Adult Heart Function Research Articles

Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation

The genetic hierarchies guiding lineage specification and morphogenesis of the mammalian embryonic heart are poorly understood. We now show by gene targeting that murine T-box transcription factor Tbx20 plays a central role in these pathways, and has important activities in both cardiac development and adult function. Loss of Tbx20 results in death of embryos at mid-gestation with grossly abnormal heart morphogenesis. Underlying these disturbances was a severely compromised cardiac transcriptional program, defects in the molecular pre-pattern, reduced expansion of cardiac progenitors and a block to chamber differentiation. Notably, Tbx20-null embryos showed ectopic activation of Tbx2 across the whole heart myogenic field. Tbx2 encodes a transcriptional repressor normally expressed in non-chamber myocardium, and in the atrioventricular canal it has been proposed to inhibit chamber-specific gene expression through competition with positive factor Tbx5. Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program. Thus, hierarchical, repressive interactions between Tbx20 and other T-box genes and factors underlie the primary lineage split into chamber and non-chamber myocardium in the forming heart, an early event upon which all subsequent morphogenesis depends. Additional roles for Tbx20 in adult heart integrity and contractile function were revealed by in-vivo cardiac functional analysis of Tbx20 heterozygous mutant mice. These data suggest that mutations in human cardiac transcription factor genes, possibly including TBX20, underlie both congenital heart disease and adult cardiomyopathies.

Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy.

The ErbB2 (Her2) proto-oncogene encodes a receptor tyrosine kinase, which is frequently amplified and overexpressed in human tumors. ErbB2 provides the target for a novel and effective antibody-based therapy (Trastuzumab/Herceptin) used for the treatment of mammary carcinomas. However, cardiomyopathies develop in a proportion of patients treated with Trastuzumab, and the incidence of such complications is increased by combination with standard chemotherapy. Gene ablation studies have previously demonstrated that the ErbB2 receptor, together with its coreceptor ErbB4 and the ligand Neuregulin-1, are essential for normal development of the heart ventricle. We use here Cre-loxP technology to mutate ErbB2 specifically in ventricular cardiomyocytes. Conditional mutant mice develop a severe dilated cardiomyopathy, with signs of cardiac dysfunction generally appearing by the second postnatal month. We infer that signaling from the ErbB2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial for adult heart function. Conditional ErbB2 mutant mice provide a model of dilated cardiomyopathy. In particular, they will allow a rigorous assessment of the role of ErbB2 in the heart and provide insight into the molecular mechanisms that underlie the adverse effects of anti-ErbB2 antibodies.

Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts.

Both aging and myocardial ischemia are associated with alterations of calcium-regulating proteins. We investigated the effects of graded levels of low-flow ischemia on myocardial function and on SR Ca(2+)-ATPase (SERCA2), Na(+)-Ca2+ exchanger (NCX) and ryanodine receptor (RyR2), at mRNA and protein levels in both adult and senescent myocardium. Isolated hearts from 4 and 24 month old (mo) rats were retrogradely perfused during 180 min at 100% (100% CF, n = 11 and n = 11 respectively. 30% (30% CF, n = 10 and n = 12) or 15% (15% CF, n = 13 and n = 8) of their initial coronary flow, and active tension and coronary resistance (in % of their baseline value) were recorded. After 180 min of perfusion. NCX, RyR2 and SERCA2 mRNAs (in % of age-matched 100% CF group value) and protein levels were quantitated in the left ventricles by slot blot and Western blot analysis, respectively. In 24 mo hearts, low-flow ischemia induced a greater fall in active tension (-65 +/- 7% vs. -40 +/- 4% in 4 mo 30% CF, p, 0.01 and -82 +/- 2% vs. -60 +/- 5% in 4 mo 15% CF groups, p < 0.05 after 15 min of ischemia) and a greater increase in coronary resistance (+357 +/- 44% vs. +196 +/- 39% in 4 mo 30% CF, p < 0.05 and +807 +/- 158% vs. +292 +/- 61% in 4 mo 15% CF groups, p < 0.001 after 15 min of ischemia). An increased accumulation of SERCA2 (+36% and NCX (+46%) transcripts, but not RyR2, already occurred in 24 mo 30% CF group while the 3 transcripts accumulated in 24 mo 15% CF group. In 4 mo rats SERCA2 (+26%), NCX (+35%) and RyR2 (+81%) mRNA levels only increased in the 15% CF group. Corresponding calcium-regulating protein levels were unaltered whatever the degree of flow reduction in both 4 mo and 24 mo hearts. Low-flow ischemia does not induce calcium-regulating protein loss in both adult and senescent hearts. The increase in mRNAs coding for calcium-handling proteins and the impairment of myocardial function which occur at a lesser degree of coronary flow reduction in senescent hearts, indicate a higher vulnerability to low-flow ischemia during aging.

Dosimetry assessment of 81Krm peripheral venous infusion studies.

Calculation of S factors for 81Krm for a full range of target organs from each source organ relevant in 81Krm peripheral venous infusion imaging has been performed. Typical equilibrium activities in the source organs have been measured using quantitative planar gamma camera imaging for a generator with a mean activity at imaging time of 468 MBq eluted at 10 ml min-1. Based on the above measurements and assuming a 10 min infusion period, the mean effective dose equivalent for 81Krm infusion imaging in the assessment of right heart function in adults was found to be 0.365 mSv.

Age-related differences in cardiac susceptibility to ischemia/reperfusion injury

Age-related differences in susceptibility to ischemia/reperfusion injury and the response to the iron chelator deferoxamine during reperfusion were studied in isolated nonworking rabbit hearts subjected to 30 or 40 minutes of ischemia at 37 degrees C followed by 30 minutes of reperfusion. In the experimental group, hearts received a bolus of deferoxamine just before the moment of reflow, followed by a continuous infusion during the first 10 minutes of reperfusion. Isovolumic systolic (peak developed pressure) and diastolic (diastolic pressure versus balloon volume relationship) function was assessed with an intracavity balloon and incremental volume changes. In separate groups of hearts, adenine nucleotide content (adenosine triphosphate, diphosphate, and monophosphate) was measured before ischemia, at end-ischemia, and 30 minutes after reperfusion. The cardiac function measurements showed that after 30 minutes of ischemia and 30 minutes of reperfusion, peak developed pressure in newborn hearts recovered to 89% +/- 5% of preischemic levels; this recovery was significantly better than that of adult hearts, which exhibited 67% +/- 6% (p less than 0.01) recovery. Deferoxamine significantly improved cardiac function only in adult hearts (p less than 0.01). However, after 40 minutes of ischemia and 30 minutes of reperfusion, peak developed pressure in newborn hearts was reduced to 61% +/- 3% and was not significantly better than that of adult hearts (54% +/- 5%). Deferoxamine significantly improved systolic function in both newborn and adult hearts (p less than 0.01) exposed to 40 minutes of ischemia. Myocardial adenosine triphosphate content fell markedly by the end of 30 and 40 minutes of ischemia in both groups. After 30 minutes of ischemia, newborn but not adult hearts were able to completely recover adenosine triphosphate content by 30 minutes of reperfusion. This advantage was lost after 40 minutes of ischemia. Deferoxamine had no effect on recovery of adenosine triphosphate content in any group. We conclude that (1) newborn hearts recover postischemic function and metabolism faster than adult hearts after shorter periods of ischemia; (2) this advantage is lost as the ischemic period is prolonged; (3) deferoxamine improved postischemic cardiac function after longer ischemic periods, in both age groups, but failed to improve the recovery of myocardial adenosine triphosphate content.

Evaluation of right heart function in adults with atrial septal defect using gated cardiac blood pool scanning

Evaluation of right heart function in adults with atrial septal defect using gated cardiac blood pool scanning