Cardiac dysfunction in solid tumours: scoping review.

Cardio-oncology is a dynamic field. Research has suggested that cancer itself can damage the heart, independent of cancer treatment-related cardiac dysfunction (CTRCD). The aim of this study was to establish the nature of cardiovascular abnormalities reported in cancer, excluding CTRCD. Scoping review search included cardiovascular abnormalities in adults with solid tumour malignancies, and excluded CTRCD and thrombotic events. Three databases (CINAHL, Embase, Medline) were searched, supplemented by a handsearch. All screening and data extraction was done by two researchers with consensus reached for any conflicts. Given the heterogeneous nature of the studies identified, data synthesis was narrative. The search identified 42 366 studies. Following deduplication and title/abstract screening, 195 studies were assessed for full-text eligibility. Forty-four studies are included in the final analysis. There are 19 prospective observational studies, 13 retrospective studies, 9 case reports and 3 cross-sectional studies. Types of abnormality identified include cardiomyopathy (16, including Takotsubo (9)), autonomic nervous system (ANS) dysfunction (10), biomarker disturbances (9), reduced myocardial strain (6) and others (3). Due to variable study design, the prevalence was not determined. Cardiovascular abnormalities were associated with morbidity (chest pain, dyspnoea, fatigue) and shortened prognosis. In conclusion: (1) There is evidence for cardiovascular dysfunction in patients with solid tumour malignancies, distinct from CTRCD. People with solid tumours have higher rates of cardiac disease, even when newly diagnosed and treatment naïve. (2) Abnormalities manifest mainly as cardiomyopathies, ANS dysfunction and raised biomarker levels and are associated with significant symptoms. (3) Treatment plans need to take account of these risks, and widen criteria for screening.

Myocardial strain: a clinical review.

BACKGROUND: Myocardial strain-change in myocardial fibre length over the cardiac cycle-is a measure of cardiac muscle function. It is obtained using conventional techniques such as echocardiography and magnetic resonance imaging, adding additional clinical information to augment the current techniques. METHODS: A narrative review of the current relevant literature with respect to myocardial strain, with a focus on strain measured by echocardiography. RESULTS: Myocardial strain identifies global and regional abnormalities in myocardial function and differentiates types of cardiomyopathy. It is an earlier marker of myocardial disease than ejection fraction and is predictive of cardiovascular adverse events. Accurate measurement requires high-quality images and experienced practitioners. CONCLUSION: This review explains advantages and disadvantages of myocardial strain imaging and explains why, through adding increased precision without additional burden, it should be a standard part of cardiac assessment.

von Willebrand factor links primary hemostasis to innate immunity.

The plasma multimeric glycoprotein von Willebrand factor (VWF) plays a critical role in primary hemostasis by tethering platelets to exposed collagen at sites of vascular injury. Recent studies have identified additional biological roles for VWF, and in particular suggest that VWF may play an important role in regulating inflammatory responses. However, the molecular mechanisms through which VWF exerts its immuno-modulatory effects remain poorly understood. In this study, we report that VWF binding to macrophages triggers downstream MAP kinase signaling, NF-κB activation and production of pro-inflammatory cytokines and chemokines. In addition, VWF binding also drives macrophage M1 polarization and shifts macrophage metabolism towards glycolysis in a p38-dependent manner. Cumulatively, our findings define an important biological role for VWF in modulating macrophage function, and thereby establish a novel link between primary hemostasis and innate immunity.

Particle swarm optimization artificial intelligence technique for gene signature discovery in transcriptomic cohorts.

The development of gene signatures is key for delivering personalized medicine, despite only a few signatures being available for use in the clinic for cancer patients. Gene signature discovery tends to revolve around identifying a single signature. However, it has been shown that various highly predictive signatures can be produced from the same dataset. This study assumes that the presentation of top ranked signatures will allow greater efforts in the selection of gene signatures for validation on external datasets and for their clinical translation. Particle swarm optimization (PSO) is an evolutionary algorithm often used as a search strategy and largely represented as binary PSO (BPSO) in this domain. BPSO, however, fails to produce succinct feature sets for complex optimization problems, thus affecting its overall runtime and optimization performance. Enhanced BPSO (EBPSO) was developed to overcome these shortcomings. Thus, this study will validate unique candidate gene signatures for different underlying biology from EBPSO on transcriptomics cohorts. EBPSO was consistently seen to be as accurate as BPSO with substantially smaller feature signatures and significantly faster runtimes. 100% accuracy was achieved in all but two of the selected data sets. Using clinical transcriptomics cohorts, EBPSO has demonstrated the ability to identify accurate, succinct, and significantly prognostic signatures that are unique from one another. This has been proposed as a promising alternative to overcome the issues regarding traditional single gene signature generation. Interpretation of key genes within the signatures provided biological insights into the associated functions that were well correlated to their cancer type.

Cancer treatment-related cardiac dysfunction.

OBJECTIVES: This paper describes cardiotoxicity and cancer treatment-related cardiac dysfunction (CTRCD). Long-term sequelae of treatment are important, and changing, and may manifest when a patient is under the care of a supportive care service. METHODS: Key messages for supportive and palliative care clinicians are outlined to facilitate identification and management of CTRCD. RESULTS: Not all cardiotoxicity is alike. Types of cardiotoxicity, cardiac complications of immunotherapy, the challenge of autonomic nervous system dysfunction in cancer and management of cardiotoxicity are highlighted. CONCLUSIONS: The key strategies are early detection of cardiotoxicity, monitoring for development of CTRCD during treatment and surveillance in survivorship.

Real-World Experience With Antiplatelet Agents After Percutaneous Coronary Intervention in Patients With an Indication for an Oral Anticoagulant.

ABSTRACT: Patients undergoing percutaneous coronary intervention (PCI) with a clinical indication for oral anticoagulation (OAC) in addition to antiplatelet therapy (APT) necessitate rigorous evaluation of bleeding and ischemic risk to guide therapy. The optimal OAC/APT drug combination and duration of treatment is not known. This study aimed to evaluate the incidence of patients undergoing PCI with an OAC indication and the rationale for post-PCI combined OAC/APT selection in clinical practice. Consecutive patients undergoing PCI with an indication for combined OAC/APT were included in a 12-month retrospective case series. Patient demographics, clinical characteristics, prescribed OAC/APT regimens, and rationale for drug selection were reviewed. PCI was performed in 1650 patients during the study period, with an indication for OAC/APT in 133 (8.1%). A combination of aspirin, P2Y12 inhibitor, and OAC was the most frequently prescribed regime on discharge (n = 103, 81%). Dual antiplatelet therapy (DAPT) in combination with OAC was continued for a mean duration of 6.4 ± 4.4 weeks (range 3-52 weeks) before one antiplatelet was discontinued. There was no significant difference between the mean CHA2DS2-VASc or HAS-BLED score of patients with atrial fibrillation discharged on OAC/DAPT compared with alternate combinations (DAPT alone or OAC/single APT), 3.6 ± 1.3 versus 3.8 ± 1, P = 0.37 and 2.04 ± 0.7 versus 2.05 ± 1.0, P = 0.98, respectively. This case series identifies high variability in OAC/APT treatment duration and limited application of risk scoring systems and high-risk PCI characteristics in the selection of OAC/APT regimens. A more systematic patient assessment is needed to help standardize OAC/APT prescribing for this important patient cohort.

Prostate cancer heterogeneity assessment with multi-regional sampling and alignment-free methods.

Combining alignment-free methods for phylogenetic analysis with multi-regional sampling using next-generation sequencing can provide an assessment of intra-patient tumour heterogeneity. From multi-regional sampling divergent branching, we validated two different lesions within a patient's prostate. Where multi-regional sampling has not been used, a single sample from one of these areas could misguide as to which drugs or therapies would best benefit this patient, due to the fact these tumours appear to be genetically different. This application has the power to render, in a fraction of the time used by other approaches, intra-patient heterogeneity and decipher aberrant biomarkers. Another alignment-free method for calling single-nucleotide variants from raw next-generation sequencing samples has determined possible variants and genomic locations that may be able to characterize the differences between the two main branching patterns. Alignment-free approaches have been applied to relevant clinical multi-regional samples and may be considered as a valuable option for comparing and determining heterogeneity to help deliver personalized medicine through more robust efforts in identifying targetable pathways and therapeutic strategies. Our study highlights the application these tools could have on patient-aligned treatment indications.

miR-191 promotes radiation resistance of prostate cancer through interaction with RXRA.

Radiation therapy is a common treatment for prostate cancer, however recurrence remains a problem. MicroRNA expression is altered in prostate cancer and may promote therapy resistance. Through bioinformatic analyses of TCGA and CPC-GENE patient cohorts, we identified higher miR-191 expression in tumor versus normal tissue, and increased expression in higher Gleason scores. In vitro and in vivo experiments demonstrated that miR-191 overexpression promotes radiation survival, and contributes to a more aggressive phenotype. Retinoid X receptor alpha, RXRA, was discovered to be a novel target of miR-191, and knockdown recapitulated radioresistance. Furthermore, treatment of prostate cancer cells with the RXRA agonist 9-cis-retinoic acid restored radiosensitivity. Supporting this relationship, patients with high miR-191 and low RXRA abundance experienced quicker biochemical recurrence. Reduced RXRA translated to a higher risk of distant failure after radiotherapy. Notably, this miR-191/RXRA interaction was conserved in a novel primary cell line derived from radiorecurrent prostate cancer. Together, our findings demonstrate that miR-191 promotes prostate cancer survival after radiotherapy, and highlights retinoids as a potential option to improve radiotherapy response.

Epigenetic modulation in the treatment of atherosclerotic disease.

Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterized by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic phenomena are a focus of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.

Two-stage percutaneous closure of mitral periprosthetic valvular leak.

Periprosthetic valve leak can develop as a complication of valve replacement surgery and may manifest as symptomatic valvular regurgitation, heart failure, or haemolysis. We report a case of severe mitral periprosthetic valve leak requiring a two-stage percutaneous closure technique with multiple Amplatzer® III vascular plugs.

Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.

OBJECTIVE: To examine the long-term effects of standard chemotherapy on myocardial function in asymptomatic breast cancer survivors using two-dimensional speckle tracking echocardiography. METHODS: Seventy women (chemotherapy group) aged 54+/-8 years who had received anthracycline treatment with (n=19) or without (n=51) adjuvant trastuzumab up to 6 years previously, and 50 female controls were studied. Left ventricular systolic (ejection fraction (EF%), peak systolic myocardial excursion, (Sm)) and diastolic (peak mitral E and A velocities, six-point average of mitral annular E' velocities) function, 2D global and regional longitudinal and radial strain were determined using standard 2D Doppler and tissue Doppler echocardiographic methods and speckle tracking software. RESULTS: Despite normal EF% (62+/-4% vs 60+/-3%, p=0.051) the chemotherapy group had reduced E/A ratios (0.9+/-0.3 vs 1.1+/-0.3, p=0.003), global E' (10.2+/-2 vs 11.2+/-2.3, p=0.036), global Sm (9.0+/-1.3 vs 9.6+/-1.3, p=0.029) and global longitudinal 2D strain (-18.1+/-2.2 vs -19.6+/-1.8, p=0.0001) in comparison with controls. In 18 (26%) of the chemotherapy group, global longitudinal strain was below the lower limit of the control group. Cigarette smoking was a negative predictor of longitudinal strain, but only in the chemotherapy group. Radial strain did not differ significantly between the two groups. There were no significant differences in EF%, global Sm and longitudinal strain between trastuzumab-treated individuals and controls. CONCLUSIONS: Subclinical systolic and diastolic myocardial abnormalities were present in asymptomatic breast cancer survivors up to 6 years after standard chemotherapy. Cigarette smoking had a negative effect on longitudinal strain in these individuals. Adjuvant trastuzumab treatment did not appear to have an additive adverse impact on myocardial function in the medium-long term.

Current status of vulnerable plaque detection.

Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high-risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high-risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high-risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow-limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high-risk but non flow-limiting plaque to establish patient-specific targeted therapy and to refine plaque stabilizing strategies in the future.

Mitral valve abnormalities in hypertrophic cardiomyopathy: echocardiographic features and surgical outcomes.

BACKGROUND: Functional and intrinsic mitral valve (MV) abnormalities are common in hypertrophic cardiomyopathy (HCM); however, morphologic characteristics constituting indications for surgical intervention are incompletely defined. This study was conducted to define the echocardiographic features of MV pathology in patients with HCM and relate these to repairability of the MV, MV procedures performed, durability of repair, and survival. METHODS: From 1986 to 2003, 851 patients with HCM underwent operation, and 115 had a concomitant MV procedure. Detailed analysis of their 784 transthoracic and transesophageal echocardiograms, performed intraoperatively and postoperatively, was conducted. Outcomes were assessed by cross-sectional follow-up. RESULTS: Sixty-seven patients (58%) underwent MV repair, and 48 (42%) had MV replacement. The mean left ventricular outflow tract peak gradient was 70 +/- 50 mm Hg. Systolic anterior motion was present in 95%. Valve abnormalities were degenerative in 36 (31%), myxomatous in 23 (20%), papillary muscle in 23 (20%), restrictive chordal in 22 (19%), restrictive leaflet in 80 (70%), and long leaflet in 64 (56%). Patients undergoing MV repair had higher prevalence of long leaflets and degenerative MV pathology. The anterior mitral leaflet was 3.0 +/- 0.49 cm in the repair group vs 2.5 +/- 0.40 cm in the replacement group (p = 0.0001). MV replacement patients were older, more symptomatic, and had more renal dysfunction and lower hematocrits. By 3 years, 91% of patients with a repair were free of reoperation. CONCLUSIONS: Intrinsic MV pathology is frequently observed in HCM patients with symptomatic obstruction who undergo myectomy. Echocardiography can identify MV features predictive of successful valve repair. Repair, although durable, is feasible in only about half of patients.

Mutations in PDLIM3 and MYOZ1 encoding myocyte Z line proteins are infrequently found in idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM), characterized by ventricular dilation and decreased systolic function, is estimated to be of genetic origin in up to 50% of cases. In the present study, we investigated the role of two genes, encoding the Z line proteins PDZ and LIM domain protein 3 (PDLIM3) and myozenin-1 (MYOZ1), in the etiology of DCM. The coding regions of PDLIM3 and MYOZ1 were first amplified from the genomic DNA of 185 unrelated DCM patients by polymerase chain reaction (PCR), followed by denaturing high-performance liquid chromatography (DHPLC) analysis. The samples that exhibited abnormal peaks on DHPLC were re-amplified, purified and sequenced using a Big-Dye Terminator cycle sequencing system. Interestingly, a 2-bp insertion (178insCA) in exon 2 of PDLIM3 was identified in one patient who presented with DCM during pregnancy and died a year later awaiting heart transplant. No other significant mutations were found in either PDLIM3 or MYOZ1. The mutation probably resulted in an unstable protein, since no exogenous protein could be detected in transfected murine myoblastoid cells by immunohistochemical or Western blot analyses. We conclude that mutations in PDLIM3 and MYOZ1, encoding myocyte Z line proteins, do not play any significant role in the genetic etiology of idiopathic DCM. The exact mechanism by which the mutation identified in the present study is linked to DCM phenotype remains unknown. The hemodynamic burden of pregnancy and/or other genetic or environmental factors could have precipitated heart failure symptoms in an individual with defective myocardial cytoarchitecture.

Use of percutaneous transluminal septal myocardial ablation for relief of outflow tract obstruction in cardiac amyloidosis: a novel therapeutic target.

Cardiac amyloidosis typically presents with diastolic heart failure, but asymmetrical septal hypertrophy with outflow tract obstruction has been described. We illustrate the case of a 71-year-old woman with biopsy-proven cardiac amyloidosis and severe medical comorbidities with refractory severe heart failure who had asymmetric septal hypertrophy, systolic anterior motion (SAM) of the mitral valve, and a resting left ventricular outflow tract gradient of 86 mm Hg, increasing to 102 mm Hg on Valsalva maneuver. She underwent percutaneous transluminal septal myocardial ablation (PTSMA) with a dramatic resolution of her SAM and outflow tract obstruction, confirmed by intracavitary pressure wire measurements. PTSMA is technically feasible in this context, and correction of outflow tract obstruction may represent a new therapeutic target in cardiac amyloidosis.

Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy.

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.

Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history.

OBJECTIVES: The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM). BACKGROUND: Adenosine monophosphate-activated protein kinase gene mutations cause HCM with Wolff-Parkinson-White syndrome and conduction disease. METHODS: Clinical evaluation of 44 patients with known AMP kinase disease was analyzed. Mutation analysis of PRKAG2 was performed by fluorescent single-strand confirmation polymorphism analysis and direct sequencing of abnormal conformers in 200 patients with HCM. RESULTS: Only one additional mutation was identified. The mean age at clinical diagnosis in the 45 gene carriers was 24 years (median 20 years, range 9 to 55 years). Symptoms of palpitation, dypspnea, chest pain, or syncope were present in 31 (69%) gene carriers; 7 (15%) complained of myalgia and had clinical evidence of proximal myopathy. Skeletal muscle biopsy showed excess mitochondria and ragged red fibers with minimal glycogen accumulation. Disease penetrance defined by typical electrocardiogram abnormalities was 100% by age 18 years. Thirty-two of 41 adults (78%) had left ventricular hypertrophy (LVH) on echocardiography, and progressive LVH was documented during follow-up. Survival was 91% at a mean follow-up of 12.2 years. Progressive conduction disease required pacemaker implantation in 17 of 45 (38%) at a mean age of 38 years. CONCLUSIONS: The AMP kinase disease is uncommon in HCM and is characterized by progressive conduction disease and cardiac hypertrophy and includes extracardiac manifestations such as a skeletal myopathy, consistent with a systemic metabolic storage disease. Defects in adenosine triphosphate utilization or in specific cellular substrates, rather than mere passive deposition of amylopectin, may account for these clinical features.

Vitamin E modulation of C-reactive protein in smokers with acute coronary syndromes.

Acute coronary syndromes are characterized by the expression of proinflammatory cytokines such as C-reactive protein (CRP). Sustained upregulation of inflammatory markers is associated with an adverse prognosis. Vitamin E is known to have significant anti-inflammatory properties and has been associated with a reduction in cardiovascular events in some studies of high-risk patients. The mechanism of benefit remains controversial. We conducted a randomized, double-blind placebo controlled trial of vitamin E 400 IU daily for 6 months in 110 patients with acute coronary syndromes. Serum samples were collected at enrollment and at 2, 4, and 6 months. CRP, interleukin-6 and the soluble cell adhesion molecules were measured. Vitamin E levels increased significantly in the treatment group (from 31 micromol/l at baseline to 51 micromol/l, p <.0001) and were unchanged in the placebo group (32 micromol/l at baseline to 34 micromol/l, p = NS). CRP levels fell in both the vitamin E group and the placebo group over the treatment period (from 17.2 +/- 2.9 to 6.1 +/- 0.8 mg/l and from 21.5 +/- 4.9 to 5.9 +/- 0.9 mg/l, p = NS for the difference between active and placebo groups). However, vitamin E treatment was associated with significantly lower 6 month CRP levels in smokers versus smokers on placebo (4.7 +/- 0.71 mg/l vs. 8.26 +/- 1.5 mg/l, p =.02). Vitamin E reduces CRP levels in smokers with acute coronary syndromes for up to 6 months after hospitalization.

Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and alpha-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in alpha-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit alpha-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.