritic cell polynucleotide vaccination for prostate cancer immunotherapy.

Immunotherapy has been successfully used to treat some human malignancies, principally melanoma and renal cell carcinoma. Genetic-based cancer immunotherapies were proposed which prime T lymphocyte recognition of unique neo-antigens arising from specific mutations. Genetic immunization (polynucleotide vaccination, DNA vaccines) is a process whereby gene therapy methods are used to create vaccines and immunotherapies. Recent findings indicate that genetic immunization works indirectly via a bone marrow derived cell, probably a type of dendritic antigen presenting cell (APC). Direct targeting of genetic vaccines to these cells may provide an efficient method for stimulating cellular and humoral immune responses to infectious agents and tumor antigens. Initial studies have provided monocytic-derived dendritic cell (DC) isolation and culture techniques, simple methods for delivering genes into these cells, and have also uncovered potential obstacles to effective cancer immunotherapy which may restrict the utility of this paradigm to a subset of patients.

Antigens, Neoplasm↗
PubMed1999

Desmin mutation responsible for idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy, of which approximately 20% of cases are familial (FDCM), is a primary myocardial disorder characterized by ventricular dilatation and impaired systolic function. It is a common cause of heart failure and the need for cardiac transplantation. Although 6 chromosomal loci responsible for autosomal dominant FDCM have been mapped by linkage analysis, none of these genes have been identified. By use of the candidate-gene approach, actin was identified recently as being responsible for dilated cardiomyopathy. Considerable evidence suggests desmin, a muscle-specific intermediate filament, plays a significant role in cardiac growth and development. METHODS AND RESULTS: To determine whether a defect of desmin induces dilated cardiomyopathy, 44 probands with FDCM underwent clinical evaluation and DNA analysis. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of >/=2.7 cm/m(2) with an ejection fraction </=50% in the absence of other potential causes. After amplification by polymerase chain reaction, the exons of the desmin gene were sequenced. A missense desmin mutation, Ile451Met, which cosegregates with FDCM without clinically evident skeletal muscle abnormalities, was identified in a 4-generation family but was not detected in 460 unrelated healthy individuals. CONCLUSIONS: A novel missense mutation of desmin, Ile451Met, was identified as the genetic cause of idiopathic dilated cardiomyopathy. This finding is of particular significance because this is the first mutation detected in the desmin tail domain, and the function of the desmin tail remains unknown. Because this mutation leads to a restricted cardiac phenotype in the family studied in the present report, it suggests that the tail of desmin plays an important functional role in cardiac tissue.

Cardiomyopathy, Dilated↗