Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter–defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $65.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Hershberger, R. E., Morales, A. & Siegfried, J. D. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet. Med. 12, 655–667 (2010). This review article provides a wide and detailed overview of clinical and genetic issues in specific types of genetic DCM.
McKenna, W. J., Maron, B. J. & Thiene, G. Classification, epidemiology, and global burden of cardiomyopathies. Circ. Res. 121, 722–730 (2017).
Maron, B. J. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113, 1807–1816 (2006).
Elliott, P. et al. Classification of the cardiomyopathies: a position statement from the european society of cardiology working group on myocardial and pericardial diseases. Eur. Heart J. 29, 270–276 (2007).
Richardson, P. et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 93, 841–842 (1996).
Pollack, A., Kontorovich, A. R., Fuster, V. & Dec, G. W. Viral myocarditis — diagnosis, treatment options and current controversies. Nat. Rev. Cardiol. 12, 670–680 (2015).
Sagar, S., Liu, P. P. & Cooper, L. T. Myocarditis. Lancet 379, 738–747 (2012).
Caforio, A. L. P. et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 34, 2636–2648 (2013). In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases, an expert consensus group reviews the knowledge on clinical presentation, diagnosis and treatment of myocarditis and proposes diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms.
Braunwald, E. Cardiomyopathies. Circ. Res. 121, 711–721 (2017).
Codd, M. B., Sugrue, D. D., Gersh, B. J. & Melton, L. J. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 80, 564–572 (1989).
Hershberger, R. E., Hedges, D. J. & Morales, A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 10, 531–547 (2013).
Maron, B. J. et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary artery risk development in (young) adults. Circulation 92, 785–789 (1995).
Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1545–1602 (2016).
Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).
Ehlert, F. A. et al. Comparison of dilated cardiomyopathy and coronary artery disease in patients with life-threatening ventricular arrhythmias: differences in presentation and outcome in the AVID registry. Am. Heart J. 142, 816–822 (2001).
Saxon, L. A. et al. Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. J. Cardiol. 72, 62–65 (1993).
Saxon, L. A. & De Marco, T. Arrhythmias associated with dilated cardiomyopathy. Card. Electrophysiol. Rev. 6, 18–25 (2002).
Fairweather, D., Cooper, L. T. & Blauwet, L. A. Sex and gender differences in myocarditis and dilated cardiomyopathy. Curr. Probl. Cardiol. 38, 7–46 (2013). This article provides an overview on sex and gender differences in myocarditis and DCM. The authors highlight the gaps in our knowledge regarding the management of women with acute DCM and discuss emerging therapies.
McGoon, M. D. & Miller, D. P. REVEAL: a contemporary US pulmonary arterial hypertension registry. Eur. Respir. Rev. 21, 8–18 (2012).
Halliday, B. P. et al. Sex- and age-based differences in the natural history and outcome of dilated cardiomyopathy. Eur. J. Heart Fail. 20, 1392–1400 (2018).
Kubo, T. et al. Improvement in prognosis of dilated cardiomyopathy in the elderly over the past 20 years. J. Cardiol. 52, 111–117 (2008).
Binkley, P. F. et al. Recovery of normal ventricular function in patients with dilated cardiomyopathy: predictors of an increasingly prevalent clinical event. Am. Heart J. 155, 69–74 (2008).
Castelli, G. et al. Improving survival rates of patients with idiopathic dilated cardiomyopathy in Tuscany over 3 decades. Circ. Heart Fail. 6, 913–921 (2013).
Dries, D. L. et al. Racial differences in the outcome of left ventricular dysfunction. N. Engl. J. Med. 340, 609–616 (1999).
Coughlin, S. S. et al. Black-white differences in mortality in idiopathic dilated cardiomyopathy: the Washington, DC, dilated cardiomyopathy study. J. Natl Med. Assoc. 86, 583–591 (1994).
McNamara, D. M. et al. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy. J. Am. Coll. Cardiol. 58, 1112–1118 (2011).
Dec, G. W. The natural history of acute dilated cardiomyopathy. Trans. Am. Clin. Climatol. Assoc. 125, 76–86 (2014).
Nieminen, M. S. et al. Gender related differences in patients presenting with acute heart failure. Results from EuroHeart Failure Survey II. Eur. J. Heart Fail. 10, 140–148 (2008).
Benjamin, E. J. et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 135, e146–e603 (2017).
Towbin, J. A. et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 296, 1867 (2006).
Nugent, A. W. et al. The epidemiology of childhood cardiomyopathy in Australia. N. Engl. J. Med. 348, 1639–1646 (2003).
Lipshultz, S. E. et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N. Engl. J. Med. 348, 1647–1655 (2003). The authors of this article estimate that the incidence of paediatric cardiomyopathy is 1.13 cases per 100,000 children. Most cases are identified at an early age, and the incidence appears to vary according to region, sex and racial or ethnic origin.
Lipshultz, S. E. et al. Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies. Future Cardiol. 9, 817–848 (2013).
Alvarez, J. A. et al. Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: results from the Pediatric Cardiomyopathy Registry. Circulation 124, 814–823 (2011).
Arola, A. et al. Epidemiology of idiopathic cardiomyopathies in children and adolescents: a nationwide study in Finland. Am. J. Epidemiol. 146, 385–393 (1997).
Rusconi, P. et al. Differences in presentation and outcomes between children with familial dilated cardiomyopathy and children with idiopathic dilated cardiomyopathy. Circ. Heart Fail. 10, e002637 (2017).
Ashley, E. A. Towards precision medicine. Nat. Rev. Genet. 17, 507–522 (2016).
Piran, S., Liu, P., Morales, A. & Hershberger, R. E. Where genome meets phenome: rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure. J. Am. Coll. Cardiol. 60, 283–289 (2012).
Ware, J. S. et al. Genetic etiology for alcohol-induced cardiac toxicity. J. Am. Coll. Cardiol. 71, 2293–2302 (2018).
McNally, E. M., Golbus, J. R. & Puckelwartz, M. J. Genetic mutations and mechanisms in dilated cardiomyopathy. J. Clin. Invest. 123, 19–26 (2013).
Japp, A. G., Gulati, A., Cook, S. A., Cowie, M. R. & Prasad, S. K. The diagnosis and evaluation of dilated cardiomyopathy. J. Am. Coll. Cardiol. 67, 2996–3010 (2016).
Morales, A. & Hershberger, R. E. The rationale and timing of molecular genetic testing for dilated cardiomyopathy. Can. J. Cardiol. 31, 1309–1312 (2015).
Burkett, E. L. & Hershberger, R. E. Clinical and genetic issues in familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 45, 969–981 (2005).
Fatkin, D. et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med. 341, 1715–1724 (1999).
Kamisago, M. et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N. Engl. J. Med. 343, 1688–1696 (2000).
Gerull, B. et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat. Genet. 30, 201–204 (2002).
Brauch, K. M. et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 54, 930–941 (2009).
Norton, N. et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am. J. Hum. Genet. 88, 273–282 (2011).
Herman, D. S. et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 366, 619–628 (2012).
Hershberger, R. E. & Siegfried, J. D. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 57, 1641–1649 (2011).
Harakalova, M. et al. A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle-specific genes. Eur. J. Heart Fail. 17, 484–493 (2015).
Hershberger, R. E. & Morales, A. Dilated cardiomyopathy overview. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1309 (updated 23 Aug 2018).
Kinnamon, D. D. et al. Toward genetics-driven early intervention in dilated cardiomyopathy. Circ. Cardiovasc. Genet. 10, e001826 (2017).
Walsh, R. et al. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur. Heart J. 38, 3461–3468 (2017).
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
Strande, N. T. et al. Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource. Am. J. Hum. Genet. 100, 895–906 (2017).
Rehm, H. L. et al. ClinGen — the clinical genome resource. N. Engl. J. Med. 372, 2235–2242 (2015).
Ingles, J. et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ. Genom. Precis. Med. 12, e002460 (2019).
Shendure, J. A deep dive into genetic variation. Nature 536, 277–278 (2016).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–423 (2015).
Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862–D868 (2015).
Pinto, Y. M. et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur. Heart J. 37, 1850–1858 (2016).
Noutsias, M. et al. Expression of functional T cell markers and T cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy. Eur. J. Heart Fail. 13, 611–618 (2011).
Liu, P. et al. The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat. Med. 6, 429–434 (2000). Viral infections have been linked to chronic DCM. The authors of this article show that the sarcoma (Src) family kinase Lck (p56-LCK) is required for efficient CVB3 replication in T cell lines and for viral replication and persistence in vivo.
Irie-Sasaki, J. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349–354 (2001).
Fairweather, D. et al. Mast cells and innate cytokines are associated with susceptibility to autoimmune heart disease following coxsackievirus B3 infection. Autoimmunity 37, 131–145 (2004).
Frisancho-Kiss, S. et al. Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J. Immunol. 178, 6710–6714 (2007).
Tschöpe, C. et al. NOD2 (nucleotide-binding oligomerization domain 2) is a major pathogenic mediator of coxsackievirus B3-induced myocarditis. Circ. Heart Fail. 10, e003870 (2017).
Fuse, K. Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation 112, 2276–2285 (2005).
Epelman, S., Liu, P. P. & Mann, D. L. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat. Rev. Immunol. 15, 117–129 (2015).
Li, A.-H., Liu, P. P., Villarreal, F. J. & Garcia, R. A. Dynamic changes in myocardial matrix and relevance to disease: translational perspectives. Circ. Res. 114, 916–927 (2014).
Cabrerizo, M. et al. Molecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain. J. Med. Virol. 89, 435–442 (2016).
Pauschinger, M. et al. Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 99, 1348–1354 (1999).
Tschope, C. High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction. Circulation 111, 879–886 (2005).
Pauschinger, M. et al. Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis. Circulation 99, 889–895 (1999).
Caforio, A. L. P. et al. A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Eur. Heart J. 28, 1326–1333 (2007).
Kuhl, U. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 112, 1965–1970 (2005).
Maekawa, Y., Ouzounian, M., Opavsky, M. A. & Liu, P. P. Connecting the missing link between dilated cardiomyopathy and viral myocarditis: virus, cytoskeleton, and innate immunity. Circulation 115, 5–8 (2006).
Kindermann, I. et al. Predictors of outcome in patients with suspected myocarditis. Circulation 118, 639–648 (2008).
Mahon, N. G. et al. Immunohistologic evidence of myocardial disease in apparently healthy relatives of patients with dilated cardiomyopathy. J. Am. Coll. Cardiol. 39, 455–462 (2002).
Caforio, A. L. et al. Evidence from family studies for autoimmunity in dilated cardiomyopathy. Lancet 344, 773–777 (1994).
Caforio, A. L. et al. Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy. J. Am. Coll. Cardiol. 15, 1527–1534 (1990).
Caforio, A. L. et al. Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation 85, 1734–1742 (1992).
Caforio, A. L. P. et al. Prospective familial assessment in dilated cardiomyopathy: cardiac autoantibodies predict disease development in asymptomatic relatives. Circulation 115, 76–83 (2006).
Mestroni, L. et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J. Am. Coll. Cardiol. 34, 181–190 (1999).
Neu, N. et al. Cardiac myosin induces myocarditis in genetically predisposed mice. J. Immunol. 139, 3630–3636 (1987).
Smith, S. C. & Allen, P. M. Myosin-induced acute myocarditis is a T cell-mediated disease. J. Immunol. 147, 2141–2147 (1991).
Li, Y., Heuser, J. S., Cunningham, L. C., Kosanke, S. D. & Cunningham, M. W. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J. Immunol. 177, 8234–8240 (2006).
Kodama, M. et al. Rat dilated cardiomyopathy after autoimmune giant cell myocarditis. Circ. Res. 75, 278–284 (1994).
Elliott, J. F. et al. Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice. Proc. Natl Acad. Sci. USA 100, 13447–13452 (2003).
Guler, M. L. et al. Two autoimmune diabetes loci influencing T cell apoptosis control susceptibility to experimental autoimmune myocarditis. J. Immunol. 174, 2167–2173 (2005).
Frustaci, A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 107, 857–863 (2003).
Frustaci, A., Russo, M. A. & Chimenti, C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur. Heart J. 30, 1995–2002 (2009).
Escher, F. et al. Long-term outcome of patients with virus-negative chronic myocarditis or inflammatory cardiomyopathy after immunosuppressive therapy. Clin. Res. Cardiol. 105, 1011–1020 (2016).
Kazzam, E. et al. Non-invasive assessmenty of systolic left ventricular function in systemic sclerosis. Eur. Heart J. 12, 151–156 (1991).
Goldenberg, J. et al. Symptomatic cardiac involvement in juvenile rheumatoid arthritis. Int. J. Cardiol. 34, 57–62 (1992).
Paradiso, M. et al. Evaluation of myocarial involvement in systemic lupus erythematosus by signal-averaged electrocardiography and echocardiography. Acta Cardiol. 56, 381–386 (2001).
Caforio, A. L. P. et al. Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy. Autoimmunity 41, 35–45 (2008).
Meder, B. et al. A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. Eur. Heart J. 35, 1069–1077 (2014).
Arbustini, E. et al. The MOGE(S) classification for a phenotype–genotype nomenclature of cardiomyopathy. J. Am. Coll. Cardiol. 62, 2046–2072 (2013).
Hazebroek, M. R. et al. Prognostic relevance of gene-environment interactions in patients with dilated cardiomyopathy. J. Am. Coll. Cardiol. 66, 1313–1323 (2015).
Schulze, K., Becker, B. F. & Schultheiss, H. P. Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo. Circ. Res. 64, 179–192 (1989).
Caforio, A. L. P. et al. Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from sera of patients with myocarditis induces experimental myocarditis in mice. Int. J. Cardiol. 179, 166–177 (2015).
Nikolaev, V. O. et al. A novel fluorescence method for the rapid detection of functional β1-adrenergic receptor autoantibodies in heart failure. J. Am. Coll. Cardiol. 50, 423–431 (2007).
Jahns, R. et al. Direct evidence for a β1-adrenergic receptor–directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J. Clin. Invest. 113, 1419–1429 (2004).
Nishimura, H. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001).
Okazaki, T. et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat. Med. 9, 1477–1483 (2003).
Kaya, Z., Leib, C. & Katus, H. A. Autoantibodies in heart failure and cardiac dysfunction. Circ. Res. 110, 145–158 (2012).
Blyszczuk, P. et al. Transforming growth factor-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis. Eur. Heart J. 38, 1413–1425 (2016).
Piano, M. R. Alcoholic cardiomyopathy. Chest 121, 1638–1650 (2002).
Manthey, J., Imtiaz, S., Neufeld, M., Rylett, M. & Rehm, J. Quantifying the global contribution of alcohol consumption to cardiomyopathy. Popul. Health Metr. 15, 20 (2017).
Lang, R. M. Adverse cardiac effects of acute alcohol ingestion in young adults. Ann. Intern. Med. 102, 742 (1985).
Hantson, P. Mechanisms of toxic cardiomyopathy. Clin. Toxicol. (Phila.) 57, 1–9 (2018).
Waszkiewicz, N., Szulc, A. & Zwierz, K. Binge drinking-induced subtle myocardial injury. Alcohol. Clin. Exp. Res. 37, 1261–1263 (2013).
Havakuk, O., Rezkalla, S. H. & Kloner, R. A. The cardiovascular effects of cocaine. J. Am. Coll. Cardiol. 70, 101–113 (2017).
Om, A., Warner, M., Sabri, N., Cecich, L. & Vetrovec, G. Frequency of coronary artery disease and left ventricular dysfunction in cocaine users. Am. J. Cardiol. 69, 1549–1552 (1992).
Chakko, S. & Myerburg, R. J. Cardiac complications of cocaine abuse. Clin. Cardiol. 18, 67–72 (1995).
Varga, Z. V., Ferdinandy, P., Liaudet, L. & Pacher, P. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am. J. Physiol. Heart Circ. Physiol. 309, H1453–H1467 (2015).
Virmani, R., Robinowitz, M., Smialek, J. E. & Smyth, D. F. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am. Heart J. 115, 1068–1076 (1988).
Bellinger, A. M. et al. Cardio-oncology: how new targeted cancer therapies and precision medicine can inform cardiovascular discovery. Circulation 132, 2248–2258 (2015).
Chatterjee, K., Zhang, J., Honbo, N. & Karliner, J. S. Doxorubicin cardiomyopathy. Cardiology 115, 155–162 (2010).
Zhang, S. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18, 1639–1642 (2012).
Lipshultz, S. E. et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J. Clin. Oncol. 23, 2629–2636 (2005).
Lipshultz, S. E. & Adams, M. J. Cardiotoxicity after childhood cancer: beginning with the end in mind. J. Clin. Oncol. 28, 1276–1281 (2010).
Cardinale, D. et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 114, 2474–2481 (2006).
Sheppard, R. et al. Myocardial expression of fas and recovery of left ventricular function in patients with recent-onset cardiomyopathy. J. Am. Coll. Cardiol. 46, 1036–1042 (2005).
Coronado, M. J. et al. Testosterone and interleukin-1β increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n. Am. J. Physiol. Heart Circ. Physiol. 302, H1726–H1736 (2012).
Cocker, M. S., Abdel-Aty, H., Strohm, O. & Friedrich, M. G. Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study. Heart 95, 1925–1930 (2009).
Fairweather, D. et al. Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart. Am. J. Pathol. 165, 1883–1894 (2004).
Baldeviano, G. C. et al. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ. Res. 106, 1646–1655 (2010).
Myers, J. M. et al. Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight 1, 85851 (2016).
Diny, N. L. et al. Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy. J. Exp. Med. 214, 943–957 (2017).
Frisancho-Kiss, S. et al. Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav. Immun. 23, 649–657 (2009).
Fairweather, D. et al. Sex differences in translocator protein 18 kDa (TSPO) in the heart: implications for imaging myocardial inflammation. J. Cardiovasc. Transl Res. 7, 192–202 (2014).
Regitz-Zagrosek, V. & Kararigas, G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol. Rev. 97, 1–37 (2017).
Abston, E. D. et al. IL-33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function. Circ. Heart Fail. 5, 366–375 (2012).
Fairweather, D. et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J. Immunol. 176, 3516–3524 (2006).
Vitale, C., Mendelsohn, M. E. & Rosano, G. M. C. Gender differences in the cardiovascular effect of sex hormones. Nat. Rev. Cardiol. 6, 532–542 (2009).
Melchert, R. B. & Welder, A. A. Cardiovascular effects of androgenic-anabolic steroids. Med. Sci. Sports Exerc. 27, 1252–1262 (1995).
Scheuer, J., Malhotra, A., Schaible, T. F. & Capasso, J. Effects of gonadectomy and hormonal replacement on rat hearts. Circ. Res. 61, 12–19 (1987).
Dec, G. W. & Fuster, V. Idiopathic dilated cardiomyopathy. N. Engl. J. Med. 331, 1564–1575 (1994).
Caforio, A. L. P. et al. Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur. Heart J. 38, 2649–2662 (2017).
Kuhl, U., Melzner, B., Schafer, B., Schultheiss, H.-P. & Strauer, B. E. The Ca-channel as cardiac autoantigen. Eur. Heart J. 12, 99–104 (1991).
Lauer, B., Schannwell, M., Kühl, U., Strauer, B.-E. & Schultheiss, H.-P. Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis. J. Am. Coll. Cardiol. 35, 11–18 (2000).
Rapezzi, C. et al. Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 34, 1448–1458 (2012).
Fatkin, D., Seidman, C. E. & Seidman, J. G. Genetics and disease of ventricular muscle. Cold Spring Harb. Perspect. Med. 4, a021063 (2014).
Lynch, T. L. et al. Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. J. Mol. Cell. Cardiol. 102, 83–93 (2017).
Knowlton, K. U. Myocarditis. J. Am. Coll. Cardiol. 69, 1666–1668 (2017).
Poller, W. et al. Genome-environment interactions in the molecular pathogenesis of dilated cardiomyopathy. J. Mol. Med. 83, 579–586 (2005).
Jan, M. F. & Tajik, A. J. Modern imaging techniques in cardiomyopathies. Circ. Res. 121, 874–891 (2017).
Kasner, M. et al. Multimodality imaging approach in the diagnosis of chronic myocarditis with preserved left ventricular ejection fraction (MCpEF): the role of 2D speckle-tracking echocardiography. Int. J. Cardiol. 243, 374–378 (2017).
Chimenti, C. & Frustaci, A. Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period. Circulation 128, 1531–1541 (2013).
Holzmann, M. et al. Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation 118, 1722–1728 (2008).
Escher, F. et al. Analysis of endomyocardial biopsies in suspected myocarditis — diagnostic value of left versus right ventricular biopsy. Int. J. Cardiol. 177, 76–78 (2014).
Lassner, D. et al. Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling. Eur. Heart J. 35, 2186–2195 (2014).
Escher, F. et al. Presence of perforin in endomyocardial biopsies of patients with inflammatory cardiomyopathy predicts poor outcome. Eur. J. Heart Fail. 16, 1066–1072 (2014). In this EMB-based analysis of the long-term disease course, perforin, a key predictor of poor outcome, was detected in the myocardium of a large cohort of patients with inflammatory cardiomyopathy.
Marchant, D. J. et al. Inflammation in myocardial diseases. Circ. Res. 110, 126–144 (2012).
Heymans, S. et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 11, 119–129 (2009).
Glezeva, N. & Baugh, J. A. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail. Rev. 19, 681–694 (2013).
O’Connor, C. M. et al. Efficacy and safety of exercise training in patients with chronic heart failure. JAMA 301, 1439 (2009).
McMurray, J. J. V. et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 371, 993–1004 (2014). This study compares the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.
Zannad, F. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. 364, 11–21 (2011).
Abraham, W. T. et al. Cardiac resynchronization in chronic heart failure. N. Engl. J. Med. 346, 1845–1853 (2002).
Packer, M. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 106, 2194–2199 (2002).
Cleland, J. G. F. et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N. Engl. J. Med. 352, 1539–1549 (2005).
Cleland, J. G. F. et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase]. Eur. Heart J. 27, 1928–1932 (2006).
Moss, A. J. et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N. Engl. J. Med. 361, 1329–1338 (2009).
Tang, A. S. L. et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N. Engl. J. Med. 363, 2385–2395 (2010).
Chen, Y. et al. Impact of etiology on the outcomes in heart failure patients treated with cardiac resynchronization therapy: a meta-analysis. PLOS ONE 9, e94614 (2014).
Schultheiss, H.-P., Kuhl, U. & Cooper, L. T. The management of myocarditis. Eur. Heart J. 32, 2616–2625 (2011). This review article aims to help bridge the widening gap between recent mechanistic insights and their potential impact on disease burden. The article provides an overview of the entire management of myocarditis, particularly with respect to aetiology-based therapy.
Kuhl, U. et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107, 2793–2798 (2003).
Kühl, U., Lassner, D., von Schlippenbach, J., Poller, W. & Schultheiss, H.-P. Interferon-beta improves survival in enterovirus-associated cardiomyopathy. J. Am. Coll. Cardiol. 60, 1295–1296 (2012).
Schultheiss, H.-P. et al. Betaferon in chronic viral cardiomyopathy (BICC) trial: effects of interferon-β treatment in patients with chronic viral cardiomyopathy. Clin. Res. Cardiol. 105, 763–773 (2016).
Felix, S. B. et al. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy. J. Am. Coll. Cardiol. 35, 1590–1598 (2000).
Mobini, R. et al. Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy. J. Autoimmun. 20, 345–350 (2003).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00558584 (2018).
Priori, S. G. et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J. 36, 2793–2867 (2015). This article includes the 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the ESC.
Desai, A. S., Fang, J. C., Maisel, W. H. & Baughman, K. L. Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy. JAMA 292, 2874 (2004).
Køber, L. et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N. Engl. J. Med. 375, 1221–1230 (2016).
Golwala, H., Bajaj, N. S., Arora, G. & Arora, P. Implantable cardioverter-defibrillator for nonischemic cardiomyopathy: an updated meta-analysis. Circulation 135, 201–203 (2017).
Shi, H.-W. et al. Prognostic value of late gadolinium enhancement in dilated cardiomyopathy patients. A meta-analysis. Saudi Med. J. 34, 719–726 (2013).
Matsuo, S., Nakajima, K. & Nakata, T. Prognostic value of cardiac sympathetic nerve imaging using long-term follow-up data. Circulation 80, 435–441 (2016).
Solomou, S., Stavrou, M. & Marley, J. Diagnosis of dilated cardiomyopathy: patient reaction and adaptation — case study and review of the literature. Case Rep. Psychiatry 2016, 1756510 (2016).
MacInnes, J. & Williams, L. A review of integrated heart failure care. Prim. Health Care Res. Dev. https://doi.org/10.1017/S1463423618000312 (2018).
Rice, H., Say, R. & Betihavas, V. The effect of nurse-led education on hospitalisation, readmission, quality of life and cost in adults with heart failure. A systematic review. Patient Educ. Couns. 101, 363–374 (2018).
Mehani, S. H. M. Correlation between changes in diastolic dysfunction and health-related quality of life after cardiac rehabilitation program in dilated cardiomyopathy. J. Adv. Res. 4, 189–200 (2013).
Ohira, H. et al. Comparison of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) and cardiac magnetic resonance (CMR) in corticosteroid-naive patients with conduction system disease due to cardiac sarcoidosis. Eur. J. Nucl. Med. Mol. Imaging 43, 259–269 (2015).
Werner, R. A. et al. Longitudinal 18F-FDG PET imaging in a rat model of autoimmune myocarditis. Eur. Heart J. Cardiovasc. Imaging 20, 467–474 (2018).
Klaeboe, L. G. & Edvardsen, T. Echocardiographic assessment of left ventricular systolic function. J. Echocardiogr. 17, 10–16 (2018).
Luis, S. A., Chan, J. & Pellikka, P. A. Echocardiographic assessment of left ventricular systolic function: an overview of contemporary techniques, including speckle-tracking echocardiography. Mayo Clin. Proc. 94, 125–138 (2019).
Weinberg, E. O. et al. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 107, 721–726 (2003).
Rehman, S. U., Mueller, T. & Januzzi, J. L. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J. Am. Coll. Cardiol. 52, 1458–1465 (2008).
Binas, D. et al. The prognostic value of sST2 and galectin-3 considering different aetiologies in non-ischaemic heart failure. Open Heart 5, e000750 (2018).
Coronado, M. J. et al. Elevated sera sST 2 is associated with heart failure in men ≤50 years old with myocarditis. J. Am. Heart Assoc. 8, e008968 (2019).
Weinberg, E. O. et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106, 2961–2966 (2002).
Villacorta, H. & Maisel, A. S. Soluble ST2 testing: a promising biomarker in the management of heart failure. Arq. Bras. Cardiol. 106, 145–152 (2016).
Lichtenauer, M. et al. A comparative analysis of novel cardiovascular biomarkers in patients with chronic heart failure. Eur. J. Intern. Med. 44, 31–38 (2017).
Jirak, P. et al. Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure. Acta Pharmacol. Sin. 39, 1189–1196 (2018).
Nair, N. & Gongora, E. Correlations of GDF-15 with sST2, MMPs, and worsening functional capacity in idiopathic dilated cardiomyopathy. J. Circ. Biomark. 7, 184945441775173 (2018).
Stojkovic, S. et al. GDF-15 is a better complimentary marker for risk stratification of arrhythmic death in non-ischaemic, dilated cardiomyopathy than soluble ST2. J. Cell. Mol. Med. 22, 2422–2429 (2018).
Pascual-Figal, D. A. et al. Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction. J. Am. Coll. Cardiol. 54, 2174–2179 (2009).
Basile, U. et al. Free light chains: eclectic multipurpose biomarker. J. Immunol. Methods 451, 11–19 (2017).
Dispenzieri, A. et al. Use of nonclonal serum immunoglobulin free light chains to predict overall survival in the general population. Mayo Clin. Proc. 87, 517–523 (2012).
Jackson, C. E. et al. Combined free light chains are novel predictors of prognosis in heart failure. JACC Heart Fail. 3, 618–625 (2015).
Jackson, C. E. et al. The incremental prognostic and clinical value of multiple novel biomarkers in heart failure. Eur. J. Heart Fail. 18, 1491–1498 (2016).
Saleh, A. et al. Assessment of cardiac involvement of hepatitis C virus; tissue Doppler imaging and NTproBNP study. J. Saudi Heart Assoc. 23, 217–223 (2011).
Wang, L. et al. The biomarker N-terminal pro-brain natriuretic peptide and liver diseases. Clin. Invest. Med. 34, E30–E37 (2011).
Minton, E. J. et al. Association between MHC class II alleles and clearance of circulating hepatitis C virus. Members of the Trent Hepatitis C Virus Study Group. J. Infect. Dis 178, 39–44 (1998).
Höhler, T. et al. MHC class II genes influence the susceptibility to chronic active hepatitis C. J. Hepatol. 27, 259–264 (1997).
Matsumori, A. et al. in Cardiomyopathies and Heart Failure: Biomolecular, Infectious, and Immune Mechanisms (Kluwer Academic Publishers, 2003).
Shichi, D. et al. The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III - class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy. Tissue Antigens 66, 200–208 (2005).
Hsu, Y.-C. et al. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology 59, 1293–1302 (2014).
Ly, K. N., Hughes, E. M., Jiles, R. B. & Holmberg, S. D. Rising mortality associated with hepatitis C virus in the United States, 2003–2013. Clin. Infect. Dis 62, 1287–1288 (2016).
Kawai, C. & Matsumori, A. Dilated cardiomyopathy update: infectious-immune theory revisited. Heart Fail. Rev. 18, 703–714 (2013). This review article focuses on immune reactions in the myocardium, evoked by external triggers, that continue insidiously and lead to the process of cardiac remodelling with ventricular dilatation, systolic dysfunction and DCM.
Matsumori, A., Shimada, T., Chapman, N. M., Tracy, S. M. & Mason, J. W. Myocarditis and heart failure associated with hepatitis C virus infection. J. Card. Fail. 12, 293–298 (2006).
Davidson, S. M. et al. Circulating blood cells and extracellular vesicles in acute cardioprotection. Cardiovasc. Res. https://doi.org/10.1093/cvr/cvy314 (2018).
Micheu, M. M., Scarlatescu, A. I., Scafa-Udriste, A. & Dorobantu, M. The winding road of cardiac regeneration—stem cell omics in the spotlight. Cells 7, 255 (2018).
Isomi, M., Sadahiro, T. & Ieda, M. Progress and challenge of cardiac regeneration to treat heart failure. J. Cardiol. 73, 97–101 (2019).
Arbustini, E. et al. Cardiac phenotypes in hereditary muscle disorders. J. Am. Coll. Cardiol. 72, 2485–2506 (2018).
Stergiopoulos, K. & Lima, F. V. Peripartum cardiomyopathy-diagnosis, management, and long term implications. Trends Cardiovasc. Med. 29, 164–173 (2018).
Willott, R. H. et al. Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function? J. Mol. Cell. Cardiol. 48, 882–892 (2010).
Hershberger, R. E. et al. Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy. Circ. Cardiovasc. Genet. 2, 306–313 (2009).
Ware, J. S. & Cook, S. A. Role of titin in cardiomyopathy: from DNA variants to patient stratification. Nat. Rev. Cardiol. 15, 241–252 (2018).
Knezevic, T. et al. BAG3: a new player in the heart failure paradigm. Heart Fail. Rev. 20, 423–434 (2015).
Liu, G.-S. et al. A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia. Cardiovasc. Res. 107, 164–174 (2015).
Sen-Chowdhry, S. et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J. Am. Coll. Cardiol. 52, 2175–2187 (2008).
Gerull, B. et al. Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy. J. Mol. Med. 84, 478–483 (2006).
Norton, N. et al. Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Circ. Cardiovasc. Genet. 6, 144–153 (2013).
Roberts, A. M. et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci. Transl Med. 7, 270ra6 (2015).
Ware, J. S. et al. Shared genetic predisposition in peripartum and dilated cardiomyopathies. N. Engl. J. Med. 374, 233–241 (2016).
Schafer, S. et al. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat. Genet. 49, 46–53 (2017).
Taylor, M. R. G. et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J. Am. Coll. Cardiol. 41, 771–780 (2003).
Parks, S. B. et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am. Heart J. 156, 161–169 (2008).
Villard, E. et al. Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Eur. Heart J. 26, 794–803 (2005).
Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S. & Kimura, A. Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes. Hum. Mutat. 32, 1481–1491 (2011).
Begay, R. L. et al. FLNC gene splice mutations cause dilated cardiomyopathy. JACC Basic Transl Sci. 1, 344–359 (2016).
Ortiz-Genga, M. F. et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J. Am. Coll. Cardiol. 68, 2440–2451 (2016).
Li, D. et al. Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin. Transl Sci. 3, 90–97 (2010).
McNair, W. P. et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 110, 2163–2167 (2004).
Olson, T. M. et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 293, 447–454 (2005).
Schmitt, J. P. et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299, 1410–1413 (2003).
DeWitt, M. M., MacLeod, H. M., Soliven, B. & McNally, E. M. Phospholamban R14 deletion results in late-onset, mild, hereditary dilated cardiomyopathy. Am. J. Coll. Cardiol. 48, 1396–1398 (2006).
Hershberger, R. E. et al. Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ. Cardiovasc. Genet. 3, 155–161 (2010).
Pinto, J. R. et al. Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. J. Biol. Chem. 286, 34404–34412 (2011).
Murphy, R. T. et al. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet 363, 371–372 (2004).
Carballo, S. et al. Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy. Circ. Res. 105, 375–382 (2009).
Olson, T. M., Kishimoto, N. Y., Whitby, F. G. & Michels, V. V. Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J. Mol. Cell. Cardiol. 33, 723–732 (2001).
Lakdawala, N. K. et al. Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy. J. Am. Coll. Cardiol. 55, 320–329 (2010).
Garg, R. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 273, 1450–1456 (1995).
Granger, C. B. et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-alternative trial. Lancet 362, 772–776 (2003).
Fauchier, L., Pierre, B., de Labriolle, A. & Babuty, D. Comparison of the beneficial effect of beta-blockers on mortality in patients with ischaemic or non-ischaemic systolic heart failure: a meta-analysis of randomised controlled trials. Eur. J. Heart Fail. 9, 1136–1139 (2007).
Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med. 341, 709–717 (1999).
Taylor, A. L. et al. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American heart failure trial. Circulation 115, 1747–1753 (2007).
Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376, 875–885 (2010).
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N. Engl. J. Med. 336, 525–533 (1997).
This work was partly supported by NIH R01 HL111938, NIH R21 ES024414 and American Heart Association grant AHA 16GRNT30950007 to D.F., and by ERA-Net grant on Cardiovascular Diseases (ERA-CVD; JTC2016-40-158), and grants of the German Research Foundation (DFG), Transregional Collaborative Research Center (CRC TR19) to H.P.S and F.E.
Nature Reviews Disease Primers thanks S. Morimoto, B. Pinamonti, Y. Sawa and the other anonymous reviewer(s), for their contribution to the peer review of this work.