Magdi Yacoub

Mitral valve disease—morphology and mechanisms

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

The role of endothelin-1 in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare but debilitating disease, which if left untreated rapidly progresses to right ventricular failure and eventually death. In the quest to understand the pathogenesis of this disease differences in the profile, expression and action of vasoactive substances released by the endothelium have been identified in patients with PAH. Of these, endothelin-1 (ET-1) is of particular interest since it is known to be an extremely powerful vasoconstrictor and also involved in vascular remodelling. Identification of ET-1 as a target for pharmacological intervention has lead to the discovery of a number of compounds that can block the receptors via which ET-1 mediates its effects. This review sets out the evidence in support of a role for ET-1 in the onset and progression of the disease and reviews the data from the various clinical trials of ET-1 receptor antagonists for the treatment of PAH.

Modulation of human valve interstitial cell phenotype and function using a fibroblast growth factor 2 formulation

Valve interstitial cells (VICs) are fibroblastic in nature however in culture it is widely accepted that they differentiate into a myofibroblastic phenotype. This study assessed a fibroblast culture media formulation for its ability to maintain the phenotype and function of VICs as in the intact healthy valve. Normal human VICs were cultured separately in standard DMEM and in fibroblast media consisting of FGF2 (10ng/ml), insulin (50ng/ml) and 2% FCS for at least a week. Cell morphology, aspect ratio, size, levels and distribution of protein expression, proliferation, cell cycle, contraction and migration were assessed. Some VICs and some valve endothelial cells expressed FGF2 in valve tissue and this expression was increased in calcified valves. VICs in DMEM exhibited large, spread cells whereas VICs in fibroblast media were smaller, elongated and spindly. Aspect ratio and size were both significantly higher in DMEM (p<0.01). The level of expression of α-SMA was significantly reduced in fibroblast media at day 2 after isolation (p<0.01) and the expression of α-SMA, SM22 and EDA-fibronectin was significantly reduced in fibroblast media at days 7 and 12 post-isolation (p<0.01). Expression of cytoskeletal proteins, bone marker proteins and extracellular matrix proteins was reduced in fibroblast media. Proliferation of VICs in fibroblast media was significantly reduced at weeks 1 (p<0.05) and 2 (p<0.01). Collagen gel contraction was significantly reduced in fibroblast media (p<0.05). VICs were found to have significantly fewer and smaller focal adhesions in fibroblast media (p<0.01) with significantly fewer supermature focal adhesions in fibroblast media (p<0.001). Ultrastructurally, VICs in fibroblast media resembled native VICs from intact valves. VICs in fibroblast media demonstrated a slower migratory ability after wounding at 72 hours (p<0.01). Treatment of human VICs with this fibroblast media formulation has the ability to maintain and to dedifferentiate the VICs back to a fibroblastic phenotype with phenotypic and functional characteristics ascribed to cells in the intact valve. This methodology is fundamental in the study of normal valve biology, pathology and in the field of tissue engineering.

Coronary endothelial function in cardiac transplant recipients with accelerated coronary disease.

BackgroundPrevious studies with the endothellum-dependent vasodilator substance P have shown a preserved vasodilator response in cardiac transplant recipients with angiographically normal coronary arteries. Although endothelial dysfunction is known to occur in cardiac transplant recipients with accelerated coronary disease, the degree to which the endothellum is atlected is not known precisely. The aim of the present study was to examine endothelial function in accelerated coronary disease following cardiac transplantation. MethodsThirteen cardiac transplant recipients with epicardial coronary disease underwent substance P infusion. The response to incremental doses of substance P was measured in smooth segments of affected coronary arteries. Substance P was infused over 2 mm with a starting dose of 1.4 pmol/min and a maximum of 22.4 pmol/mm, reached by doubling the dose in steps, followed by an infusion of 2 mg isosorbide dmitrate over 2 mm. ResultsSubstance P caused less vasodilation at lower concentrations, with a significantly higher dose required to achieve half maximal dilation compared with cardiac transplant recipients with no coronary disease. The mean maximal dilation achieved with substance P was 22.98 ± 4.62% compared to 21.95 ± 4.9% with isosorbide dmitrate; the latter value was not significantly different from the maximal dilation achieved in cardiac transplant recipients without coronary disease. ConclusionsIn cardiac transplant recipients with accelerated coronary disease the functional vasodilatory ability of the coronary endothelium is impaired in segments of apparently unaffected epicardial arteries, which may lead to an increase in the resting vasoconstrictor tone and have important functional and therapeutic implications.

Genetic modifiers to the PLN L39X mutation in a patient with DCM and sustained ventricular tachycardia

[first paragraph of article] Idiopathic dilated cardiomyopathy (DCM) is a leading cause of heart failure characterized by an enlarged ventricular cavity leading to systolic dysfunction. DCM patients have a considerable annual mortality rate of 5–10%, with half of them being sudden unexpected deaths due to ventricular tachycardia (VT) or ventricular fibrillation (VF). Although a multifactorial disease, DCM appears to be inheritable in approximately 70% of cases. Causative gene mutations have been identified in a broad range of genes coding for proteins with a variety of function, such as cytoskeletal, sarcomeric or ion homeostasis related. Among the latter category, several mutations have been identified in Ca 2+ handling proteins in familial and sporadic DCM cases. An increasing body of evidence indicates that abnormal intracellular Ca 2+ handling underlies contractile dysfunction and contributes to ventricular arrhythmogenesis in failing myocardium. A prime example is phospholamban (PLN), which is directly involved in the uptake of Ca 2+ by the sarcoplasmic reticulum (SR), on a beat-to-beat basis, thereby regulating cardiac contraction and relaxation. PLN mutations have been directly associated with the development of dilated cardiomyopathy and heart failure in patients and animal models. However, modifier genes are thought to influence the clinical outcome both in PLN cases, as well as DCM cases in general. We herein describe a DCM case which illustrates the complex genetic contribution to disease development and progression.

Controlling the Uptake and Regulating the Release of Nitric Oxide in Microporous Solids

Representative compounds from three classes of microporous solids, namely, metal-organic frameworks (MOFs), hybrid ultra-microporous materials (HUMs), and porous-organic polymers (POPs), were investigated for their nitric oxide gas uptake and release behavior. Low-pressure sorption studies indicated strong chemisorption of NO on the free amine groups decorating the MOF UiO-66-NH2 when compared to its non-amine-functionalized parent. The HUMs demonstrated reversible physisorption within the low-pressure regime, but interestingly in one case there was evidence for chemisorption following pressurization with NO at 10 bar. Significant release of chemisorbed NO from the UiO-66-NH2 and one of the HUMs was triggered by addition of acid to the medium, a pH change from 7.4 to 5.4 being sufficient to trigger NO release. An imidazole-based POP exhibited chemisorption of NO at high pressure wherein the ring basicity facilitated both NO uptake and spontaneous release upon contact with the aqueous release medium.

Late stimulation of myocardial recovery, following insertion of a continuous flow LVAD

The use of mechanical assist devices for the treatment of advanced heart failure has increased dramatically in recent years. Significant recovery of myocardial function following insertion of left ventricular assisted device (LVAD) occurs in a small percentage of patients due to unloading alone. Several strategies for enhancing the degree of recovery using combination therapy have been introduced. Most of these strategies depend on early use of pharmacologic agents to stimulate reverse remodelling followed by inducing physiologic hypertrophy. We here report the use of the funny current inhibitor ivabradine late after insertion of Heart Mate II in Doha. This was performed following experimental studies in a small animal model which showed the drug induces reverse re-modelling when used in combination with unloading by abdominal heart transplantation. Sequential studies were performed using non-invasive myocardial function and exercise testing after reducing the pump speed to 6,000 RPM, which in effect stops forward flow through the pump. This was performed under full heparinisation. These tests have shown progressive recovery of function following the institution of the combination therapy. Further studies using LVADs as a platform for recovery are being investigated at QCRC. These studies include formal exercise program and gene and cell therapy. In addition, an extensive basic science program to investigate the mechanisms of recovery is in progress.