Ismail El-Hamamsy

Cellular and molecular mechanisms of thoracic aortic aneurysms

Thoracic aortic aneurysms (TAA) increase the risk of aortic dissection or rupture and represent an important source of morbidity and mortality. Inherited forms of the disease, including Marfan syndrome, have been recognized for a long time but were considered degenerative diseases characterized by cystic medial necrosis of the aortic wall. Improved definition of the structure and function of the normal aortic wall, coupled with the discovery of genetic mutations in key regulatory molecules, have contributed to a more detailed understanding of the pathophysiology of syndromic, familial and sporadic TAAs. We here review the cellular and molecular mechanisms involved in TAA formation and outline areas for future research.

Side-Specific Endothelial-Dependent Regulation of Aortic Valve Calcification: Interplay of Hemodynamics and Nitric Oxide Signaling

Arterial endothelial cells maintain vascular homeostasis and vessel tone in part through the secretion of nitric oxide (NO). In this study, we determined how aortic valve endothelial cells (VEC) regulate aortic valve interstitial cell (VIC) phenotype and matrix calcification through NO. Using an anchored in vitro collagen hydrogel culture system, we demonstrate that three-dimensionally cultured porcine VIC do not calcify in osteogenic medium unless under mechanical stress. Co-culture with porcine VEC, however, significantly attenuated VIC calcification through inhibition of myofibroblastic activation, osteogenic differentiation, and calcium deposition. Incubation with the NO donor DETA-NO inhibited VIC osteogenic differentiation and matrix calcification, whereas incubation with the NO blocker l-NAME augmented calcification even in 3D VIC-VEC co-culture. Aortic VEC, but not VIC, expressed endothelial NO synthase (eNOS) in both porcine and human valves, which was reduced in osteogenic medium. eNOS expression was reduced in calcified human aortic valves in a side-specific manner. Porcine leaflets exposed to the soluble guanylyl cyclase inhibitor ODQ increased osteocalcin and α-smooth muscle actin expression. Finally, side-specific shear stress applied to porcine aortic valve leaflet endothelial surfaces increased cGMP production in VEC. Valve endothelial-derived NO is a natural inhibitor of the early phases of valve calcification and therefore may be an important regulator of valve homeostasis and pathology.

Scanning ion conductance microscopy: a convergent high-resolution technology for multi-parametric analysis of living cardiovascular cells.

Cardiovascular diseases are complex pathologies that include alterations of various cell functions at the levels of intact tissue, single cells and subcellular signalling compartments. Conventional techniques to study these processes are extremely divergent and rely on a combination of individual methods, which usually provide spatially and temporally limited information on single parameters of interest. This review describes scanning ion conductance microscopy (SICM) as a novel versatile technique capable of simultaneously reporting various structural and functional parameters at nanometre resolution in living cardiovascular cells at the level of the whole tissue, single cells and at the subcellular level, to investigate the mechanisms of cardiovascular disease. SICM is a multimodal imaging technology that allows concurrent and dynamic analysis of membrane morphology and various functional parameters (cell volume, membrane potentials, cellular contraction, single ion-channel currents and some parameters of intracellular signalling) in intact living cardiovascular cells and tissues with nanometre resolution at different levels of organization (tissue, cellular and subcellular levels). Using this technique, we showed that at the tissue level, cell orientation in the inner and outer aortic arch distinguishes atheroprone and atheroprotected regions. At the cellular level, heart failure leads to a pronounced loss of T-tubules in cardiac myocytes accompanied by a reduction in Z-groove ratio. We also demonstrated the capability of SICM to measure the entire cell volume as an index of cellular hypertrophy. This method can be further combined with fluorescence to simultaneously measure cardiomyocyte contraction and intracellular calcium transients or to map subcellular localization of membrane receptors coupled to cyclic adenosine monophosphate production. The SICM pipette can be used for patch-clamp recordings of membrane potential and single channel currents. In conclusion, SICM provides a highly informative multimodal imaging platform for functional analysis of the mechanisms of cardiovascular diseases, which should facilitate identification of novel therapeutic strategies.

Long-Term Results After Systematic Off-Pump Coronary Artery Bypass Graft Surgery in 1000 Consecutive Patients

Background— Off-pump coronary artery bypass surgery (OPCAB) is currently used as an alternative to conventional “on-pump” surgery, but there are very little data available on long-term follow-up. The aim of this study was to review our long-term experience with the use of systematic OPCAB. Methods and Results— 1000 consecutive OPCAB surgeries were systematically performed between 1996 and 2004, representing 95% of all coronary revascularization during that same time frame, with a 97% complete follow-up. Average age of the patients was 64±10 years (778 men and 222 women). Seventy-three percent had triple-vessel disease. Operative 30-day mortality was 1.6%. Overall survival at 96 months was 74±3.5% and cardiac survival was 94±1.3%. By Cox regression analysis, age (odds ratio [OR], 1.07), congestive heart failure (CHF) (OR, 1.90), peripheral vascular disease (OR, 1.74), chronic renal insufficiency (OR, 2.04), previous myocardial infarction (MI) (OR, 1.60), and New York Heart Association functional class (OR, 1.60) were risk factors for long- term mortality. Survival free of any cardiac events (cardiac death, MI, unstable angina, heart failure, or reintervention) was 80±3.4%. Survival free of any type of reintervention alone was 90±3%. By Cox regression analysis, mitral regurgitation (OR, 2.3), peripheral vascular disease (OR, 2.1), and diffuse coronary disease (OR, 2.3) were significant predictors of recurrent cardiac events. Conversion to “on-pump” (OR, 14.3) was predictor of long-term need for repeat revascularization. Conclusion— In this series, systematic OPCAB surgery was shown to be an acceptable alternative to conventional “on-pump” coronary artery bypass graft for the treatment of coronary artery disease.

Integrated morphologic and functional assessment of the aortic root after different tissue valve root replacement procedures

OBJECTIVESnThis study was undertaken to explore aspects of the hemodynamic function of different biologic tissue aortic valve root replacements. We set out to image and display the spatiotemporal distributions of axially directed blood velocity through the aortic root.nnnMETHODSnThe flow velocities through a plane transecting the aortic root were measured by 2-dimensional cine phase-contrast magnetic resonance velocity mapping in 44 subjects: 29 patients who had undergone aortic root replacement approximately 10 years previously (13 autografts, 10 stentless xenografts, and 6 homografts) and 15 healthy control subjects. With cine as well as velocity images, aortic sinus dimensions, effective orifice area, and several velocity parameters were measured. Color-coded plots of velocity relative to the sinus cross sections and velocity-time plots were used to compare spatiotemporal distributions of velocity.nnnRESULTSnPeak flow velocity was similar between the autografts (102 ± 28.0 cm/s) and control valves (119 ± 20.0 cm/s) but was higher in xenografts (167 ± 36.0 cm/s) and homografts (206 ± 91.0 cm/s). These measurements showed an inverse relationship with the effective orifice area (7.27 ± 0.20, 4.24 ± 0.81, 3.37 ± 0.32, and 3.28 ± 0.87 cm(2), respectively). Autograft peak flow velocity showed no significant difference from control valve peak flow velocity, despite larger root dimensions (P < .001). The graphic displays provided further spatiotemporal information.nnnCONCLUSIONSnPeak velocities and spatiotemporal flow patterns depend on the type of valve substitute. In the parameters measured, autograft replacements differed least from normal aortic valves.

Early and long-term results of reoperative total aortic root replacement with reimplantation of the coronary arteries

BACKGROUNDnTotal root replacement with biologic valves and reimplantation of the coronaries gives good early and midterm results. There is continuing concern, however, regarding the risks and long-term results for reoperation after total replacement of the aortic root with reimplantation of the coronaries.nnnMETHODSnBetween June 1981 and July 2010, a total of 84 patients underwent reoperative aortic root replacement with reimplantation of the coronaries (60 male, mean age 38 ± 15 years). All patients had undergone first-time total aortic root replacement with homografts (82 patients) or autografts (2 patients). Indication for reoperation was structural valve deterioration in 72 patients (85%) and infective endocarditis in 12 patients (15%). Mean interval between first operation and reoperation was 11.1 ± 4.7 years (range, 1 month-24.7 years). Median length of follow-up was 9.7 ± 5.6 years (range, 1 month-24.4 years).nnnRESULTSnThirty-day mortality was 2.4% (nxa0=xa02 patients). Both patients died postoperatively of low-output syndromes with multiorgan failure. At reoperation, 74 patients received homografts (87%), 7 patients underwent a Ross procedure (9%), and 3 received stentless porcine roots (4%). One patient required pacemaker implantation (1%). Actuarial survivals were 89% ± 4% and 81% ± 5% at 5 and 10 years, respectively. Nine patients underwent a successful third root replacement during follow-up. Freedom from third-time aortic root operation was 97% ± 3% at 10 years.nnnCONCLUSIONSnReoperative aortic root replacement can be performed safely with good short-term and midterm outcomes in a young patient cohort.

Pattern and degree of left ventricular remodeling following a tailored surgical approach for hypertrophic obstructive cardiomyopathy.

Abstract Background The role of a tailored surgical approach for hypertrophic cardiomyopathy (HCM) on regional ventricular remodelling remains unknown. The aims of this study were to evaluate the pattern, extent and functional impact of regional ventricular remodelling after a tailored surgical approach. Methods From 2005 to 2008, 44 patients with obstructive HCM underwent tailored surgical intervention. Of those, 14 were ineligible for cardiac magnetic resonance (CMR) studies. From the remainder, 14 unselected patients (42±12 years) underwent pre- and post-operative CMR studies at a median 12 months post-operatively (range 4–37 months). Regional changes in left ventricular (LV) thickness as well as global LV function following surgery were assessed using CMR Tools (London, UK). Results Pre-operative mean echocardiographic septal thickness was 21±4 mm and mean LV outflow gradient was 69±32 mmHg. Following surgery, there was a significant degree of regional regression of LV thickness in all segments of the LV, ranging from 16% in the antero-lateral midventricular segment to 41% in the anterior basal segment. Wall thickening was significantly increased in basal segments but showed no significant change in the midventricular or apical segments. Globally, mean indexed LV mass decreased significantly after surgery (120±29g/m2 versus 154±36g/m2; p<0.001). There was a trend for increased indexed LV end-diastolic volume (70±13 mL versus 65±11 mL; p=0.16) with a normalization of LV ejection fraction (68±7% versus 75±9%; p<0.01). Conclusion Following a tailored surgical relief of outflow obstruction for HCM, there is a marked regional reverse LV remodelling. These changes could have a significant impact on overall ventricular dynamics and function.