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Cardiomyopathies are an important and diverse group of heart muscle diseases in which the heart muscle itself is structurally or functionally abnormal and in which coronary artery disease, hypertension, valvular and congenital heart disease are absent or do not sufficiently explain the observed myocardial abnormality. This often results in severe heart failure accompanied by arrhythmias and/or sudden death. Clinical and morphological diversity of cardiomyopathies can reflect the broad spectrum of distinct underlying molecular causes or genetic heterogeneity. In many cases the disease is inherited and is termed familial dilated cardiomyopathy (FDC), which may account for up to 30% of dilated cardiomyopathies (DCM). FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal, nuclear and sarcomeric proteins in the cardiac myocyte. In addition, modifying genes, lifestyle and additional factors were reported to influence onset of disease, disease progression, and prognosis. The individual patient's phenotype may reflect a summation and/or interaction of the underlying mutation(s) with other genetic or environmental factors. During the last years major advances have been made in the understanding of the molecular and genetic basis of this type of disease. Nevertheless, much more progress in the identification of underlying mutations, susceptibility genes and modifier genes is important and indispensable for the development of new etiology-orientated forms of therapy. A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM goes ahead with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. These relatives suffer from a higher risk for the development of DCM after years. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. There is reasonable clinical and experimental evidence, that DCM in addition may occur as late stage of cardiac infection and inflammation. The large spectrum of clinical forms depends on several factors such as genetic determinants of the infective agent, the genetics, age and gender of the host, and the host immunocompetence. In general, infectious agents, including viruses such as entero-, cytomegalo-, and adenoviruses, bacteria such as Borrelia burgdorferi or Chlamydia pneumoniae, protozoa and even fungi can cause inflammatory heart disease leading to DCM. The infectious agents most often identified in DCM nowadays are parvovirus B19, human herpesvirus 3, and Epstein-Barr virus. Persistence of these viruses within the myocardium is associated with reduction of ejection fraction after 6 months. For patients with suspected inflammatory heart disease the immunohistochemical detection of inflammatory infiltrates is related to poor outcome. Many faces of inflammatory heart disease coexist where different phases of the disease progress simultaneously: phase 1 is dominated by viral infection itself, phase 2 by the onset of (probably) multiple autoimmune reactions, and phase 3 by the progression to cardiac dilatation. Further investigations with regard to the etiology of structural heart diseases should include an intensive clinical investigation of the given patient. A possible family history including a pedigree should be ascertained and with regard to a possible inflammatory or viral heart disease, endomyocardial biopsies should be investigated by polymerase chain reaction and immunohistochemistry.

The first classifications of cardiomyopathies from 1980 and 1996 described them as heart muscle diseases, with dilated (DCM), hypertrophic (HCM), restrictive (RCM), arrhythmogenic right ventricular (ARVC), and nonclassifiable cardiomyopathies. Furthermore, the World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) classification from 1996 listed among the specific cardiomyopathies inflammatory cardiomyopathy as a new and distinct entity, which was defined histologically as myocarditis in association with cardiac dysfunction. Infectious and autoimmune forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy was defined as viral persistence in a dilated heart without ongoing inflammation. If it was accompanied by myocardial inflammation, it was termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). This entity was further elucidated in a World Heart Federation consensus meeting in 1999 by quantitative immunohistological criteria (< 14 infiltrating cells/mm(2)) and the etiology by molecular biological methods, e.g., polymerase chain reaction, as viral, bacterial, or autoimmune (= nonmicrobial). The development of molecular genetics, with the discovery of a genetic background in several forms of cardiomyopathies previously alluded to as "of unknown origin", was the origin of a debate on a new classification based on genomics. A genomic/postgenomic classification was postulated taking the underlying gene mutations and the cellular level of expression of encoded proteins into account, thus distinguishing cytoskeleton (cytoskeletalopathies, e.g., DCM or ARVC), sarcomeric (sarcomyopathies as in HCM and RCM) and ion channel (channelopathies, e.g., long or short QT syndrome and Brugada's syndrome) cardiomyopathies. Such a classification of cardiomyopathies was proposed in 2006 by the American Heart Association (AHA), which took the rapid evolution of molecular genetics in cardiology into account. It also introduced several recently described diseases, and is unique in that it incorporated ion channelopathies even without hemodynamic dysfunction as a "primary" cardiomyopathy. The ESC (European Society of Cardiology) Working Group on Myocardial and Pericardial Diseases has deliberately taken a different approach based on a clinically oriented classification in which heart muscle disorders were grouped according to morphology and function. This obviously remains the clinically most useful approach for the diagnosis and management of patients and families with heart muscle disease. In the ESC position statement published in 2008, cardiomyopathies were defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal, and in which coronary artery disease, hypertension, valvular and congenital heart disease are absent or do not sufficiently explain the observed myocardial abnormality. The aim was to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses. In parallel, a scientific statement on the role of endomyocardial biopsy in the management of cardiovascular disease was published at the end of 2007 making useful recommendations for clinical practice and providing an understanding for the use of endomyocardial biopsy in an individual patient. Taking the classification of cardiomyopathies and the statement on the role of endomyocardial biopsies in different clinical scenarios together, the clinician is now able to identify genetic, autoimmune and viral causative factors by using a thorough and logical approach to reach a diagnosis in patients with familial and nonfamilial forms of the underlying structural heart muscle diseases.

Recent advances in cytokine signaling have broadened our knowledge of the fundamental role of innate immunity in inflammatory heart diseases. Cytokines and other extracellular mediators play critical roles in the amplification and/or damping of myocardial injuries caused by various cardiac insults, including cardiotropic viruses, cardiotoxic drugs, oxidative damage, and tissue remodeling. Signal transducer and activator of transcription (STAT) proteins transmit cytokine signals from the plasma membrane to the nucleus, where they bind to sequence-specific DNA elements and modulate the expression of a broad range of target genes. This review summarizes the mechanistic design of the Janus kinase-STAT signaling circuit and discusses its pathophysiological implications in myocarditis and dilated cardiomyopathy.

Inflammation is an important component in the pathogenesis of many common cardiovascular diseases. In most cases, the role of inflammation is a natural response to injury, and an important mechanism for healing and tissue repair. However, the inflammatory response can be either inadequate or overwhelming, leading to direct injury or severe host disease. Accumulating data has revealed an important inflammatory component in the pathogenesis of dilated cardiomyopathy (DCM), and there is growing evidence, that myocarditis and DCM are closely related. Many faces of DCM coexist, while different phases of the disease progress simultaneously: phase 1 is dominated by viral infection itself, phase 2 by the onset of (probably) multiple autoimmune reactions, and phase 3 by the progression to cardiac dilatation without an infectious agent and cardiac inflammation. Separation between the phases is not always distinct, they may overlap one another and phase 1 and 2 may recur after progression of DCM. Appropriate treatment during phase 1 includes eradication of virus and amelioration of injury caused by the virus. During phase 2, which is characterized by autoimmune processes, immunosuppression is the most appropriate therapy and warrants sophisticated diagnostic strategies including molecular biological and immunohistochemical techniques. Phase 3, DCM, although a result of viral and autoimmune injury, may then progress independently. The more attention given to serologic, molecular and immunologic factors to characterize and diagnose DCM lead to several changes in the terminology. The term cardiomyopathy is no longer reserved for the idiopathic forms but can be used interchangeably with the term heart muscle diseases including specific, secondary forms. Right ventricular cardiomyopathy (RVCM), valvular, hypertensive, ischemic, and inflammatory cardiomyopathy have been introduced. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and is then termed inflammatory viral cardiomyopathy. Because of the overlap of pathophysiological stages in DCM, design of the appropriate therapy is important. It requires the immunohistochemical and molecular biological investigation of endomyocardial biopsies in parallel. In the modern molecular era the infective agent-immune system-host interaction has to be clarified leading to a better knowledge of the etiology of DCM. This may change the management of the disease in the future. One of the hopes is to discern the underlying dominant mechanism in a given patient to make a decision for the most promising therapy.

Background: Hypertension is a multifactorial disease involving interactions among genetic, environmental, demographic, vascular and neuroendocrine factors. Essential hypertension is the most frequent diagnosis in this syndrome, indicating that a monocausal etiology has not been identified. However, a number of risk factors underlying essential hypertension have also been identified including age, sex, genetics, demographic factors, and others. Remarkable progress in molecular biological research has been achieved in clarifying the molecular basis of Mendelian hypertensive disorders. Causative genes and chromosomal fragments harboring disease susceptibility genes have been identified, e. g., for glucocorticoid-remediable aldosteronism, Liddle's syndrome, mineralocorticoid excess., Molecular Genetic Studies: Molecular genetic studies have now identified mutations in eight genes that cause Mendelian forms of hypertension and nine genes that cause Mendelian forms of hypotension in humans. No single genetic variant has emerged from linkage or association analyses as consistently related to blood pressure level in every sample and in all populations. However, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. Most prominent have been the polymorphisms in the renin-angiotensin-aldosterone system., Conclusion: Essential hypertension is likely to be a polygenic disorder that results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors is intended.

Structural changes in the mitochondrial DNA (mtDNA) have been implicated in the pathogenesis of a number of diseases. In this study we report on deletions in the mtDNA of patients with dilated cardiomyopathy (DCM) and post mortem control samples. Total DNA was extracted from left ventricular tissue and nearly the whole mtDNA was amplified using the long PCR technique. For quantitative analysis of the PCR-products with mtDNA deletions the fragments were scanned by a laser densitometer. With the method of long PCR we could detect wild-type and deleted mtDNA in 1 reaction. A total of 14 different deletions ranging from 3.3 to 12.6 kb could be detected. The highest rate of deleted as compared to wild-type mtDNA was 12% in 1 control and 9% in a patient with dilated cardiomyopathy. The number of mitochondrial deletions increase with age in the control group. Additional deletions appear sooner in cardiomyopathic hearts than in control hearts. With regard to the low quantity of the deleted mtDNA and the cumulative nature of these deletions by ageing, we conclude that they may be relevant in individual cases only. A general pathogenic effect on the development of dilated cardiomyopathy is less likely. The mutations may be a sign of increasing stress to the heart, however, thus promoting consecutive damage of mtDNA by initiating a vicious circle.