The impact of aerobic and isometric exercise on different measures of dysfunctional high-density lipoprotein in patients with hypertension.

BACKGROUND: Exercise training increases high-density lipoprotein (HDL) cholesterol, but its effect on HDL function is unclear. In hypertensives, exercise improves endothelial dysfunction, which is related to HDL function. In the present study, we assess for the first time the effects of different exercise modalities on two cell-free assays of HDL function. DESIGN: The study was conducted as a prospective randomized controlled trial in 75 hypertensive patients. METHODS: Patients were randomized in three groups: (a) handgrip isometric training five times weekly; (b) placebo-handgrip; and (c) aerobic exercise training at least three times per week. HDL function was assessed in serum samples at baseline and after 12 weeks of training by two independent assays that determine the proinflammatory phenotype (haptoglobin content) of a specific amount of HDL (Haptoglobin-HDL [HPHDL]) and oxidized HDL (HDLox) as a measure of reduced antioxidant function of HDL. HDL function measures were normalized by the measures of a pooled control of sera from healthy participants and by HDL-C levels (normalized ratio, no units). RESULTS: Aerobic exercise led to significant reduction of the HDLox from 0.99 ± 0.27 to 0.90 ± 0.29 (no units, p = 0.03). The HPHDL did not change in any training group. Changes of HDLox correlated with reduction of the systolic blood pressure only after aerobic exercise (R = 0.64, p = 0.03). CONCLUSIONS: Aerobic but not isometric exercise improves the antioxidant function of HDL in patients with hypertension. This improvement correlates positively with reductions of blood pressure.

Contrast-Induced Nephropathy: Update on the Use of Crystalloids and Pharmacological Measures.

Contrast-induced nephropathy (CIN) is a frequent and severe complication in subjects receiving iodinated contrast media for diagnostic or therapeutic purposes. Several preventive strategies were evaluated in the past. Recent clinical studies and meta-analyses delivered some new aspects on preventive measures used in the past and present. We will discuss all pharmacological and nonpharmacological procedures. Finally, we will suggest individualized recommendations for CIN prevention.

Short-term external counterpulsation augments cerebral blood flow and tissue oxygenation in chronic cerebrovascular occlusive disease.

BACKGROUND AND PURPOSE: External counterpulsation improves cerebral perfusion velocity in acute stroke and may stimulate collateral artery growth. However, whether (non-acute) at-risk patients with high-grade carotid artery disease may benefit from counterpulsation needs to be validated. METHODS: Twenty-eight patients (71 ± 6.5 years, five women) with asymptomatic unilateral chronic severe internal carotid artery stenosis (>70%) or occlusion were randomized to receive 20 min active counterpulsation followed by sham treatment or vice versa. Cerebral blood flow velocity (CBFV) (measured bilaterally by transcranial middle cerebral artery Doppler), tissue oxygenation index (TOI) (measured over the bilateral prefrontal cortex by near-infrared spectroscopy) and cerebral hemodynamic parameters, such as relative pulse slope index (RPSI), were monitored. RESULTS: Ipsilateral mean CBFV (ΔVmean +3.5 ± 1.2 cm/s) and tissue oxygenation (ΔTOI +2.86 ± 0.8) increased significantly during active counterpulsation compared to baseline, whilst the sham had little effect (ΔVmean +1.13 ± 1.1 cm/s; ΔTOI +1.25 ± 0.65). On contralateral sides, neither counterpulsation nor sham control had any effect on either parameter. During counterpulsation, early dynamic changes in ΔRPSI of the ipsilateral CBFV signal predicted improved tissue oxygenation during counterpulsation (odds ratio 1.179, 95% confidence interval 1.01-1.51), whilst baseline cerebrovascular reactivity to hypercapnia failed to show an association. CONCLUSIONS: In patients with high-grade carotid disease, ipsilateral cerebral oxygenation and blood flow velocity are increased by counterpulsation. This is a necessary condition for the stimulation of regenerative collateral artery growth and thus a therapeutic concept for the prevention of cerebral ischaemia. This study provides a rationale for further clinical investigations on the long-term effects of counterpulsation on cerebral hemodynamics and collateral growth.

[S1 guideline on intermittent pneumatic compression (IPC)]. / S1-Leitlinie Intermittierende Pneumatische Kompression (IPK, AIK).

Under the direction of the German Society of Phlebology (Deutsche Gesellschaft für Phlebologie) and in cooperation with other specialist associations, the S1 guideline on intermittent pneumatic compression (IPC) was adopted in January 2018. It replaces the previous guideline from March 2005. The aim of the guideline is to optimize the indication and therapeutic use of IPC in vascular diseases and edema. An extensive literature search of MEDLINE, existing guidelines, and work relevant to the topic was performed. In view of the often methodologically weak study quality with often small numbers of cases and heterogeneous treatment protocols, recommendations can often only be derived from the available data using good clinical practice/expert consensus. Intermittent pneumatic compression is used for thromboembolism prophylaxis, decongestive therapy for edema, and to positively influence arterial and venous circulation to improve clinical symptoms and accelerate ulcer healing in both the outpatient and inpatient care setting. The therapy regimens and devices used depend on the indication and target location. They can be used as outpatient and inpatient devices as well as at home for long-term indications. A target indication is thrombosis prophylaxis. IPC should be used in severe chronic venous insufficiency (stages C4b to C6), in extremity lymphedema as an add-on therapy and in peripheral arterial occlusive disease (PAOD) with stable intermittent claudication or critical ischemia. IPC can be used in post-traumatic edema, therapy-resistant venous edema, lipedema and hemiplegia with sensory deficits and edema. Absolute and relative contraindications to IPC must be taken into account and risks considered and avoided as far as possible. Adverse events are extremely rare if IPC is used correctly. If the indication and application are correct-also as an add-on therapy-it is a safe and effective treatment method, especially for the treatment of the described vascular diseases and edema as well as thrombosis prophylaxis.

Acute physical exercise and long-term individual shear rate therapy increase telomerase activity in human peripheral blood mononuclear cells.

AIM: Physical activity is a potent way to impede vascular ageing. However, patients who suffer from peripheral artery disease (PAD) are often unable to exercise adequately. For those patients, we have developed individual shear rate therapy (ISRT), which is an adaptation of external counterpulsation and enhances endovascular fluid shear stress to increase collateral growth (arteriogenesis). To evaluate the effects of physical exercise and ISRT on the telomere biology of peripheral blood mononuclear cells (PBMCs), we conducted two clinical trials. METHODS: In the ISRT-1 study, we assessed PBMC telomerase activity in 26 young healthy volunteers upon a single (short-term) ISRT session and a single treadmill running session. In the ISRT-2 study, we investigated PBMC telomere biology of 14 elderly patients with PAD, who underwent 30 h of (long-term) ISRT within a 5-week period. RESULTS: We demonstrate that telomerase activity significantly increased from 39.84 Total Product Generated (TPG) Units ± 6.15 to 58.10 TPG ± 10.46 upon a single treadmill running session in healthy volunteers. In the ISRT-2 trial, PBMC telomerase activity and the mRNA expression of the telomere-protective factor TRF2 increased from 40.87 TPG ± 4.45 to 60.98 TPG ± 6.83 and 2.10-fold ± 0.40, respectively, upon long-term ISRT in elderly patients with PAD. CONCLUSION: In summary, we show that acute exercise and long-term ISRT positively affect PBMC telomerase activity, which is indicative for an improved regenerative potential of immune cells and vascular tissues. Long-term ISRT also enhances the gene expression of the telomere-protective factor TRF2.

PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain.

AIMS: PPARγ stimulation improves cardiovascular (CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell (EC), monocyte and smooth muscle cell (SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth. METHODS: In a rat model of adaptive cerebral arteriogenesis (3-VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg(-1); 10 mg kg(-1) compared with metformin 62.2 mg kg(-1) or sitagliptin 6.34 mg kg(-1)) for 21 days or (iii) after adding pioglitazone to G-CSF (40 µg kg(-1) every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied. RESULTS: PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity (CVRC controls: 12 ± 7%; pio low: -2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G-CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration. CONCLUSION: Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G-CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients.

Protocolo Bruce: errores habituales en la evaluación de la capacidad funcional y en el diseño de un entrenamiento físico en cardiopatía isquémica / Bruce protocol: common errors in the evaluation of functional capacity and in exercise prescription in ischemic heart disease

Introducción. La utilización de pruebas de esfuerzo con incrementos bruscos en la carga de trabajo puede acentuar la pérdida de relación lineal entre el VO2 y la frecuencia cardíaca. La falta de datos objetivos para considerar la frecuencia cardíaca como máxima puede ocasionar aplicaciones de intensidades de trabajo insuficientes durante los entrenamientos. Objetivos. Determinar la variabilidad de la capacidad funcional y de la frecuencia cardíaca máxima, realizando en un mismo paciente una prueba de esfuerzo indirecta y directa. Determinar la intensidad de entrenamiento óptima con una prueba de esfuerzo indirecta. Métodos. Veintinueve pacientes con cardiopatía isquémica realizaron, en un plazo inferior a 4 semanas, una prueba de esfuerzo indirecta (protocolo Bruce) y una directa (ergoespirometría). Se analizaron parámetros de trabajo, metabólicos y cardíacos. Resultados. Objetivamos una sobrestimación de la capacidad funcional con el protocolo Bruce del 10,4%. La frecuencia cardíaca máxima fue de 125 lpm en el protocolo Bruce y de 132 lpm en la ergoespirometría. Los umbrales aerobio/anaerobio se produjeron a 99 y 119 lpm. La intensidad de entrenamiento diseñada a partir del protocolo Bruce y según el método de 75-85% de la frecuencia cardíaca máxima fue de 95 vs. 107 lpm. Utilizando el método Karvonen al 60-80% fue de 103 vs. 113 lpm. Conclusiones. La capacidad funcional está sobrestimada con la utilización del protocolo Bruce estandarizado. El diseño de un entrenamiento en función de porcentajes de frecuencia cardíaca puede hacernos trabajar de una forma submáxima. La metodología de Karvonen estima la intensidad de trabajo de una manera más óptima(AU)

Introduction. The use of stress tests with sudden increases in the workload may accentuate the loss of the linear relationship between VO2 and heart rate. Lack of objective data to consider heart rate as maximum may result in the application of submaximum workloads during exercise training. Objectives. To determine variability in functional capacity and maximum heart rate by means of an indirect and direct exercise test in the same patient. To determine optimum training intensity using an indirect stress test. Methods. In a period under 4 weeks, 29 patients with ischemic heart disease performed an indirect exercise test (Bruce protocol) and a direct exercise test (ergospirometry). Work, metabolic and cardiac parameters were analyzed. Results. We observed an overestimation of functional capacity with the Bruce protocol of 10.4%. Maximum heart rate was 125 bpm in the Bruce protocol and 132 bpm in the ergospirometry test. Aerobic and anaerobic thresholds occurred at 99 vs 119 bpm, respectively. Workload intensity designed according to the Bruce Protocol and in accordance with the 75-85% maximum heart rate method was 95 vs 107 bpm. This was 103 vs 113 bpm with the Karvonen method at 60 - 80%. Conclusions. Functional capacity is overestimated when the standardized Bruce protocol is used. The design of training based on heart rate percentages may cause us to work submaximally. The Karvonen method estimates work load more optimally (AU)

Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib.

Several retrospective studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. We thus prospectively screened for PAOD in patients with chronic phase chronic myeloid leukemia (CP CML) being treated with tyrosine kinase inhibitors (TKI), including imatinib and nilotinib. One hundred and fifty-nine consecutive patients were evaluated for clinical and biochemical risk factors for cardiovascular disease. Non-invasive assessment for PAOD included determination of the ankle-brachial index (ABI) and duplex ultrasonography. A second cohort consisted of patients with clinically manifest PAOD recruited from additional collaborating centers. Pathological ABI were significantly more frequent in patients on first-line nilotinib (7 of 27; 26%) and in patients on second-line nilotinib (10 of 28; 35.7%) as compared with patients on first-line imatinib (3 of 48; 6.3%). Clinically manifest PAOD was identified in five patients, all with current or previous nilotinib exposure only. Relative risk for PAOD determined by a pathological ABI in first-line nilotinib-treated patients as compared with first-line imatinib-treated patients was 10.3. PAOD is more frequently observed in patients receiving nilotinib as compared with imatinib. Owing to the severe nature of clinically manifest PAOD, longitudinal non-invasive monitoring and careful assessment of risk factors is warranted.

Entrenamiento interválico en pacientes con cardiopatía isquémica: metodología y análisis de resultados ergoespirométricos / Interval training in patients with coronary artery disease: methodology and ergospirometric data analysis

Introducción. El ejercicio de tipo interválico es una modalidad de entrenamiento poco utilizada en pacientes con cardiopatía isquémica aunque sus beneficios fisiológicos han sido demostrados por distintos autores. Objetivo. Describir un método sencillo de entrenamiento interválico, así como evaluar los beneficios y la seguridad del mismo en pacientes con cardiopatía isquémica. Método. Se estudiaron 25 pacientes con cardiopatía isquémica estable que realizaron un entrenamiento interválico de alta intensidad en cicloergómetro. Para programar la intensidad del entrenamiento se realizó un Steep Ramp Test. El entrenamiento consistió en intervalos de 20 s al 50% de la carga máxima alcanzada en el Steep Ramp Test, seguido de intervalos de 40 s al 10% de la misma. Se realizó una ergoespirometría sobre cicloergómetro pre y posprograma para comparar resultados. Resultados. Tras 8 semanas de entrenamiento se produjeron incrementos significativos en el VO2pico (19,9 ± 5,3 vs. 23,8 ± 6ml/kg/min), en la carga máxima (103,5 ± 42,6 vs. 124,6 ± 53,4 vatios), en la frecuencia cardíaca (FC) máxima (117,6 ± 15,7 vs. 128 ± 16,5 lat./min) y en el índice de recuperación de la FC en el primer minuto (16,5 ± 9,2 vs. 21,3 ± 7,7 lat./min). No se registraron efectos adversos. Conclusión. El ejercicio interválico de alta intensidad es una modalidad de entrenamiento sencilla y segura que permite mejorar de forma significativa el VO2pico y la tolerancia al ejercicio en pacientes con cardiopatía isquémica (AU)

Background. Interval training is an exercise modality underused in patients with coronary artery disease even though different authors have shown its physiological benefits. Objective. To describe a simple method of interval training and to evaluate its benefits and safety in patients with coronary artery disease. Method. Twenty-five patients with stable coronary artery disease underwent high-intensity interval training on a cycle ergometer. To determine the training work rate, we performed a steep ramp test. The training consisted of intervals of 20seconds at 50% of the maximum load achieved in the steep ramp test, followed by intervals of 40seconds at 10%. A cycle ergospirometry was performed before and after the programme to compare data. Results. After 8 weeks of interval training, there were significant gains in V02 peak (19.9±5.3 vs. 23.8±6mL·kg-1·min−1), maximal work rate (103.5±42.6 vs.124.6±53.4 watts), maximal heart rate (117.6±15.7 vs. 128±16.5 bpm) and heart rate recovery index in the first minute (16.5±9.2 vs. 21.3±7.7 bpm). There were no adverse events. Conclusion. In patients with coronary artery disease, high-intensity interval training is an easy, safe exercise modality that produces improvement in VO2 peak and exercise tolerance (AU)

Therapeutic arteriogenesis in peripheral arterial disease: combining intervention and passive training.

The prevalence of peripheral arterial disease (PAD) is on the rise in an aging population, significantly affecting quality of life, morbidity and mortality. Besides medical treatment and surgical or interventional revascularization, supervised exercise programs are a primary treatment modality for PAD. Training may significantly increase pain-free walking time (+ 180 %) while avoiding the associated complications of (repeated) invasive revascularization. Training effects rely on an improvement of risk factor management, muscle function, economy of movement, hemorheology, vascular growth and collateral vessel growth. Exercise training upregulates pulsatile fluid shear stress on the vascular endothelium, prompting an improvement of endothelial function (eNOS, NO) and an outgrowth of preexistent collaterals (arteriogenesis) to functional conductance arteries outside the ischemic area at risk. However, the necessary intense minimum training intervals compromise patient compliance, and the impaired functional status of many PAD patients limits active exercise training. Strategies are necessary to a) increase training compliance, b) make the benefits of exercise training available to patients unable to exercise actively and c) therapeutically enhance the adaptive growth of biological bypasses (arteriogenesis). A modified form of “passive exercise training” derived from enhanced external counterpulsation (low-pressure ECP) which was originally developed for the therapy of heart failure, may prove to be an option for this group of patients. Therefore, this review article suggests a tailored combination therapy, consisting of a facilitating revascularization procedure to restore arterial inflow, succeeded by supervised exercise training, which has yielded promising therapeutic results in clinical trials. Further studies, using appropriate imaging methods and controls, are under way to (a) establish the efficacy of low-pressure EECP in PAD patients and (b) to directly correlate training-induced improvements of collateral flow to the functional improvements seen with exercise training.

Does external counterpulsation augment mean cerebral blood flow in the healthy brain? Effects of external counterpulsation on middle cerebral artery flow velocity and cerebrovascular regulatory response in healthy subjects.

BACKGROUND AND PURPOSE: External counterpulsation (ECP) noninvasively improves myocardial and organ perfusion via diastolic augmentation. The effects on cerebral blood flow velocities (CBFV) and hemodynamics are controversial. In this study, the effect of active ECP treatment on CBF in healthy subjects was continuously measured. METHODS: In 9 healthy volunteers (mean age 34.1 ± 11.1 years, 4 females), 20-min active ECP treatment was performed. CBFV in the middle cerebral artery were detected via transcranial Doppler. CBFV were registered continuously before, during and after ECP. The protocol was repeated twice. RESULTS: At onset of ECP, immediate changes in CBFV were observed: peak diastolic blood flow velocities increased from baseline to treatment (63 vs. 76 cm/s; p < 0.001) and diastolic blood flow augmentation was maintained throughout ECP. Peak systolic (87 vs. 78 cm/s; p < 0.001) and end-diastolic velocities (40 vs. 28 cm/s; p < 0.001) decreased significantly, while mean CBFV maintained constant (59 vs. 58 cm/s; not significant). The pulsatility index and resistance index as indirect parameters for peripheral vascular resistance increased during ECP (pulsatility index 0.79 vs. 0.89, p < 0.001; resistance index 0.54 vs. 0.64; p < 0.001). CONCLUSIONS: ECP did not increase mean CBFV in healthy subjects even though peak diastolic CBFV were significantly augmented. Changes in CBFV and transcranial Doppler waveform characteristics suggest that the mean flow of the middle cerebral artery is maintained stable via cerebrovascular autoregulatory mechanisms.

Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial).

BACKGROUND: Arteriogenesis (collateral artery growth) is nature's most efficient rescue mechanism to overcome the fatal consequences of arterial occlusion or stenosis. The goal of this trial was to investigate the effect of external counterpulsation (ECP) on coronary collateral artery growth. MATERIALS AND METHODS: A total of 23 patients (age 61 +/- 2.5 years) with stable coronary artery disease and at least one haemodynamic significant stenosis eligible for percutaneous coronary intervention were prospectively recruited into the two study groups in a 2 : 1 manner (ECP : control). One group (ECP group, n = 16) underwent 35 1-h sessions of ECP in 7 weeks. In the control group (n = 7), the natural course of collateral circulation over 7 weeks was evaluated. All patients underwent a cardiac catheterization at baseline and after 7 weeks, with invasive measurements of the pressure-derived collateral flow index (CFIp, primary endpoint) and fractional flow reserve (FFR). RESULTS: In the ECP group, the CFIp (from 0.08 +/- 0.01 to 0.15 +/- 0.02; P < 0.001) and FFR (from 0.68 +/- 0.03 to 0.79 +/- 0.03; P = 0.001) improved significantly, while in the control group no change was observed. Only the ECP group showed a reduction of the Canadian Cardiovascular Society (CCS, P = 0.008) and New York Heart Association (NYHA, P < 0.001) classification. CONCLUSION: In this study, we provide direct functional evidence for the stimulation of coronary arteriogenesis via ECP in patients with stable coronary artery disease. These data might open a novel noninvasive and preventive treatment avenue for patients with non-acute vascular stenotic disease.

Uridine adenosine tetraphosphate acts as an autocrine hormone affecting glomerular filtration rate.

Recently, uridine adenosine tetraphosphate (Up(4)A) was described as a strong vasoconstrictor released from endothelial cells after stimulation with mechanical stress. In this study, we isolated and identified Up(4)A from kidney tissue, and we characterized the essential varying effects of Up(4)A on the afferent and efferent arterioles. Porcine and human kidney tissue was fractionated by size exclusion chromatography, affinity chromatography, anion exchange chromatography and reverse phase chromatography. In fractions purified to homogeneity, Up(4)A was identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS), MALDI-LIFT fragment mass spectrometry (MALDI-TOF/TOF MS), retention-time comparison and enzymatic cleavage analysis. We analysed the release of Up(4)A from cultivated renal proximal tubule cells after stimulation of protein kinase C with oleoyl-2-acetyl-sn-glycerol (OAG). Up(4)A was identified in renal tissue, and the effect of Up(4)A on the vascular tone of isolated perfused afferent and efferent arterioles was tested. Stimulation of tubule cells with OAG increased the release rate of Up(4)A from tubule cells about tenfold. Up(4)A acts as a strong vasoconstrictive mediator on afferent arterioles, but has no significant effect on the tone of efferent arterioles, suggesting a functional role of Up(4)A as an autocrine hormone for glomerular perfusion. Because of the predominant effect of the Up(4)A on afferent arterioles, we assume that Up(4)A may decrease glomerular perfusion, intra-glomerular pressure and, hence, glomerular filtration rate. The release of Up(4)A from renal tubular cells may be an additional mechanism whereby tubular cells could affect renal perfusion. Up(4)A release may further contribute to renal vascular autoregulation mechanisms. In conclusion, as Up(4)A occurs in renal tissue and has marked effects on afferent but not efferent arterioles, Up(4)A may play a role in renal hemodynamics and possibly blood pressure regulation.

[Inducing collaterals in due time. Arteriogenesis as a preventive principle]. / Kollateralen rechtzeitig induzieren. Arteriogenese als präventives Prinzip.

A stimulation of collateral vessel growth is an attractive alternative therapeutic tool especially for patients with diffuse occlusive vessel disease. Extensive in vivo and in vitro studies in the preceding decades have led us to a thorough understanding of basic arteriogenic principles. Due to the timeline of naturally occurring arteriogenesis, a well-timed therapeutic induction appears to be limiting for effective proarteriogenic therapies in high-risk patients. Potential therapeutic approaches are based on a stimulation of monocyte function through cytokine application. First clinical studies have, nevertheless, demonstrated the limits of a unifactorial therapy. Therefore, a stimulation of the mechanical inductor of arteriogenic proliferation, i. e. fluid shear stress acting on the arteriolar endothelium, appears as a feasible therapeutic addition. Current results show the feasibility of that principle not only through active physical training, but also through passive application of an external counterpulsation (EECP), a method showing promising first results in the clinical setting.

Aspirin in peripheral arterial disease: breakthrough or pitfall?

BACKGROUND: This paper introduces a proof-of-concept trial in progress, supposedly providing new important information on anti-platelet drugs used in patients with peripheral arterial disease (PAD). The Arteriogenesis Competence Network (Art.Net.) of the Universities of Basel, Berlin, and Freiburg could show in animal models that Aspirin (ASA), in contrast to Clopidogrel, inhibits the formation of an appropriate collateral network (arteriogenesis). This trial is supposed to reproduce the animal data in man. MATERIALS AND METHODS: In a prospective, double-blind, parallel-group, bi-national (D, CH), multicentre trial, 250 patients will be randomised to either 100 mg ASA or 75 mg Clopidogrel once daily. Patients will then enter a three months structured rehabilitation programme with daily physical training supposed to induce arteriogenesis. The claudication distances will be tested as the primary endpoint at baseline, 6 weeks, and at 3 months. Also, the 24h physical activity profile of all patients will be electronically documented. CONCLUSIONS: This trial will provide information on potential disadvantages when using ASA in PAD patients. If data emerging from animal pharmacology can be reproduced in man, the present standard scheme of anti-aggregant treatment in PAD patients has to be reconsidered.

[Therapeutically induced arteriogenesis in the brain. A new approach for the prevention of cerebral ischemia with vascular stenosis]. / Therapeutisch induzierte Arteriogenese im Gehirn. Ein neuer Ansatz zur Prävention der zerebralen Ischämie bei stenosierenden Gefässerkrankungen.

Stroke is the leading cause of disability and a major cause of death in Germany and the western world. Ischemic stroke involves different pathophysiologic mechanisms such as thromboembolic vascular occlusion, cerebral micro- or macroangiopathy, extracranial arterial stenosis, and cardiac embolism. Experimental and clinical studies have shown that arteriogenesis, the adaptive growth of pre-existing collateral arteries, can be therapeutically enhanced in peripheral circulation and the heart. We examined the consequences to time course and hemodynamics of brain arteriogenesis in a chronic hypoperfusion model following systemic administration of the hemopoietic growth factor called granulocyte macrophage colony stimulating factor (GM-CSF). Treatment with GM-CSF led to the growth of intracranial collateral arteries, which improved the cerebral hemodynamic reserve and significantly reduced energy failure when brains were additionally challenged by hypotension. Therapeutically induced arteriogenesis may be of considerable interest for preventing infarction in patients with uncompensated cerebrovascular disease.

CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization.

BACKGROUND: Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis. METHODS AND RESULTS: CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44-/- mice (wild-type, 54.5+/-14.9% versus CD44-/-, 24.1+/-9.2%, P<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29+/-12% versus CD44-/-, 18+/-7% CD11b-positive cells/square, P<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764+/-572 versus good collateralization, 2817+/-1029 AU, P<0.05). CONCLUSIONS: For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.

Local monocyte chemoattractant protein-1 therapy increases collateral artery formation in apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression, neointimal formation, and plaque progression.

Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation on arterial occlusion. The present study served to determine whether these proarteriogenic properties of MCP-1 are preserved in hyperlipidemic apolipoprotein E-deficient (apoE-/-) mice and whether it affects the systemic development of atherosclerosis. A total of 78 apoE-/- mice were treated with local infusion of low-dose MCP-1 (1 microg/kg per week), high-dose MCP-1 (10 microg/kg per week), or PBS as a control after unilateral ligation of the femoral artery. Collateral hindlimb flow, measured with fluorescent microspheres, significantly increased on a 1-week high-dose MCP-1 treatment (PBS 22.6+/-7.2%, MCP-1 31.3+/-10.3%; P<0.05). These effects were still present 2 months after the treatment (PBS 44.3+/-4.6%, MCP-1 56.5+/-10.4%; P<0.001). The increase in collateral flow was accompanied by an increase in the number of perivascular monocytes/macrophages on MCP-1 treatment. However, systemic CD11b expression by monocytes also increased, as did monocyte adhesion at the aortic endothelium and neointimal formation (intima/media ratio, 0.097+/-0.011 [PBS] versus 0.257+/-0.022 [MCP-1]; P<0.0001). Moreover, Sudan IV staining revealed an increase in aortic atherosclerotic plaque surface (24.3+/-5.2% [PBS] versus 38.2+/-9.5% [MCP-1]; P<0.01). Finally, a significant decrease in the percentage of smooth muscle cells was found in plaques (15.0+/-5.2% [PBS] versus 5.8+/-2.3% [MCP-1]; P<0.001). In conclusion, local infusion of MCP-1 significantly increases collateral flow on femoral artery ligation in apoE-/- mice up to 2 months after the treatment. However, the local treatment did not preclude systemic effects on atherogenesis, leading to increased atherosclerotic plaque formation and changes in cellular content of plaques.

Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits.

OBJECTIVE: The objective of our study was to quantify the arteriogenic potency of Monocyte Chemoattractant Protein-1 (MCP-1) under hyperlipidemic conditions. Additionally, we aimed to determine the effects of locally applied MCP-1 on systemic serum lipid levels as well as on atherosclerosis. METHODS: A total of sixty-four Watanabe rabbits was treated with either low dose MCP-1 (1 microg/kg/week), high dose MCP-1 (3.3 microg/kg/week) or PBS as a control substance. Substances were applied directly into the collateral circulation via an osmotic minipump with the catheter placed in the proximal stump of the ligated femoral artery. Either 1 week or 6 months after initiation of the treatment X-ray angiography was performed as well as measurements of collateral conductance using fluorescent microspheres. The extent of atherosclerosis was quantified in whole aortas using Sudan IV staining. RESULTS: One week after ligation of the femoral artery a significant increase in collateral conductance was observed in animals treated with high dose MCP-1 (control: 2.2+/-0.8 ml/min/100 mmHg vs. MCP-1 high dose: 8.9+/-2.0 ml/min/100 mmHg, P<0.05). Six months after femoral artery ligation no differences were found between the treated and the control group (PBS; 44.9+/-11.6 ml/min/100 mmHg, MCP-1; 47.8+/-11.5 ml/min/100 mmHg, P=NS). No influence was found on serum lipids or on the development of atherosclerosis in the present model. CONCLUSION: MCP-1 accelerates arteriogenesis upon femoral artery ligation under hyperlipidemic conditions. Six months after treatment these pro-arteriogenic effects of MCP-1 can no longer be observed. The present data do not show an effect of local MCP-1 treatment on serum lipids or on atherosclerosis. It should be noted however that a high standard deviation was observed for the data on atherosclerotic surface area, necessitating additional experiments in a different model of atherosclerosis.

NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors.

A monoreactive NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) derived prochelator (1-(1-carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)(3))) was synthesized in five steps with an overall yield of 21%. It is useful for the coupling to the N-terminus of peptides on solid phase and in solution; it was coupled to [Tyr3]-octreotide (TOC) on solid phase, and the resulting peptide, NODAGA-Tyr3-octreotide (NODAGATOC), was labeled with the radiometals 111In and 67Ga in high yields and good specific activities. [67Ga]- and [111In]-NODAGA-Tyr3-octreotide appear to be useful to visualize primary tumors and metastases which express somatostatin receptors subtype 2 (sstr2), such as neuroendocrine tumors, because of their high affinity to this receptor subtype with IC(50) = 3.5 +/- 1.6 nM and 1.7 +/- 0.2 nM, respectively. NODAGATOC could be used as a SPECT and PET tracer, when labeled with 111In, 67Ga, or 68Ga, and even for therapeutic applications. Surprisingly, [111In]-NODAGATOC shows 2 times higher binding affinity to sstr2, but also a factor of 4 higher affinity to sstr5 compared to [67Ga]-NODAGATOC. [67Ga]-NODAGATOC is very stable in serum and rat liver homogenate. There is no difference in the rate of internalization into AR4-2J rat pancreatic tumor cells; both radioligands are highly internalized, at 4 h a 3 times higher uptake compared to [111In]-DOTA-Tyr3-octreotide ([111In]-DOTATOC) was found. The biodistribution of [67Ga]-NODAGATOC in AR4-2J tumor bearing nude mice is very favorable at short times after injection; there is fast excretion from all nontarget organs except the kidneys and high uptake in sst receptor rich organs and in the AR4-2J tumor. Again it is superior to [111In]-DOTATOC in this respect. The results indicate an improved biological behavior which is likely due to the fact that an additional spacer group separates the chelate from the pharmacophoric part of the somatostatin analogue.