2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

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Rebuild, restore, reinnervate: do human tissue engineered dermo-epidermal skin analogs attract host nerve fibers for innervation?

PURPOSE: Tissue engineered skin substitutes are a promising tool to cover large skin defects, but little is known about reinnervation of transplants. In this experimental study, we analyzed the ingrowth of host peripheral nerve fibers into human tissue engineered dermo-epidermal skin substitutes in a rat model. Using varying cell types in the epidermal compartment, we wanted to assess the influence of epidermal cell types on reinnervation of the substitute. METHODS: We isolated keratinocytes, melanocytes, fibroblasts, and eccrine sweat gland cells from human skin biopsies. After expansion, epidermal cells were seeded on human dermal fibroblast-containing collagen type I hydrogels as follows: (1) keratinocytes only, (2) keratinocytes with melanocytes, (3) sweat gland cells. These substitutes were transplanted into full-thickness skin wounds on the back of immuno-incompetent rats and were analyzed after 3 and 8 weeks. Histological sections were examined with regard to myelinated and unmyelinated nerve fiber ingrowth using markers such as PGP9.5, NF-200, and NF-145. RESULTS: After 3 weeks, the skin substitutes of all three epidermal cell variants showed no neuronal ingrowth from the host into the transplant. After 8 weeks, we could detect an innervation of all three types of skin substitutes. However, the nerve fibers were restricted to the dermal compartment and we could not find any unmyelinated fibers in the epidermis. Furthermore, there was no distinct difference between the constructs resulting from the different cell types used to generate an epidermis. CONCLUSION: Our human tissue engineered dermo-epidermal skin substitutes demonstrate a host-derived innervation of the dermal compartment as early as 8 weeks after transplantation. Thus, our substitutes apparently have the capacity to attract nerve fibers from adjacent host tissues, which also grow into grafts and thereby potentially restore skin sensitivity

Alterations in vasomotor control of coronary resistance vessels in remodelled myocardium of swine with a recent myocardial infarction

The mechanism underlying the progressive deterioration of left ventricular (LV) dysfunction after myocardial infarction (MI) towards overt heart failure remains incompletely understood, but may involve impairments in coronary blood flow regulation within remodelled myocardium leading to intermittent myocardial ischemia. Blood flow to the remodelled myocardium is hampered as the coronary vasculature does not grow commensurate with the increase in LV mass and because extravascular compression of the coronary vasculature is increased. In addition to these factors, an increase in coronary vasomotor tone, secondary to neurohumoral activation and endothelial dysfunction, could also contribute to the impaired myocardial oxygen supply. Consequently, we explored, in a series of studies, the alterations in regulation of coronary resistance vessel tone in remodelled myocardium of swine with a 2 to 3-week-old MI. These studies indicate that myocardial oxygen balance is perturbed in remodelled myocardium, thereby forcing the myocardium to increase its oxygen extraction. These perturbations do not appear to be the result of blunted β-adrenergic or endothelial NO-mediated coronary vasodilator influences, and are opposed by an increased vasodilator influence through opening of KATP channels. Unexpectedly, we observed that despite increased circulating levels of noradrenaline, angiotensin II and endothelin-1, α-adrenergic tone remained negligible, while the coronary vasoconstrictor influences of endogenous endothelin and angiotensin II were virtually abolished. We conclude that, early after MI, perturbations in myocardial oxygen balance are observed in remodelled myocardium. However, adaptive alterations in coronary resistance vessel control, consisting of increased vasodilator influences in conjunction with blunted vasoconstrictor influences, act to minimize the impairments of myocardial oxygen balance

Tissue-engineered dermo-epidermal skin analogs exhibit de novo formation of a near natural neurovascular link 10 weeks after transplantation

PURPOSE: Human autologous tissue-engineered skin grafts are a promising way to cover skin defects. Clearly, it is mandatory to study essential biological dynamics after transplantation, including reinnervation. Previously, we have already shown that human tissue-engineered skin analogs are reinnervated by host nerve fibers as early as 8 weeks after transplantation. In this study, we tested the hypothesis that there is a de novo formation of a "classical" neurovascular link in tissue-engineered and then transplanted skin substitutes. METHODS: Keratinocytes, melanocytes, and fibroblasts were isolated from human skin biopsies. After expansion in culture, keratinocytes and melanocytes were seeded on dermal fibroblast-containing collagen type I hydrogels. These human tissue-engineered dermo-epidermal skin analogs were transplanted onto full-thickness skin wounds on the back of immuno-incompetent rats. Grafts were analyzed after 3 and 10 weeks. Histological sections were examined with regard to the ingrowth pattern of myelinated and unmyelinated nerve fibers into the skin analogs using markers such as PGP9.5, NF-200, and NF-160. Blood vessels were identified with CD31, lymphatic vessels with Lyve1. In particular, we focused on alignment patterns between nerve fibers and either blood and/or lymphatic vessels with regard to neurovascular link formation. RESULTS: 3 weeks after transplantation, blood vessels, but no nerve fibers or lymphatic vessels could be observed. 10 weeks after transplantation, we could detect an ingrowth of myelinated and unmyelinated nerve fibers into the skin analogs. Nerve fibers were found in close proximity to CD31-positive blood vessels, but not alongside Lyve1-positive lymphatic vessels. CONCLUSION: These data suggest that host-derived innervation of tissue-engineered dermo-epidermal skin analogs is initiated by and guided alongside blood vessels present early post-transplantation. This observation is consistent with the concept of a cross talk between neurovascular structures, known as the neurovascular link

Reliability of echocardiography in assessing cardiac output

Because of the potential benefits from a noninvasive technique in assessing cardiac output, we compared cardiac output estimates from left ventricular echocardiograms with results obtained simultaneously by a standard technique, dye dilution in 10 healthy normal volunteers. During rest, cardiac outputs by echocardiographic and dye dilution techniques were reproducible and not significantly different. Increases in cardiac output produced by intravenous infusion of isoproterenol (15 ng/kg/min for 4 min) were accurately estimated by echocardiography in subjects whose stroke volume increased less than 40%, but were significantly underestimated when stroke volume increased more than 40%. Decreased cardiac output produced by intravenous propranolol (0.2 mg/kg) was comparable by both methods. Although echocardiography accurately estimated mean cardiac output for the group it over- or underestimated cardiac output in individual subjects. We propose that echocardiography can reliably estimate cardiac output in groups at rest and when stroke volume changes less than 40%. Einer nicht invasiven Methode zur akkuraten Bestimmung des Herzminutenvolumens (HMV) käme eine große Bedeutung zu. Wir verglichen deshalb aus links-ventriculären Echocardiogrammen bestimmte mit gleichzeitig mittels Farbstoffverdünnungsmethode (Cardiogreen) bestimmten HMV in 10 normalen Versuchspersonen. Unter Ruhebedingungen war das HMV mit beiden Methoden reproduzierbar und nicht signifikant verschieden. Anstiege des HMV nach intravenöser Infusion von Isoproterenol (15 ng/kg/min über 4 min) wurden mittels Echocardiographie zuverlässig nur bei Probanden erfaßt, bei denen das Schlagvolumen weniger als 40% anstieg. Bei größeren Anstiegen wurde der Anstieg des HMV signifikant unterschätzt. Ein erniedrigtes HMV nach intravenöser Injektion von Propranolol (0,2 mg/kg) wurde von beiden Methoden gleichermaßen erfaßt. Obwohl das HMV mittels Echocardiographie für das Untersuchungskollektiv nicht signifikant von den Farbstoffverdünnungswerten verschieden war, wichen die echocardiographisch bestimmten HMV bei einzelnen Probanden deutlich von den Farbstoffverdünnungswerten ab. Unsere Ergebnisse zeigen, daß die links-ventriculäre Echocardiographie zur Bestimmung des HMV in Gruppen und bei Änderungen des Schlagvolumens von weniger als 40% benutzt werden kann.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45985/1/109_2005_Article_BF01746199.pd

Reduced coronary flow reserve during exercise in cardiac transplant recipients

BACKGROUND: Coronary flow reserve (CFR) is reduced in a majority of patients after heart transplantation (HTx). Pharmacological interventions, however, provide only limited information on CFR under physiological conditions. Thus, CFR during exercise was evaluated in the present study. METHODS AND RESULTS: Coronary angiography was performed at rest and during supine bicycle exercise in 35 patients early (2 to 3 months; n = 10) or late (1 to 6 years; mean, 2.5 years; n = 25) after HTx and in 8 controls (C). CFR was determined by parametric imaging after administration of 10 mg intracoronary papaverine, during exercise, and after 1.6 mg sublingual nitroglycerin. Epicardial coronary artery size was measured by quantitative coronary angiography. CFR after papaverine was normal early (3.6 +/- 0.5 versus C, 3.6 +/- 0.7; P = NS) and late (3.8 +/- 1.3 P = NS) after HTx. During exercise, CFR was normal early (3.1 +/- 0.6 versus C, 3.9 +/- 0.9; P = NS) but decreased late (2.3 +/- 0.6; P < .01) after HTx. The increase in coronary cross-sectional area during exercise was also diminished late after HTx (14 +/- 10% versus C, 22 +/- 10%; P < .05). Both exercise-induced CFR (r = -.39, P < .05) and coronary vasodilation (r = -.44, P < .01) were inversely correlated with time after HTx. CONCLUSIONS: CFR during exercise is normal early but reduced late after HTx, whereas CFR after papaverine administration is maintained. This difference between physiological and pharmacological vasodilation suggests progressive endothelial dysfunction after HTx

[Bone density and laboratory parameters of bone metabolism in patients with terminal heart disease]

The purpose of this study was to assess bone mineral density (BMD) and parameters for bone metabolism in patients with end-stage heart disease awaiting heart transplantation to determine whether these patients are at increased risk of bone disease

Low-dose cyclosporine treatment fails to prevent coronary luminal narrowing after heart transplantation

BACKGROUND: Cyclosporine has been reported to induce endothelial dysfunction, arterial vasculitis, and accelerated atherosclerosis in experimental models. The purpose of the present study was to evaluate whether low-dose cyclosporine treatment started 1 year after heart transplantation reduces graft coronary artery narrowing compared with conventional cyclosporine doses. METHODS: One year after heart transplantation, 30 patients were randomly assigned to receive low-dose cyclosporine A (whole-blood polyclonal cyclosporine target trough levels 200 to 400 micrograms/L; group A; n = 15) or usual cyclosporine dosage (target levels 400 to 600 micrograms/L; group B; n = 15). Proximal and distal diameters of the left anterior descending, circumflex, and right coronary arteries were measured by quantitative coronary angiography at baseline (1 year after transplantation) and at 2 and 3 years after transplantation. RESULTS: One major cardiac event occurred in group A (retransplantation) and two in group B (sudden deaths). Moderate to severe allograft rejection (International Society for Heart and Lung Transplantation score 3A or higher) occurred in seven patients in group A and five in group B during the study period. Mean biopsy sample rejection score during the same period was increased in group A compared with that in group B (1.44 +/- 0.63 versus 1.05 +/- 0.59; p < 0.05). New angiographic evidence of vascular disease was observed in four patients of group A and in one patient of group B. Proximal coronary artery diameter was slightly, although not significantly, reduced in both groups at follow-up angiography. Distal segments showed a significant diameter reduction, which was greater in group A than in group B (-9.7% +/- 1.1% and -5.2% +/- 1.3%, respectively; p < 0.05). CONCLUSIONS: Cyclosporine dose reduction started 1 year after heart transplantation is ineffective in reducing coronary luminal narrowing and may be associated with an increased prevalence of cardiac allograft vasculopathy, especially in the distal coronary tree. Low-dose cyclosporine treatment may slightly enhance the risk of allograft rejection. Further investigations are needed to evaluate the effects of cyclosporine dose reduction started at an earlier time after heart transplantation