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1.  The living aortic valve: From molecules to function 
The aortic valve lies in a unique hemodynamic environment, one characterized by a range of stresses (shear stress, bending forces, loading forces and strain) that vary in intensity and direction throughout the cardiac cycle. Yet, despite its changing environment, the aortic valve opens and closes over 100,000 times a day and, in the majority of human beings, will function normally over a lifespan of 70–90 years. Until relatively recently heart valves were considered passive structures that play no active role in the functioning of a valve, or in the maintenance of its integrity and durability. However, through clinical experience and basic research the aortic valve can now be characterized as a living, dynamic organ with the capacity to adapt to its complex mechanical and biomechanical environment through active and passive communication between its constituent parts. The clinical relevance of a living valve substitute in patients requiring aortic valve replacement has been confirmed. This highlights the importance of using tissue engineering to develop heart valve substitutes containing living cells which have the ability to assume the complex functioning of the native valve.
PMCID: PMC4104380  PMID: 25054122
Cells; endothelium; nerves; developmental biology; mechanobiology; nanostructure aortic stenosis; calcification
2.  Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences 
Acute renal failure (ARF) frequently complicates lung transplantation. This study determined the prevalence, predictive factors, and consequences of ARF on long-term renal function and survival.
One hundred and seventy-four lung transplantation recipients were divided into two groups based on the presence or absence of ARF defined as a 50% decrease in creatinine clearance from baseline (group I: 67 patients with ARF; group II: 107 patients without ARF). Multivariate analysis compared pre-operative, operative, and post-operative risk factors to assess predictive factors. Renal function over time was assessed by two-way repeated measures analysis of variance (ANOVA).
ARF developed in 67 (39%) of patients. Multivariate analysis identified aprotinin (OR 2.20 (1.11; 4.36), p = 0.02) and double lung transplantation (OR 2.61 (1.32; 5.15), p = 0.006) as risk factors for post-operative renal failure. At 5 years following transplant, creatinine clearance was similar between the two groups (group I CrCl: 73 ml s−1; group II CrCl: 53 ml s−1; p = 0.54). Survival at 5 years was the same in the two groups. Multivariate analysis associated age at the time of transplantation (HR 1.030 (1.004; 1.057), p = 0.02) and intensive care unit (ICU) length of stay (HR 1.029 (1.008; 1.051), p = 0.007) with decreased survival.
The use of aprotinin and double lung transplantation are associated with ARF following lung transplantation. Age at the time of transplantation and a longer intensive care stay predict decreased survival. ARF after lung transplantation is not predictive of late renal dysfunction or decreased long-term survival.
PMCID: PMC3241081  PMID: 21665487
Lung transplantation; Acute renal failure; Aprotinin
3.  Characterization of Porcine Aortic Valvular Interstitial Cell ‘Calcified’ Nodules 
PLoS ONE  2012;7(10):e48154.
Valve interstitial cells populate aortic valve cusps and have been implicated in aortic valve calcification. Here we investigate a common in vitro model for aortic valve calcification by characterizing nodule formation in porcine aortic valve interstitial cells (PAVICs) cultured in osteogenic (OST) medium supplemented with transforming growth factor beta 1 (TGF-β1). Using a combination of materials science and biological techniques, we investigate the relevance of PAVICs nodules in modeling the mineralised material produced in calcified aortic valve disease. PAVICs were grown in OST medium supplemented with TGF-β1 (OST+TGF-β1) or basal (CTL) medium for up to 21 days. Murine calvarial osteoblasts (MOBs) were grown in OST medium for 28 days as a known mineralizing model for comparison. PAVICs grown in OST+TGF-β1 produced nodular structures staining positive for calcium content; however, micro-Raman spectroscopy allowed live, noninvasive imaging that showed an absence of mineralized material, which was readily identified in nodules formed by MOBs and has been identified in human valves. Gene expression analysis, immunostaining, and transmission electron microscopy imaging revealed that PAVICs grown in OST+TGF-β1 medium produced abundant extracellular matrix via the upregulation of the gene for Type I Collagen. PAVICs, nevertheless, did not appear to further transdifferentiate to osteoblasts. Our results demonstrate that ‘calcified’ nodules formed from PAVICs grown in OST+TGF-β1 medium do not mineralize after 21 days in culture, but rather they express a myofibroblast-like phenotype and produce a collagen-rich extracellular matrix. This study clarifies further the role of PAVICs as a model of calcification of the human aortic valve.
PMCID: PMC3482191  PMID: 23110195
4.  Pattern and degree of left ventricular remodeling following a tailored surgical approach for hypertrophic obstructive cardiomyopathy 
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.
PMCID: PMC4239823  PMID: 25610840
hypertrophic cardiomyopathy; tailored myectomy; ventricular remodelling
5.  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.
PMCID: PMC3104336  PMID: 21325316
scanning ion conductance microscopy; vascular disease; heart failure; electrophysiology; receptors
6.  Loeys–Dietz syndrome: a primer for diagnosis and management 
Genetics in Medicine  2014;16(8):576-587.
Loeys–Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some individuals is complex. This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys–Dietz syndrome.
Genet Med 16 8, 576–587.
PMCID: PMC4131122  PMID: 24577266
7.  The Ross operation in infants and children, when and how? 
Heart  2014;100(24):1905-1906.
PMCID: PMC4251164  PMID: 25324536

Results 1-7 (7)