Hugo A. Katus

Hypertrophy of the Heart: A New Therapeutic Target?

Recent studies call into question the necessity of hypertrophic growth of the heart as a compensatory response to hemodynamic stress. These findings, coupled with recent progress in dissecting the molecular bases of hypertrophy, raise the prospect of suppressing hypertrophy without provoking circulatory insufficiency. In this article, we focus on signaling pathways that hold promise as potential targets for therapeutic intervention. We also summarize observations from animal models and clinical trials that suggest benefit from an antihypertrophic strategy.

Myocardial Damage: The role of Troponin T

The troponin complex is located on the thin filament of the contractile apparatus (Figure 1). It consists of the subunits-troponin T (39 kD), troponin I (26 kD), and troponin C (18 kD) [1]. These subunits are the products of different genes and are not related to each other in protein structure [2].

Tissue-Specific Gene Delivery by Recombinant Adenoviruses Containing Cardiac-Specific Promoters

OBJECTIVEnTo approach heart muscle diseases by gene transfer, an adenoviral vector system was intended to be established suitable for gene expression in ventricular and/or atrial myocardium.nnnMETHODSnTwo adenoviral vectors (Ad-mhcLuc, Ad-mlcLuc) were constructed, in which the luciferase reporter gene is under control of either the ventricle-specific myosin light chain-2 (mlc-2v) or the atrial- and ventricular-specific alpha-myosin heavy chain (alpha-mhc) promoter. For controls, a recombinant adenovirus without promoter (Ad-Luc) and one with the Rous sarcoma virus (rsv) promoter (Ad-rsvLuc) were generated. A volume of 20 microliters containing 2 x 10(9) plaque forming units (pfu) of the recombinant adenoviruses Ad-mhcLuc, Ad-mlcLuc, Ad-rsvLuc or Ad-Luc was injected into the cardiac cavity or the quadriceps femoris muscle of neonatal rats. After five days animals were sacrificed and nine different tissues were analyzed for reporter gene expression by detection of light activity relative to mg of tissue.nnnRESULTSnInjections of recombinant adenoviruses into the cardiac cavity of neonatal rats resulted in heart-specific gene expression of Ad-mlcLuc (20 fold of Ad-Luc; 11% of Ad-rsvLuc), whereas Ad-mhcLuc gave mainly luciferase activity in the heart (6.5-fold of Ad-Luc; 3% of Ad-rsvLuc) with additional activity in lung and liver (2-4 fold of Ad-Luc). In the ventricular tissue Ad-mlcLuc revealed a 35-fold higher luciferase activity, whereas Ad-mhcLuc, Ad-rsvLuc and Ad-Luc showed only 2-fold higher luciferase activities compared to the atrium. Viral DNA in atrial and ventricular tissue was detected by PCR at approximately the same abundance independent of the injected type of adenovirus. Direct injection of Ad-mhcLuc and Ad-mlcLuc into the thigh muscle revealed only background luciferase activities.nnnCONCLUSIONSnIn the adenoviral system only the mlc-2v promoter may fulfil the safety requirements for a myocardial specific gene expression with a high selectivity for the ventricular myocardium, thus providing a promising tool for future gene therapy of cardiomyopathies.