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.

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.

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.

[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.