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1.  Atherosclerosis Alters Loading-Induced Arterial Damage: Implications for Robotic Surgery 
PLoS ONE  2016;11(6):e0156936.
Lack of intra-operative haptic information during robotic surgery increases the risk for unintended tissue overload and damage. Knowledge about the acute and chronic fundamental relationship between force load and induced damage in healthy and diseased arteries is crucial to enable intra-operative haptic feedback or shared autonomy and improve patient safety.
Arteries of wildtype and atherosclerotic mice were clamped in vivo for 2 minutes (0.0N, 0.6N or 1.27N). Histological analysis (Verhoeff’s-Van Gieson, Osteopontin, CD45, CD105) was performed immediately, or after 6 hours, 2 weeks or 1 month. Endothelium-dependent and–independent vasodilatation was assessed immediately or 1 month after clamping.
Endothelium dependent vasodilatation is worse after clamping of wildtype arteries, but is restored after one month. Clamping also results in flattening of the innermost elastic membrane of both genotypes, which is reversed over time for wildtype arteries but not for vessels from atherosclerotic mice. Higher osteopontin content in wildtype and LDLR-/- mice after 2 weeks suggests a phenotypic switch of the medial smooth muscle cells (SMCs), an effect that is reversed after 1 month. While inflammation in the intima diminishes, medial CD45 content rises through time in both genotypes. CD105 staining shows that even manipulation without clamping results in endothelial cell loss in both LDLR+/+ and LDLR-/- mice.
Arterial clamping induces different acute and long-term injury to the vessel wall of atherosclerotic and healthy arteries.
PMCID: PMC4905651  PMID: 27295082
2.  Arterial Vasoreactivity is Equally Affected by In Vivo Cross-Clamping with Increasing Loads in Young and Middle-Aged Mice Aortas 
Purpose: To compensate for the lack of haptic feedback by surgical robots, limitation of exerted forces could be implemented. The limits should be based on the observed relationship between tissue load and induced damage. This study examines whether age-related changes influence this relationship.
Methods: Descending thoracic aortas of male C57BL/6J mice of 10, 25 and 40 weeks were clamped in vivo (no clamp, 0.5N or 2.0N) for 2 min. Functional integrity was tested in vitro by studying endothelium-dependent and -independent vasoreactivity.
Results: Endothelium-dependent relaxation deteriorated with increased clamping force at all ages. Clamping did not influence endothelium-independent vasodilation. Age (10, 25 and 40 weeks) did not significantly impact on the effect of clamping on endothelium-dependent and independent vasoreactivity.
Conclusions: Within the tested conditions, mechanical clamping induces damage to the vascular endothelium, but not to the smooth muscle cells. Age has no effect on the obtained results in mice from 10 to 40 weeks old.
PMCID: PMC4981779  PMID: 26548538
age; arterial clamping; mouse model; damage; aorta
3.  An electro-responsive hydrogel for intravascular applications: an in vitro and in vivo evaluation 
There is a growing interest in using hydrogels for biomedical applications, because of more favourable characteristics. Some of these hydrogels can be activated by using particular stimuli, for example electrical fields. These stimuli can change the hydrogel shape in a predefined way. It could make them capable of adaptation to patient-specific anatomy even post-implantation. This is the first paper aiming to describe in vivo studies of an electro-responsive, Pluronic F127 based hydrogel, for intravascular applications. Pluronic methacrylic acid hydrogel (PF127/MANa) was in vitro tested for its haemolytic and cytotoxic effects. Minimal invasive implantation in the carotid artery of sheep was used to evaluate its medium-term biological effects, through biochemical, macroscopic, radiographic, and microscopic evaluation. Indirect and direct testing of the material gave no indication of the haemolytic effects of the material. Determination of fibroblast viability after 24 h of incubation in an extract of the hydrogel showed no cytotoxic effects. Occlusion was obtained within 1 h following in vivo implantation. Evaluation at time of autopsy showed a persistent occlusion with no systemic effects, no signs of embolization and mild effects on the arterial wall. An important proof-of-concept was obtained showing biocompatibility and effectiveness of a pluronic based electro-responsive hydrogel for obtaining an arterial occlusion with limited biological impact. So the selected pluronic-methacrylic acid based hydrogel can be used as an endovascular occlusion device. More importantly it is the first step in further development of electro-active hydrogels for a broad range of intra-vascular applications (e.g. system to prevent endoleakage in aortic aneurysm treatment, intra-vascular drug delivery).
PMCID: PMC4608972  PMID: 26474577
4.  Xenon for the prevention of postoperative delirium in cardiac surgery: study protocol for a randomized controlled clinical trial 
Trials  2015;16:449.
Postoperative delirium (POD) is a manifestation of acute postoperative brain dysfunction that is frequently observed after cardiac surgery. POD is associated with short-term complications such as an increase in mortality, morbidity, costs and length of stay, but can also have long-term sequelae, including persistent cognitive deficits, loss of independence, and increased mortality for up to 2 years. The noble gas xenon has been demonstrated in various models of neuronal injury to exhibit remarkable neuroprotective properties. We therefore hypothesize that xenon anesthesia reduces the incidence of POD in elderly patients undergoing cardiac surgery with the use of cardiopulmonary bypass.
One hundred and ninety patients, older than 65 years, and scheduled for elective cardiac surgery, will be enrolled in this prospective, randomized, controlled trial. Patients will be randomized to receive general anesthesia with either xenon or sevoflurane. Primary outcome parameter will be the incidence of POD in the first 5 postoperative days. The occurrence of POD will be assessed by trained research personnel, blinded to study group, with the validated 3-minute Diagnostic Confusion Assessment Method (3D-CAM) (on the intensive care unit in its version specifically adapted for the ICU), in addition to chart review and the results of delirium screening tools that will be performed by the bedside nurses). Secondary outcome parameters include duration and severity of POD, and postoperative cognitive function as assessed with the Mini-Mental State Examination.
Older patients undergoing cardiac surgery are at particular risk to develop POD. Xenon provides remarkable hemodynamic stability and has been suggested in preclinical studies to exhibit neuroprotective properties. The present trial will assess whether the promising profile of xenon can be translated into a better outcome in the geriatric population.
Trial registration
EudraCT Identifier: 2014-005370-11 (13 May 2015).
PMCID: PMC4600284  PMID: 26452540
Xenon; Sevoflurane anesthesia; Postoperative delirium; Cardiac surgery
5.  Migration of a broken scalpel into the heart after spine surgery 
Iatrogenic vascular problems during posterior lumbar interbody fusion are a rare entity. Migration of a broken scalpel towards the heart has, to our knowledge, never been reported. We present the successful surgical retrieval of a broken scalpel from the heart after posterior lumbar interbody fusion without the use of a cardiopulmonary bypass.
PMCID: PMC4046866  PMID: 24435837
Foreign body; Iatrogenic; Off-pump surgery
6.  Prospective evaluation of clinical outcomes in all-comer high-risk patients with aortic valve stenosis undergoing medical treatment, transcatheter or surgical aortic valve implantation following heart team assessment 
Transcatheter aortic valve implantation (TAVI) has been proposed as a treatment alternative for patients with aortic valve stenosis (AS) at high or prohibitive risk for surgical aortic valve replacement (AVR). We aimed to assess real-world outcomes after treatment according to the decisions of the multidisciplinary heart team.
At a tertiary centre, all high-risk patients referred between 1 March 2008 and 31 October 2011 for symptomatic AS were screened and planned to undergo AVR, TAVI or medical treatment. We report clinical outcomes as defined by the Valve Academic Research Consortium.
Of 163 high-risk patients, those selected for AVR had lower logistic EuroSCORE and STS scores when compared with TAVI or medical treatment (median [interquartile range] 18 [12–26]; 26 [17–36]; 21 [14–32]% (P = 0.015) and 6.5 [5.1–10.7]; 7.6 [5.8–10.5]; 7.6 [6.1–15.7]% (P = 0.056)). All-cause mortalities at 1 year in 35, 73 and 55 patients effectively undergoing AVR, TAVI and medical treatment were 20, 21 and 38%, respectively (P = 0.051). Cardiovascular death and major stroke occurred in 9, 8 and 33% (P < 0.001) and 6, 4 and 2% (P = 0.62), respectively. For patients undergoing valve implantation, device success was 91 and 92% for AVR and TAVI, respectively. The combined safety endpoint at 30 days was in favour of TAVI (29%) vs AVR (63%) (P = 0.001). In contrast, the combined efficacy endpoint at 1 year tended to be more favourable for AVR (10 vs 24% for TAVI, P = 0.12).
Patients who are less suitable for AVR can be treated safely and effectively with TAVI with similar outcomes when compared with patients with a lower-risk profile undergoing AVR. Patients with TAVI or AVR have better survival than those undergoing medical treatment only.
PMCID: PMC3745142  PMID: 23702465
Transcatheter aortic valve implantation; Aortic valve replacement; Valve academic research consortium
7.  External aortic root support: a histological and mechanical study in sheep† 
Personalized external aortic root support has completed initial evaluation and has technology appraisal in the UK for patients with Marfan syndrome for use as an alternative to root replacement. Its long-term success in preventing aortic dissection remains uncertain. Here, we report a study in sheep to establish whether the externally supporting mesh, as used clinically, is biologically incorporated. The strength of the resulting mesh/artery composite has been tested.
The carotid artery of growing sheep (n = 6) was enclosed in a mesh sleeve made of a polymer, polyethylene terephthalate. After a predefined interval of 4–6 months, a length of the artery was excised, including the sleeved and unsleeved portions, and was stress tested and examined histologically.
One animal died of pneumonia 7 days after implantation. Comparing sleeved with normal segments, the overall thickness was increased and there was a fibrotic sheet in the periarterial space. The overall vessel wall architecture was preserved in all specimens. Although media thickness of ensleeved arteries was smaller and in one animal mild oedema was found in one quadrant of the outer part of the media. There was a significant increase in stiffness and maximum tensile strength of the supported segments compared with normal arterial tissue.
Polyethylene terephthalate mesh, as used for the external support of the dilated aortic root in Marfan syndrome, becomes incorporated in the periadventitial tissue of the carotid artery of sheep. Limited thinning of the media, without any signs of inflammation or medial necrosis, was visible. There was a significantly greater tensile strength in the carotid artery/mesh composite compared with the unsleeved carotid artery.
PMCID: PMC3715175  PMID: 23624982
Experimental; Thoracic aortic aneurysm; Blood vessel prosthesis
8.  Transapical transcatheter aortic valve implantation in a heart transplant recipient with severely depressed left ventricular function 
Transcatheter aortic valve implantation (TAVI) is becoming a valuable alternative to surgical aortic valve replacement in non-operable and high-risk surgical patients. As the population of heart donors and recipients ages, the prevalence of degenerative valvular disease after transplantation will increase. The optimal treatment strategy of valvulopathies in these patients with extensive comorbidity is still unknown because of insufficient published experience. We present a heart transplant recipient with renal failure, systolic heart failure and severe aortic stenosis who was successfully treated with transapical TAVI.
PMCID: PMC3653466  PMID: 23460597
Transcatheter aortic valve implantation; Transplant; Heart failure
9.  Ventricular phosphodiesterase 5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice 
Circulation  2009;119(3):408-416.
Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction (MI) in transgenic mice with cardiomyocyte-specific over-expression of PDE5 (PDE5-TG).
Methods and Results
Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening and calcium handling in isolated cardiomyocytes, and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates (WT). Ten days after MI, LV cGMP levels increased to a greater extent in WT than PDE5-TG (P<0.05). Ten weeks after MI, LV end-systolic and -diastolic volumes were larger in PDE5-TG than in WT (57±5 vs 39±4 and 65±6 vs 48±4 µL, respectively, P<0.01 for both). LV systolic and diastolic dysfunction was more marked in PDE5-TG than WT associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium.
Increased PDE5 expression predisposes mice to adverse LV remodeling after MI. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.
PMCID: PMC3791110  PMID: 19139381
phosphodiesterase-5; cyclic guanosine monophosphate (cGMP); myocardial infarction; heart failure
10.  Transcatheter aortic valve implantation in situs inversus totalis 
A frail 84-year old lady with situs inversus totalis and symptomatic aortic stenosis underwent a successful transcatheter aortic valve implantation (TAVI) after extensive diagnostic work-up. We show illustrative pre- and postintervention three-dimensional reconstruction imaging and describe how conventional and dedicated imaging software can support the planning and performance of TAVI.
PMCID: PMC3422939  PMID: 22645293
Percutaneous valve implantation; Dextrocardia; Aortic stenosis
11.  ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome 
Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.
This study was performed in LDL-receptor (LDLR−/−) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR−/−, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during β-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp.
In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and β-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to β-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+.
Cardiomyocyte contractility and β-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to β-adrenergic stimulation in MS.
PMCID: PMC3729821  PMID: 23848952
Metabolic syndrome; Cardiomyocyte contractility; β-adrenergic stimulation; Hypocaloric diet; ACE-inhibition
12.  Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling 
PLoS ONE  2013;8(3):e58841.
The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC).
Methodology/Principal Findings
In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro.
Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target.
PMCID: PMC3601083  PMID: 23527037
13.  Angiotensin-converting enzyme inhibition and food restriction restore delayed preconditioning in diabetic mice 
Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential.
Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student’s t-test or one-way ANOVA followed by a Fisher’s LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher’s LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant.
Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob.
Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.
PMCID: PMC3598767  PMID: 23432808
Myocardial protection; Preconditioning; Ischemia/reperfusion injury; Diabetes mellitus; Metabolic syndrome
14.  Hematopoietic Stem/Progenitor Cell Proliferation and Differentiation Is Differentially Regulated by High-Density and Low-Density Lipoproteins in Mice 
PLoS ONE  2012;7(11):e47286.
Hematopoietic stem/progenitor cells (HSPC) are responsible for maintaining the blood system as a result of their self-renewal and multilineage differentiation capacity. Recently, studies have suggested that HDL cholesterol may inhibit and impaired cholesterol efflux may increase HSPC proliferation and differentiation.
We hypothesized that LDL may enhance HSPC proliferation and differentiation while HDL might have the opposing effect which might influence the size of the pool of inflammatory cells.
Methods and Results
HSPC number and function were studied in hypercholesterolemic LDL receptor knockout (LDLr−/−) mice on high fat diet. Hypercholesterolemia was associated with increased frequency of HSPC, monocytes and granulocytes in the peripheral blood (PB). In addition, an increased proportion of BM HSPC was in G2M of the cell cycle, and the percentage of HSPC and granulocyte-macrophage progenitors (GMP) increased in BM of LDLr−/− mice. When BM Lin-Sca-1+cKit+ (i.e. “LSK”) cells were cultured in the presence of LDL in vitro we also found enhanced differentiation towards monocytes and granulocytes. Furthermore, LDL promoted lineage negative (Lin−) cells motility. The modulation by LDL on HSPC differentiation into granulocytes and motility was inhibited by inhibiting ERK phosphorylation. By contrast, when mice were infused with human apoA-I (the major apolipoprotein of HDL) or reconstituted HDL (rHDL), the frequency and proliferation of HSPC was reduced in BM in vivo. HDL also reversed the LDL-induced monocyte and granulocyte differentiation in vitro.
Our data suggest that LDL and HDL have opposing effects on HSPC proliferation and differentiation. It will be of interest to determine if breakdown of HSPC homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression.
PMCID: PMC3492382  PMID: 23144813
15.  Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury 
The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.
C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student’s t-test or factorial ANOVA followed by a Fisher’s LSD post hoc test.
Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.
ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.
PMCID: PMC3444392  PMID: 22853195
Ischemia/reperfusion; Diabetes mellitus; Metabolic syndrome; In vivo contractility; Infarct size
16.  Glucose Tolerance and Left Ventricular Pressure-Volume Relationships in Frequently Used Mouse Strains 
We investigated glucose tolerance and left ventricular contractile performance in 4 frequently used mouse strains (Swiss, C57BL/6J, DBA2, and BalbC) at 24 weeks. Glucose tolerance was tested by measuring blood glucose levels in time after intraperitoneal glucose injection (2 mg/g body weight). Left ventricular contractility was assessed by pressure-conductance analysis. Peak glucose levels and glucose area under the curve were higher (all P < .05) in C57BL/6J (418 ± 65 mg/dL and 813 ± 100 mg·h/dL) versus Swiss (237 ± 66 mg/dL and 470 ± 126 mg·h/dL), DBA2 (113 ± 20 mg/dL and 304 ± 49 mg·h/dL, P < .01), and BalbC mice (174 ± 55 mg/dL and 416 ± 70 mg·h/dL). Cardiac output was higher (all P < .05) in Swiss (14038 ± 4530 μL/min) versus C57BL/6J (10405 ± 2683 μL/min), DBA2 (10438 ± 3251 μL/min), and BalbC mice (8466 ± 3013 μL/min). Load-independent left ventricular contractility assessed as recruitable stroke work (PRSW) was comparable in all strains. In conclusion, glucose tolerance and load-dependent left ventricular performance parameters were different between 4 mice background strains, but PRSW was comparable.
PMCID: PMC3035009  PMID: 21318112
17.  Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice 
The Journal of Clinical Investigation  2010;120(9):3267-3279.
Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4–/– and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4–/– mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholine-induced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension.
PMCID: PMC2929713  PMID: 20679729
18.  Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance 
European Heart Journal  2008;30(1):116-124.
Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drug’s potential to improve mitochondrial respiratory chain function and reduce oxidative stress.
Methods and results
In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice.
We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.
PMCID: PMC2639086  PMID: 18784063
Muscular dystrophy; Therapy; Cardiomyopathy; Hemodynamics; Heart failure; Animal model

Results 1-18 (18)