Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.
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Alternative Splicing↗
Biomedical subjects
W Flameng
Publications and source records attributed to W Flameng.
Coronary artery bypass graft with biventricular microaxial pumps.
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Coronary Artery Bypass↗
Distortion of the stentless porcine valve induces accelerated leaflet fibrosis and calcification in juvenile sheep.
BACKGROUND AND AIM OF THE STUDY: Stent mounting of a porcine aortic valve induces loss of mobility and reduces the effective orifice area. Any stentless design conserves the flexibility of the valvular apparatus, but unfortunately, these valves require a more elaborate implantation technique which is considered a major drawback by many surgeons. In an attempt to see if the insertion of the Toronto SPV stentless valve could be made easier, we altered the configuration by lowering the profile at the depth of both coronary sinuses. Theoretically, this could enable insertion of the valve by a single suture layer under the two coronary ostia, in addition to some fixation points at the commissures. METHODS: Two modified 20 mm Toronto SPV valves were tested in vitro for hydrodynamics in a computer-controlled pulse duplicator system and compared with two standard 20 mm valves. Animal implant studies using three standard versus three modified valves (21, 23 and 25 mm) were conducted in juvenile sheep for durability and biocompatibility over a period of three months. RESULTS: The standard Toronto SPV valve provided excellent hemodynamics. The altered configuration performed less optimally during hydrodynamic testing with increased transvalvular gradients. In animal implant studies, cusps adjacent to all reduced-height sinuses showed markedly accelerated fibrosis and substantial calcification, in contrast to only mild fibrosis on the inflow aspects of the standard leaflets. CONCLUSIONS: The more pronounced the deformation of the stentless valve, the faster the calcification of the leaflets adjacent to the distorted sinuses. As both valves types were prepared using an identical preservation technique, the role of loss of mobility in leading to early failure is clearly demonstrated. These findings also underline the extreme importance of correct implantation technique for all stentless valves in order to prevent degeneration.
Animals↗
Anomalous origin of a coronary artery in a transplanted heart.
Upon routine coronary angiography one year after surgery in a 62-year-old male recipient of a heart transplant, an abnormal origin of the left anterior descending coronary artery from the pulmonary artery was found in the donor heart. This very rare congenital anomaly had not been detected during harvesting and transplantation of the heart, and to our knowledge it has never been described before in a heart transplant patient. The donor was a 43-year-old male who died of a spontaneous intracranial bleeding. The recipient continues to enjoy a normal functional capacity and is free of anginal complaints, though there is evidence of ischaemia in the left anterior descending artery territory on exercise thallium-201 myocardial perfusion imaging.
Adult↗
The enabler cannula pump: a novel circulatory support system.
BACKGROUND: The enabler circulatory support system is a catheter pump which expels blood from the left or right ventricular cavity and provides pulsatile flow in the ascending aorta or pulmonary artery. It is driven by a bedside installed pulsatile driving console. The device can easily be implanted by a minimal invasive approach, similar to the Hemopump. PURPOSE: To demonstrate the hemodynamic performance of this new intracardiac support system. METHODS: In a series of 9 sheep, hemodynamic evolutions were recorded in various conditions of myocardial contractility (the non-failing, the moderately failing and the severely failing heart). Heart failure was induced by injection of microspheres in the coronary arteries. RESULTS: Introduction of the cannula through the aortic valve was feasible in all cases. Pump flow by the enabler was gradually increased to a maximum of 3.5 L/min. Diastolic (and mean) aortic blood pressure is significantly increased in the non-failing and moderately failing condition (counterpulsation mode). In heart failure, cardiac output is significantly increased by the pump (p < 0.0001). A drop in left atrial pressure (indicating unloading) is achieved in all conditions but reaches significant levels only during heart failure (p=0.0068). CONCLUSIONS: This new circulatory support system contributes to stabilization of the circulation in the presence of cardiac unloading. In heart failure it actually supports the circulation by increasing cardiac output and perfusion pressure.
Animals↗
Chronic heart failure model induced by coronary embolization in sheep.
OBJECTIVE: To create a model of chronic heart failure in a large animal. METHODS: Heart failure was induced in sheep by single intracoronary injection of polymer macrobeads, which were administered into left main coronary artery (n=3) or selectively into left anterior descending (n=4) or left circumflex (n=5) coronary artery. The animals were followed by echocardigraphy for 20 weeks. Measurements comprised fractional area change (FAC), and diastolic ventricular area (EDVA) and regional wall-thickening fraction (WT%). RESULTS: EDVA increased from 14.2+/-2.1 cm2 prior to embolization to 16.9+/-3.1 cm2 on day 1 (p<0.05), and remained significantly increased until completion of the follow-up period. FAC dropped from 47.9+/-4.6% at baseline to 29.3+/-4.4% on day 1 (p<0.001) and remained significantly depressed until 20 weeks later. In 9 selectively embolized animals WT% of the embolized area decreased from 33.8+/-8.0% at baseline to 5.3+/-2.6% on day 1 and remained significantly decreased. CONCLUSIONS: A simple model of chronic heart failure was developed. It shows relatively high stability over time and may prove beneficial in experimental work on ventricular assist devices.
Animals↗
Deformation of the stentless porcine valve scaffold enhances accelerated leaflet fibrosis and calcification in juvenile sheep.
Stent mounting of xenografts induces a loss of mobility and reduces the effective valve orifice. By contrast, the higher surgical technical expertise required for stentless procedures is a major obstacle for many surgeons. To facilitate the insertion of the Toronto SPV (St Jude Medical Inc, St Paul, Minneapolis, MN) stentless aortic valve, we tried to alter the porcine design by lowering the invasive profile at the depth of the sinuses on both coronary sites. This technique could theoretically facilitate implantation of the modified stentless valve with an easygoing single-layer suture at the challenging subcoronary level and make it more attractive for the surgeon. The standard model was modified by lowering the profile at the depth of the sinuses on both coronary sites, whether by plication (in 3 specimens, one of each size) or excision (in 3 others) of the protruding porcine aortic wall at the nadir of each coronary sinus. Animal implants in juvenile sheep (6 standard Toronto versus 6 modified valves of 21, 23, and 25 mm) were studied for durability and biocompatibility for 3 to 6 months. All valves were evaluated by postoperative echocardiography and after explantation examined macroscopically, radiographically, histologically, and electron microscopically. The standard valves performed well, although at 6 months after implantation, marked fibrosis was found at the outflow parts with scattered calcifications, essentially in the porcine aortic wall. The leaflets remained mobile and contained scant mineralization. By contrast, the modified specimen showed markedly accelerated fibrosis and significant cusp calcifications at distance from the altered zones. Severe restriction of the mobility of the leaflets was visible 3 months after implantation in the juvenile sheep model. The more pronounced the deformation of the modified scaffold, the faster and more intense the degradation and calcification of the leaflets far from the altered zones (worse in the heavily deformed, plicated cusps). Because all valve types were prepared by identical preservation techniques, this study shows that loss of mobility by distortion of the natural scaffold induces early failure. It is extremely important to correct implantation of stentless valves to prevent early degeneration.
Age Factors↗
The No-React anticalcification treatment: a comparison of Biocor No-React II and Toronto SPV stentless bioprostheses implanted in sheep.
Calcification of stentless aortic heterografts still limits the use of these bioprostheses in young patients despite their superior hemodynamic profile. The No-React treatment is described as an anticalcification treatment for biomaterials. We compared the Biocor No-React treated stentless bioprosthesis with the routine glutaraldehyde-fixed Toronto SPV bioprosthesis in a juvenile sheep model. Toronto SPV or Biocor No-React valves were implanted in pulmonary position in juvenile sheep (n = 6). The valves were explanted after 3 months and analyzed by gross inspection, x-ray studies, histological examination, and transmission electron microscopy. The Toronto SPV valve showed calcification of the aortic wall portion at both the inflow and outflow sides of the valve. No significant calcification of the cusps was found by gross inspection or by radiographic or histological examinations. Calcification was visible with electron microscopy in cell remnants and between collagen fibers in the cusps. The Biocor No-React valve showed extensive calcification of the residual aortic wall portion that is contained in the valve. With x-ray and histological examinations, clear calcification of the pericardial wrap, largely replacing the aortic wall tissue, was seen. Calcification scattered throughout the cusp was seen by electron microscopy. We conclude that the Biocor No-React process did not prevent calcification of glutaraldehyde-fixed stentless bioprostheses in a juvenile sheep experimental model. Furthermore, replacement of a large part of the aortic wall by a pericardial wrap did not prevent calcification of the stentless valve "wall."
Animals↗
Are stentless aortic heterografts suitable for right ventricular outflow tract reconstruction? An experimental study in juvenile sheep.
Allograft valved conduits are used routinely for reconstruction of the right ventricular outflow tract in children with congenital heart disease; however, allografts are scarce. The purpose of this study was to evaluate two stentless aortic valves that might be suitable alternatives for right ventricular outflow tract reconstruction. Twelve juvenile sheep underwent implantation of stentless aortic heterografts as an interposition in the pulmonary artery: six porcine aortic valves (Freestyle) and six fully pericardial valves (Pericarbon stentless). In each series, three valves were explanted after 3 months, the other three after 6 months. Valves were analyzed by gross inspection, radiography, and light microscopy. The porcine aortic stentless valve (Freestyle) showed extensive calcification of its aortic wall portion, with perfectly functioning, pliable cusps without calcification or fibrous overgrowth up to 6 months. The pericardial valves (Pericarbon stentless) showed extensive fibrous sheathing, causing progressive retraction of the leaflets and severe regurgitation. After 3 months, minimal calcification was seen in the pericardial wall. Calcification was more pronounced after 6 months, sometimes causing complete calcification of pericardial wall and leaflets, leading to a significant stenosis. We conclude that the pericardial stentless valve becomes rapidly dysfunctional after right-sided implantation as a result of fibrous sheathing and severe calcification. The porcine aortic stentless valve remains functional, but severe calcification of the aortic wall portion is problematic.
Age Factors↗
A critical role for L-type Ca2+ current in the regulation of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from dilated cardiomyopathy.
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Calcium↗
Modulation of transient outward current by extracellular protons and Cd2+ in rat and human ventricular myocytes.
1. The effects of extracellular acidosis and Cd2+ on the transient outward current (Ito) have been investigated in rat and human ventricular myocytes, using the whole-cell patch-clamp technique. 2. In rat myocytes, exposure to acidic extracellular solution (pH 6.0) shifted both steady-state activation and inactivation curves to more positive potentials, by 20.5 +/- 2.7 mV (mean +/- S.E.M.; n = 4) and 19.8 +/- 1.2 mV, respectively. Cd2+ also shifted the activation and inactivation curves in a positive direction in a concentration-dependent manner. 3. In human myocytes, the steady-state activation and inactivation curves were located at more positive potentials. The effect of Cd2+ was similar, but acidosis had less effect than in rat myocytes (e.g. pH 6.0 shifted activation by only 7.2 +/- 2.2 mV and inactivation by 13.7 +/- 0.5 mV; n = 4). 4. In both species, the effect of acidosis decreased with increasing concentrations of Cd2+ and vice versa, suggesting competition between H+ and Cd2+ for a common binding site. 5. The data indicate that acidosis and divalent cations influence Ito via a similar mechanism and act competitively in both rat and human myocytes, but that human cells are less sensitive to the effects of acidosis.
Acidosis↗
Calcium uptake by the sarcoplasmic reticulum, high energy content and histological changes in ischemic cardiomyopathy.
OBJECTIVES: Sarcoplasmic reticulum (SR) Ca2+ uptake, myocardial high energy content and histology were examined in different zones of hearts from patients with ischemic cardiomyopathy. METHODS AND RESULTS: Unfractionated homogenates were prepared from left ventricular samples obtained in three zones of each heart: an infarct-remote zone, an outer peri-infarct zone, and an inner peri-infarct zone. Oxalate-supported 45Ca2+ uptake was measured at 37 degrees C using a filtration method. Maximum rate (Vmax) of uptake in absence or in presence of ryanodine was lower in inner peri-infarct (7.4 +/- 0.7 and 9.5 +/- 0.8 nmol min-1 mg-1 of protein, respectively; mean +/- SEM) and outer peri-infarct tissues (8.8 +/- 0.8 and 12.0 +/- 0.8 nmol min-1 mg-1) than in infarct-remote myocardium (12.7 +/- 2.1 and 15.8 +/- 2.2 nmol min-1 mg-1). The apparent affinity constants for Ca2+ (KCa) as well as the Hill coefficients were not different. Homogenate DNA (1.6 +/- 0.1, 1.6 +/- 0.1 and 1.7 +/- 0.1 mg/g of remote, inner peri-infarct and outer peri-infarct myocardium, respectively) and adenine nucleotides contents (ATP: 15 +/- 1.3, 14 +/- 0.8 and 15 +/- 1.0 mumol/g dry weight, respectively) were similar in all tissues. Fibrosis was increased in inner peri-infarct tissue (37 +/- 6%; vs. 13 +/- 2% and 12 +/- 2% in both remote and outer peri-infarct tissues, respectively), but the number of abnormal cells was not significantly different. CONCLUSION: The decrease of Ca2+ uptake in ischemic cardiomyopathy is not homogeneous in the ventricular wall, and reflects a decreased number/activity of SR Ca(2+)-ATPase, without altered Ca(2+)-affinity or increased Ca2+ leakage through ryanodine receptors.
Adult↗
Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure.
OBJECTIVES: Human cardiac muscle from failing heart shows a decrease in active tension development and a rise in diastolic tension at stimulation frequencies above 50-60 beats/min due to both systolic and diastolic dysfunction. We have investigated underlying changes in cellular [Ca2+]i regulation. METHODS: Single ventricular myocytes were isolated enzymatically from the explanted hearts of transplant recipients with ischemic cardiomyopathy (nhearts = 5 ncells = 15) or dilated cardiomyopathy (nhearts = 6, ncells = 19). Cells were studied during whole-cell patch clamp with fluo-3 and fura-red as [Ca2+]i indicators (36 +/- 1 degrees C). RESULTS: In current clamp mode (action potential recording), the amplitude of Ca2+ release from the sarcoplasmic reticulum (SR) decreased at stimulation frequencies above 0.5 Hz; this decrease was more pronounced for cells from dilated cardiomyopathy. Diastolic [Ca2+]i increased at 1 and 2 Hz for both groups. Action potential duration (APD90) decreased with frequency in all cells; in addition there was a drop in plateau potential of 10 +/- 1 mV for cells from ischemic cardiomyopathy and of 13 +/- 2 mV for cells from dilated cardiomyopathy. In voltage clamp mode the L-type Ca2+ current showed reversible decrease during stimulation at 1 and 2 Hz. Recovery from inactivation during a double pulse protocol was slow (75 +/- 3% at 500 ms, 89 +/- 3% at 1000 ms) and followed the decay of the [Ca2+]i transient. CONCLUSIONS: The negative force-frequency relation of the failing human heart is due to a decrease in Ca2+ release of the cardiac myocytes at frequencies > or = 0.5 Hz, more pronounced in dilated than in ischemic cardiomyopathy. Inhibition of ICaL at higher frequencies, at least partially related to an increase in diastolic [Ca2+]i, will contribute to this negative staircase because of a decrease in the trigger for Ca2+ release, and of decreased loading of the SR.
Action Potentials↗
The effect of brain death on cardiovascular function in rats. Part II. The cause of the in vivo haemodynamic changes.
OBJECTIVE: Brain death-induced haemodynamic collapse in rats is not caused by intrinsic myocardial damage as shown in the accompanying paper. We investigated whether this collapse could be caused by the withdrawal of the basal adrenergic tone. METHODS: Heart rate and blood pressure variability was studied in rats before and after brain death. The effect of high doses of phentolamine, propranolol or their combination administered before or after brain death was assessed. RESULTS: Heart rate variability in the respiratory frequency range significantly increased, whereas in the low-frequency range it tended to decrease after brain death. Systolic and diastolic blood pressure variability up to 0.18 Hz largely disappeared, but stayed unchanged in the respiratory frequency range. High-dose combined phentolamine and propranolol pretreatment induced a haemodynamic picture comparable to the situation seen after brain death without pharmacological intervention. Brain death did not further deteriorate the haemodynamic situation after combined pretreatment. On the other hand, once the haemodynamic collapse after brain death had settled, adrenergic blockade had no important influence any more. CONCLUSION: We conclude that the haemodynamic situation seen after brain death is one of profound sympathetic withdrawal.
Adrenergic alpha-Antagonists↗
The effect of brain death on cardiovascular function in rats. Part I. Is the heart damaged?
OBJECTIVE: Brain death induces important haemodynamic changes in rats, with a drop in arterial blood pressure, left ventricular developed pressure and dP/dtmax to less than 50% of its control value. Myocardial damage was reported to contribute to this paradigm. The role of potential underlying pathogenetic mechanisms, such as a circulating cardiodepressant factor, NO, endogenous opioid peptides, vagal or beta-adrenergic activation, or hypophyseal dysfunction, were explored, but none of them could be demonstrated as the culprit. This study investigated whether functionally important intrinsic myocardial damage was induced by brain death in the rat, and whether coronary endothelial cell dysfunction, possibly causing multifocal ischaemia, contributed to this. METHODS: Brain death was induced in rats by sudden inflation of an intracranial balloon. Extensive haemodynamic measurements, including heart rate, arterial blood pressure central venous pressure, left ventricular pressure, and cardiac output, were performed. Hearts excised 1 and 4 h after brain death were examined histologically. The contractile reserve of these hearts was tested by administration of increasing doses of adrenaline (10(-9) to 10(-6) mol/l) in a Langendorff system. The coronary endothelium was tested with regard to its barrier function for macromolecules by determining the extravasation of injected Evans blue, and with regard to its vasoactive function by testing the effects of serotonin and nitroglycerin in a Langendorff system. RESULTS: The haemodynamic measurements suggested that the cardiovascular collapse consisted mainly in alterations in afterload. Contractile reserve, as tested with increasing adrenaline doses, revealed a normal dose-response curve. No histological myocardial damage was found after brain death in rats. No abnormal extravasation of Evans blue was seen. Coronary vasoreactivity towards nitroglycerin and serotonin was normal. CONCLUSION: Myocardial damage, if present at all, contributes only minimally to the changes in haemodynamic profile seen after brain death in the rat, and the coronary endothelium appears to preserve its barrier and vasoactive function.
Animals↗
Phenylephrine-induced stimulation of Na+/Ca2+ exchange in rat ventricular myocytes.
OBJECTIVE: The effect of an alpha-adrenergic agonist, phenylephrine, on the Na+/Ca2+ exchange current in rat ventricular myocytes was investigated. METHODS: The Na+/Ca2+ exchange current was measured at room temperature in rat ventricular myocytes as the whole-cell current induced by addition of extracellular Na+ and Ca2+, while blocking Na+ current by setting the holding potential at -30 mV, K+ currents by intracellular Cs+, TEA+ and by extracellular Ba2+, Ca2+ current by nifedipine and Na+ pump current by ouabain or by 0 extracellular K+. RESULTS: Under these experimental conditions, application of external Na+ and Ca2+ induced a current which was further increased by phenylephrine. Phenylephrine (80 microM) increased the current by up to 31.0 +/- 5.4% of control at all membrane potentials tested both below and above the reversal potential. The reversal potential (+21.0 +/- 3.2 mV), which corresponded with the theoretical reversal potential for the Na+/Ca2+ exchange current under our ionic conditions (+21.3 mV), was not changed by phenylephrine (+23.2 +/- 4.1 mV). Applying phenylephrine in the absence of Na+/Ca2+ exchange (0 Na+e, 0 Ca2+e) did not change the current. The effect was resistant to propranolol, a beta-adrenergic blocker, but prevented by prazosin, an alpha-receptor antagonist, by neomycin, an inhibitor of phospholipase C, and by chelerythrine, a selective inhibitor of protein kinase C. Phorbol 12-myristate 13-acetate failed to stimulate the current. The effect remained similar under conditions of high (HEPESi = 5 mM) and low (HEPESi = 0.5 mM) intracellular pH buffering. CONCLUSION: Our data indicate that phenylephrine stimulates the Na+/Ca2+ exchange, both in the forward and the reverse modes, probably via a protein kinase C-dependent pathway.
Adrenergic alpha-Agonists↗
Na+/H+ exchange inhibition improves post-transplant myocardial compliance in 4-hour stored donor hearts.
Na+/H+ exchange inhibitors have cardioprotective properties. The effects of the new Na+/H+ exchange inhibitor, HOE642 on myocardial function were assessed after transplantation of canine brain-dead and non-brain-dead donor hearts preserved for 4 h. Four groups were studied: brain-dead donors; non-brain-dead donors; brain-dead donors and recipients treated with HOE642 (2 mg/kg); and treated non brain-dead donors and recipients. Donor hearts were stored in NIH2. At the end of 60 min reperfusion after transplantation, pressure-volume curves were constructed. Biopsies were analysed histologically and ultrastructurally. Afterwards, weaning from cardiopulmonary bypass was accomplished. HOE642 improved compliance in hearts from both brain-dead and non-brain-dead donors. No differences in myocardial water content nor in myocardial performance were detected. No irreversible damage was seen ultrastructurally. It is concluded that myocardial compliance after transplantation was improved by administration of HOE642. The use of this inhibitor might improve the current myocardial preservation technique for transplantation.
Animals↗
Miniaturized implantable rotary blood pump in atrial-aortic position supports and unloads the failing heart.
The purpose of this study was to test the pump performance of a miniaturized, newly developed, implantable rotary blood pump (the diagonal pump). In a series of six sheep, the pump was interposed in an atrial-aortic connection. Heart failure was induced by serial injection of glass beads into the left coronary artery. The assistance of the non-failing heart (with pump output up to 4.5 liter/min) did not change the total cardiac output or the blood pressure of the animal. The heart was significantly unloaded as demonstrated by a drop in first derivative of the left ventricular pressure (dP/dt) max (from 1645 to 1113 mmHg/s; P = 0.0003). Because of the specific interaction between heart function and rotary blood pump performance, the pump provided considerably more flow in the failing than in the non-failing heart. Cardiac output and perfusion pressures were restored to pre-assist values in the failing heart model. The heart-rotary blood pump interaction is an ideal substrate for long-term assistance. With this miniaturized rotary blood pump, hemodynamics in a severely failing heart can be restored. Atrial cannulation, which leaves the left ventricle untouched, provides similar results as apical cannulation in the failing heart.
Animals↗