The clinical work in the established Clinic for Inherited Heart Diseases deals with the diagnosis, management and treatment of inherited heart diseases comprising a broad spectrum of disorders andconditions: cardiomyopathies, channelopathies, ischemic heart disease, storage disorders and other inherited heart diseases.
An important aspect is the molecular genetics/biology of these conditions whichis often crucial to the correct diagnosis and treatment. Our research in this area is mainly focused on cardiomyopathies and channelopathies/primary ventricular arrhythmias which represent a heterogeneous group of diseases that can all lead to sudden unexpected cardiac death in children and adult patients. During the last decades major progress has been made in the understanding of the genetic basis of hereditary cardiac diseases and on the evaluation of the risk of sudden cardiac death.

Cardiomyopathies

Inherited cardiomyopathies isa group of cardiac conditions characterised by structural and functional abnormalities of the myocardium. They are major causes of heart disease at all ages as well as sudden cardiac death in young adults. Within recent years a large number of disease genes have been identified enabling genetic diagnosis of affected families (Watkins et al. 2011). However, the disease expression of the condition is extremely heterogeneous and poorly understood (Mogensen et al. 2004). It is therefore essential to further elucidate disease mechanisms to improve risk-stratification and management of affected families. Our team is investigating genotype-phenotype correlations in hypertrophic (HCM), restrictive (RCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). In addition to clinical and genetic investigations we have established robust in vitro expression systems to investigate disease mechanisms of individual patients.

Channelopathies/primary ventricular arrhythmias

Inherited channelopathies comprise a group of syndromes with unique genetic abnormalities in a growing number of ion-channel genes and presentations but with very similar clinical outcomes and complications, such as life-threatening ventricular arrhythmias and sudden cardiac death. A national research collaboration regarding long QT syndrome and Brugada syndrome has been established (Ref. 3 puplikation??, Holst et al. 2012). In patients with catecholaminergic polymorphic ventricular tachycardia a growing number of mutations in the gene encoding the ryanodine receptor are identified and important genotype-phenotype research is ongoing.

Sudden cardiac death

First-degree relatives of victims with sudden cardiac death may be at increased risk of having an inherited cardiac disorder. If a test is positive, this information is important for relatives who might be at risk of carrying the pathogenic mutation. A growing number of genes are implicated in these syndromes/disorders which often makes the molecular genetic testing cumbersome and expensive with the present DNA technology. Therefore, it is reasonable to tailor the molecular genetic testing in relation to the autopsy findings. In cases where a morphological explanation for sudden death is lacking – autopsy negative findings – a primary electrical disorder is most likely and genes responsible for the cardiac channelopathies should be the target i.e. potassium and sodium ion channel genes. If the autopsy demonstrates morphological changes - autopsy positive findings – a structural cardiac disease is suspected and focus should be directed towards genes underlying the inherited cardiomyopathies i.e. genes encoding the sarcomeric proteins, cell adhesions (desmosomal) proteins and intermediate filament proteins. Further, genes responsible for LDL cholesterol metabolism and thereby premature ischemic heart disease are of great importance (Thybjaerg-Hansen et al. 2005, Larsen et al. 2011). In future, however, such a tailored molecular genetic test strategy may change in accordance with the development of the molecular-genetic testing/screening technologies.

Contacts

Torsten Bloch Rasmussen, MD, PhD- student; torsten.bloch.rasmussen@ki.au.dk
Tenna Gadgaard, MD, PhD- student; t.gadgaard@hotmail.com
Maiken Kudahl Larsen, MD, PhD- student; ml@retsmedicin.au.dk
Henning Mølgaard, MD, DMSci, Associate professor, Consultant; h.molgaard@dadlnet.dk
Jens Mogensen, MD, DMSc, PhD, Consultant; jens.mogensen@dadlnet.dk
Henrik Kjærulf Jensen, MD, DMSci, PhD, Associate professor, Consultant; hkjensen@dadlnet.dk