Adèle J. Pope

Regeneration of the Heart in Diabetes by Selective Copper Chelation

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

Three-dimensional transmural organization of perimysial collagen in the heart

There is strong support for the view that the ventricular myocardium has a laminar organization in which myocytes are grouped into branching layers separated by cleavage planes. However, understanding of the extent and functional implications of this architecture has been limited by the lack of a systematic three-dimensional description of the organization of myocytes and associated perimysial collagen. We imaged myocytes and collagen across the left ventricular wall at high resolution in seven normal rat hearts using extended volume confocal microscopy. We developed novel reconstruction and segmentation techniques necessary for the quantitative analysis of three-dimensional myocyte and perimysial collagen organization. The results confirm that perimysial collagen has an ordered arrangement and that it defines a laminar organization. Perimysial collagen is composed of three distinct forms: extensive meshwork on laminar surfaces, convoluted fibers connecting adjacent layers, and longitudinal cords. While myolaminae are the principal form of structural organization throughout most of the wall, they are not seen in the subepicardium, where perimysial collagen is present only as longitudinal cords.

Reduced contraction strength with increased intracellular [Ca2+] in left ventricular trabeculae from failing rat hearts

Intracellular calcium ([Ca2+]i) and isometric force were measured in left ventricular (LV) trabeculae from spontaneously hypertensive rats (SHR) with failing hearts and normotensive Wistar‐Kyoto (WKY) controls. At a physiological stimulation frequency (5 Hz), and at 37 °C, the peak stress of SHR trabeculae was significantly (P≤; 0.05) reduced compared to WKY (8 ± 1 mN mm−2(n= 8)vs. 21 ± 5 mN mm−2(n= 8), respectively). No differences between strains in either the time‐to‐peak stress, or the time from peak to 50 % relaxation were detected. Measurements using fura‐2 showed that in the SHR both the peak of the Ca2+ transient and the resting [Ca2+]i were increased compared to WKY (peak: 0.69 ± 0.08 vs. 0.51 ± 0.08 μm (P≤ 0.1) and resting: 0.19 ± 0.02 vs. 0.09 ± 0.02 μm (P≤ 0.05), SHR vs. WKY, respectively). The decay of the Ca2+ transient was prolonged in SHR, with time constants of: 0.063 ± 0.002 vs. 0.052 ± 0.003 s (SHR vs. WKY, respectively). Similar results were obtained at 1 Hz stimulation, and for [Ca2+]o between 0.5 and 5 mm. The decay of the caffeine‐evoked Ca2+ transient was slower in SHR (9.8 ± 0.7 s (n= 8)vs. 7.7 ± 0.2 s (n= 8) in WKY), but this difference was removed by use of the SL Ca2+‐ATPase inhibitor carboxyeosin. Histological examination of transverse sections showed that the fractional content of perimysial collagen was increased in SHR compared to WKY (18.0 ± 4.6 % (n= 10)vs. 2.9 ± 0.9 % (n= 11) SHR vs. WKY, respectively). Our results show that differences in the amplitude and the time course of the Ca2+ transient between SHR and WKY do not explain the reduced contractile performance of SHR myocardium per se. Rather, we suggest that, in this animal model of heart failure, contractile function is compromised by increased collagen, and its three‐dimensional organisation, and not by reduced availability of intracellular Ca2+.

Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes

The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS). Transgenic mice overexpressing AT2 (AT2TG-AS) and nontransgenic mice (NTG-AS) were studied after 70 days of aortic banding. Nonbanded NTG mice were used as controls. LV function was determined by catheterization via LV puncture and cardiac magnetic resonance imaging. LV myocyte diameter and interstitial collagen were determined by confocal microscopy. Atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP) were analyzed by Northern blot. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2, inducible nitric oxide synthase (iNOS), endothelial NOS, ERK1/2, p70S6K, Src-homology 2 domain-containing protein tyrosine phosphatase-1, and protein serine/threonine phosphatase 2A were analyzed by Western blot. LV myocyte diameter and collagen were significantly reduced in AT2TG-AS compared with NTG-AS mice. LV anterior and posterior wall thickness were not different between AT2TG-AS and NTG-AS mice. LV systolic and diastolic dimensions were significantly higher in AT2TG-AS than in NTG-AS mice. LV systolic pressure and end-diastolic pressure were lower in AT2TG-AS than in NTG-AS mice. ANP, BNP, and SERCA2 were not different between AT2TG-AS and NTG-AS mice. Phospholamban (PLB) and the PLB-to-SERCA2 ratio were significantly higher in AT2TG-AS than in NTG-AS mice. iNOS was higher in AT2TG-AS than in NTG-AS mice but not significantly different. Our results indicate that AT2 receptor overexpression modified the pathological hypertrophic response to aortic banding in transgenic mice.

Atrial fibrillation and the risk of death in patients with heart failure: a literature-based meta-analysis.

Background: Heart failure (HF) and atrial fibrillation (AF) are common, associated with significant morbidity and mortality, and frequently coexist. It is uncertain from published data if the presence of AF in patients with HF is associated with an incremental adverse outcome. The aim of this study was to combine the results of all studies investigating prognosis for patients with HF and AF compared with those in sinus rhythm (SR) to asses the mortality risk associated with this arrhythmia.

The Architecture of the Heart: Myocyte Organization and the Cardiac Extracellular Matrix

Bioengineering research is providing new insights into the mechanical function of the heart and the extent to which this is underpinned by myocardial architecture and the cardiac extracellular matrix [1]. The normal left ventricle ejects more than 60% of its end-diastolic cavity volume during systole and analyses of left ventricular wall motion and regional deformation using imaging modalities such as MRI‚ reveal that this is due to relatively uniform shortening of myocytes across the ventricular wall‚ slippage or shearing of adjacent groups of myocytes‚ and the twisting or torsion of the ventricle about its axis. Computer modeling studies indicate that this optimal mechanical performance is critically dependent on the geometry of the cardiac chambers and the organization of cardiac myocytes [1]. Cardiac myocytes and coronary vessels are embedded in a complex extracellular matrix that consists of collagen‚ elastin‚ fibronectin‚ laminin and proteoglycans [2]. The cardiac extracellular matrix is highly responsive to mechanical loading and plays a central role in the remodeling that occurs in response to altered loading conditions. To understand the functions of the extracellular connective tissue matrix more completely‚ we need to see them within a broader structural context. In this chapter‚ we will review the current understanding of myocardial architecture in the hope that it will provide a framework for integrating other more detailed information on the cardiac extracellular matrix found elsewhere in this monograph.