Peter E. Lange

Magnetic Resonance Imaging Analysis of Right Ventricular Pressure-Volume Loops In Vivo Validation and Clinical Application in Patients With Pulmonary Hypertension

Background—The aims of this study were to validate MRI-derived right ventricular (RV) pressure-volume loops for assessment of RV myocardial contractility and then to apply this technique in patients with chronic RV pressure overload for assessment of myocardial contractility, ventricular pump function, and VA coupling. Methods and Results—Flow-directed catheters were guided under MR fluoroscopy (1.5 T) into the RV for invasive pressure measurements. Simultaneously, ventricular volumes and myocardial mass were assessed from cine MRI. From sampled data, RV pressure-volume loops were constructed, and maximal ventricular elastance indexed to myocardial mass (Emax_i) was derived by use of a single-beat estimation method. This MRI method was first validated in vivo (6 swine), with conductance techniques used as reference. Bland-Altman test showed good agreement between methods (Emax_i=5.1±0.5 versus 5.8±0.7 mm Hg · mL−1 · 100 g−1, respectively; P=0.08). Subsequently, the MRI method was applied in 12 subjects: 6 control subjects and 6 patients with chronic RV pressure overload from pulmonary hypertension. In these patients, indexes of RV pump function (cardiac index), Emax_i, and VA coupling (Emax/Ea) were assessed. In patients with pulmonary hypertension, RV pump function was decreased (cardiac index, 2.2±0.5 versus 2.9±0.4 L · min−1 · m−2; P<0.01), myocardial contractility was enhanced (Emax_I, 9.2±1.1 versus 5.0±0.9 mm Hg · mL−1 · 100 g−1; P<0.01), and VA coupling was inefficient (Emax/Ea, 1.1±0.3 versus 1.9±0.4; P<0.01) compared with control subjects. Conclusions—RV myocardial contractility can be determined from MRI-derived pressure-volume loops. Chronic RV pressure overload was associated with reduced RV pump function despite enhanced RV myocardial contractility. The proposed MRI approach is a promising tool to assess RV contractility in the clinical setting.

Genome-Wide Array Analysis of Normal and Malformed Human Hearts

Background—We present the first genome-wide cDNA array analysis of human congenitally malformed hearts and attempted to partially elucidate these complex phenotypes. Most congential heart defects, which account for the largest number of birth defects in humans, represent complex genetic disorders. As a consequence of the malformation, abnormal hemodynamic features occur and cause an adaptation process of the heart. Methods and Results—The statistical analysis of our data suggests distinct gene expression profiles associated with tetralogy of Fallot, ventricular septal defect, and right ventricular hypertrophy. Applying correspondence analysis, we could associate specific gene functions to specific phenotypes. Furthermore, our study design allows the suggestion that alterations associated with primary genetic abnormalities can be distinguished from those associated with the adaptive response of the heart to the malformation (right ventricular pressure overload hypertrophy). We provide evidence for the molecular transition of the hypertrophic right ventricle to normal left ventricular characteristics. Furthermore, we present data on chamber-specific gene expression. Conclusions—Our findings propose that array analysis of malformed human hearts opens a new window to understand the complex genetic network of cardiac development and adaptation. For detailed access, see the online-only Data Supplement.

Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors

The basic helix‐loop‐helix transcription factors eHAND and dHAND are involved in developmental cardiac growth and differentiation. We investigated HAND gene expression in the normal and in the hypertrophied right and left ventricle of patients with tetralogy of Fallot (ToF) and hypertrophic obstructive cardiomyopathy (HOCM). HAND mRNA was constitutively expressed in the hypertrophied heart and increased in the hypertrophic tissue of both patient groups. HAND genes had a complementary left‐right cardiac asymmetry of expression with dHAND predominantly in the right and eHAND in the left ventricle. The two cardiac bHLH factors have the ability to form heterodimers with the ubiquitous bHLH protein E12, subsequently recognizing E‐boxes in the promoter region of target genes like ALC‐1. We found a highly significant positive correlation between HAND and ALC‐1 mRNA. The total ALC‐1 protein level in ToF was smaller than in HOCM, although ALC‐1 mRNA as well as HAND mRNA levels were significantly higher. ToF patients expressed around four times more ALC‐1 mRNA for similar amounts of ALC‐1 than HOCM patients. Suggesting disturbed ALC‐1 translation in ToF, we found ALC‐1 antisense mRNA expression in the hypertrophied, but not in the normal, ventricles. The higher the antisense/sense ALC‐1 mRNA ratio, the lower ALC‐1 protein was expressed. J. Cell. Biochem. 74:551–561, 1999.

Expression of calcium channel subunits in the normal and diseased human myocardium

We investigated the expression of α1 and β subunits of the L-type Ca2+ channel on the protein level in cardiac preparations from normal human heart ventricles and from the hypertrophied septum of patients with hypertrophic obstructive cardiomyopathy (HOCM). 1,4-Dihydropyridine (DHP) binding and immunorecognition by polyclonal antibodies directed against the C-terminal amino acid sequences of the β2 and β3 subunits were used for detection and quantification of α1, β2, and β3 subunits. Bmax of high-affinity DHP binding was 35±2 fmol/mg protein in HOCM and 20±2 fmol/mg protein in normal human hearts (P<0.05). In rabbit hearts the anti-β2 subunit antibody immunoprecipitated 80% of the total amount of DHP-labeled Ca2+ channels present in the assay. Under identical experimental conditions 25% of labeled Ca2+ channels were recovered in the immunoprecipitates of both normal and HOCM ventricles. A similar partial immunoprecipitation was observed in pig hearts. Immunoblot analysis demonstrated that the β2 subunit was associated with the DHP receptor/Ca2+ channel in cardiac muscle of rabbit, pig, and human heart. In neither of these purified cardiac Ca2+ channels was the β3 subunit isoform detected. Our results suggest that both α1 and β2 subunit expression is upregulated in HOCM in a coordinate manner.