Physiological Ischemic Training Research Articles

Physiological ischemic training improves cardiac function through the attenuation of cardiomyocyte apoptosis and the activation of the vagus nerve in chronic heart failure.

This study investigated the functional outcomes of patients with chronic heart failure (CHF) after physiological ischemic training (PIT), identified the optimal PIT protocol, evaluated its cardioprotective effects and explored the underlying neural mechanisms. Patients with CHF were randomly divided into experimental group (n = 25, PIT intervention + regular treatment) and control group (n = 25, regular treatment). The outcomes included the left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP) and cardiopulmonary parameters. LVEF and cardiac biomarkers in CHF rats after various PIT treatments (different in intensity, frequency, and course of treatment) were measured to identify the optimal PIT protocol. The effect of PIT on cardiomyocyte programmed cell death was investigated by western blot, flow cytometry and fluorescent staining. The neural mechanism involved in PIT-induced cardioprotective effect was assessed by stimulation of the vagus nerve and muscarinic M2 receptor in CHF rats. LVEF and VO2max increased while BNP decreased in patients subjected to PIT. The optimal PIT protocol in CHF rats was composed of five cycles of 5 min ischemia followed by 5 min reperfusion on remote limbs for 8 weeks. LVEF and cardiac biomarker levels were significantly improved, and cardiomyocyte apoptosis was inhibited. However, these cardioprotective effects disappeared after subjecting CHF rats to vagotomy or muscarinic M2 receptor inhibition. PIT improved functional outcomes in CHF patients. The optimal PIT protocol required appropriate intensity, reasonable frequency, and adequate treatment course. Under these conditions, improvement of cardiac function in CHF was confirmed through cardiomyocyte apoptosis reduction and vagus nerve activation.

Eight weeks of resistance training with blood flow restriction improve cardiac function and vascular endothelial function in healthy young Asian males.

BackgroundResistance training with blood flow restriction (BFR) is a physiological ischaemic training method. Before it is applied to patients with coronary artery disease, it must be proven safe and effective.MethodsTwenty-four healthy adult males were randomly assigned to three groups: the resistance training (RT) group, low-pressure BFR and resistance training (LP-RT) group and high-pressure BFR and resistance training (HP-RT) group. The training protocol was 20 times/min/set, with a 2-min break, five sets/day and 5 d/week for 8 weeks. Cardiac function, haemodynamics and vascular endothelial function were evaluated before and after the first training and the last training.ResultsThere were no significant differences among groups before and after training. After 8 weeks of training, the resting heart rate (p<0.05) of the three groups significantly decreased (p<0.05). The rate–pressure product in the LP-RT group significantly decreased (p<0.05) compared with before training. Just after the last training, heart rate (p<0.05) and cardiac output (p<0.05) in the LP-RT and HP-RT groups significantly decreased compared with those just after the first training. At the end of the experiment, vascular endothelial growth factor (VEGF; p<0.01), soluble VEGF receptor (VEGFR) (p<0.05) and interleukin-6 (p<0.01) significantly increased, except for soluble VEGFR in the RT group.ConclusionsLow-intensity resistance training with BFR moderately alters cardiac function. The expression levels of proteins related to vascular endothelial function have significantly changed. Both findings suggest that low-intensity resistance training with BFR may be safely and effectively applied to patients with coronary artery disease.

Amelioration of ischemic cardiomyopathy in patients using physiological ischemic training.

This study aimed to observe the effect and potential mechanism of physiological ischemic training (PIT) in patients with ischemic cardiomyopathy. Atotal of 165 patients with ischemic cardiomyopathy were randomly selected by the convenience sampling method and were divided into the control and experimental groups. The control group received conventional drug treatment, while the experimental group received additional PIT. All patients were followed up for 6months and renin-angiotensin-aldosterone system (RAS) activity parameters and myocardial remodeling indicators were recorded. After the 6‑month intervention, cardiac function indicators in the two groups were significantly improved compared with before intervention (all P < 0.01), but the experimental group showed significantly more improvement compared with the control group (all P < 0.01). Similarly, RAS activity parameters and myocardial remodeling indicators of the two groups were significantly reduced after intervention compared with before intervention (all P < 0.01). However, the experimental group showed significantly lower myocardial remodeling indicators than the control group (all P < 0.01). Vascular endothelial growth factor (VEGF) and nitric oxide (NO) concentrations in peripheral blood in the experimental group were significantly increased after intervention compared with before intervention (both P < 0.01). PIT can be applied in patients with ischemic cardiomyopathy on the basis of the original standardized drug treatment. PIT ameliorates cardiac blood flow reserve by increasing VEGF and NO concentrations in the peripheral blood, as well as by inhibiting the RAS system and myocardial remodeling. This ultimately improves the patient's cardiac function to agreater extent.

Comparison of the Clinical Outcomes of Two Physiological Ischemic Training Methods in Patients with Coronary Heart Disease.

The aim of the present study was to verify the effectiveness of physiological ischemic training (PIT) in patients with coronary heart disease (CHD) and compare differences in clinical outcomes between isometric exercise training (IET) and cuff inflation training (CIT).Fifty-five CHD patients were randomized into three groups: IET group (n=19), CIT group (n=18), and no-exercise group (n=18). PIT was practiced in the IET and CIT groups. Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded. The cardiac structure and function were evaluated and vascular endothelial growth factor (VEGF) measured.SBP and DBP decreased significantly in both PIT groups after 3-month training (P<0.01). Cardiac function and structure were significantly improved in both PIT groups after 3-month training (P<0.01). Cardiac structure and function in the IET group were both superior to those in the CIT group by the end of training (P<0.01). The VEGF level in both PIT groups increased significantly after 3-month training (P<0.01).PIT was safe and feasible when performed in CHD patients. An appropriate period of PIT helped improve blood pressure and the cardiac structure and function, with the outcome more positive in the IET group.

Effects of physiological ischemic training on post-stroke neuroprotection and angiogenesis in adult rats

To examine potentially beneficial effects of physiological ischemic training (PIT) following stroke. Three hundred seventy-five adult male rats were subjected to 90-min transient middle cerebral artery occlusion (MCAO) and randomized into a PIT group and a non-PIT control group. A sham-operated group was used as negative control. After 1- and 2-weeks of PIT, brain infarct volume was measured by Triphenyl tetrazolium chloride (TTC) staining, and behavioral outcomes, presence of intact neurons, apoptosis, and cerebral edema were assessed with modified neurological severity score (mNSS), Nissl staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and cerebral water volume. The mRNA expression of vascular endothelial growth factor (VEGF) was assayed with RT-PCR and protein expression of VEGF was quantified with Western blot. Cerebral infarction, neurological deficits and neuronal apoptosis were reduced significantly in the PIT groups, while the presence of neurons was increased in comparison with MCAO controls. Moreover, mRNA and protein expression of VEGF were enhanced after 1 and 2 weeks of PIT. PIT may promote angiogenesis and neuroprotection during post-stroke rehabilitation and provide a novel strategy for rehabilitation of stroke patients.

Randomized clinical trial of physiological ischemic training for patients with coronary heart disease complicated with heart failure: Safety of training, VEGF of peripheral blood and quality of life.

Effects of a 12-week physiological ischemic training (PIT) programme on safety of training and quality of life (QOL) in patients with coronary heart disease (CHD) complicated with heart failure were evaluated. A total of 30 patients with CHD complicated with heart failure were randomized to either an intervention group (n=15) or to controls (n=15) after baseline testing. A 12-week, 5 times a week, maximum subjective force group PIT was conducted. Safety of the training was measured with ECG and heart rate and blood pressure, QOL was measured using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and vascular endothelial growth factor (VEGF) was measured with peripheral blood. VEGF and MLHFQ were improved in the intervention group. The finding of the study shows PIT is safe to patients with CHD complicated with heart failure by improving VEGF of peripheral blood and QOL.

Remote physiological ischemic training promotes coronary angiogenesis via molecular and cellular mobilization after myocardial ischemia.

This study was designed to explore the mechanism of physiological ischemic training (PIT) on remote limbs, with a special focus on the potential role of endothelial progenitor cells (EPCs), vascular endothelial growth factor (VEGF), and nitric oxide (NO) in local ischemic myocardium. Myocardial ischemia (MI) rabbit models were randomly assigned to sham-operated group (SO), training-only group (TO), MI group, PIT group, VEGF inhibitor group (VEGF-), NO inhibitor group (NO-), VEGF and NO inhibitor group (VEGF-/NO-), and EPC inhibitor group (EPC-). A constrictor was implanted around the left ventricular branch to induce controlled MI. The PIT procedure consisted of three cycles of a 3-minutes cuff inflation on the hindlimbs with a reperfusion of 5minutes. Plasma and myocardial EPC numbers, VEGF level, and NO concentration, as well as capillary density (CD), coronary blood flow (CBF), and coronary collateral blood flow (CCBF) in myocardium, were measured. Nonparametric statistical techniques were applied to identify the differences between groups, and regression models were used to detect correlations between agents. VEGF levels, NO concentrations, and also EPC counts in both plasma and myocardium were highest in the PIT group. Capillary density, CCBF, and CCBF/CBF were also statistically elevated in the PIT group. VEGF explained 74% of variance in NO. NO explained 65% of variance in EPCs. EPCs explained 68% of variance in capillary density. Capillary density explained 78% of variance in CCBF and CCBF/CBF. PIT mobilized EPCs and promoted revascularization through upregulating VEGF and NO level.

Physiological Ischemic Training Promotes Brain Collateral Formation and Improves Functions in Patients with Acute Cerebral Infarction.

To observe the effectiveness and mechanisms of physiological ischemic training (PIT) on brain cerebral collateral formation and functional recovery in patients with acute cerebral infarction. 20 eligible patients with acute cerebral infarction were randomly assigned to either PIT group (n = 10) or Control group (n = 10). Both groups received 4 weeks of routine rehabilitation therapy, while an additional session of PIT, which consisted of 10 times of maximal voluntary isometric handgrip for 1 min followed by 1 min rest, was prescribed for patients in the PIT groups. Each patient was trained with four sections a day and 5 days a week for 4 weeks. The Fugl-Meyer Assessment (FMA), the Modified Barthel Index (MBI), and the short-form 36-item health survey questionnaire (SF-36) were applied for the evaluation of motor impairment, activity of daily living, and quality of life at the baseline and endpoint. MRI was applied to detect the collateral formation in the brain. The concentration of vascular endothelial growth factor (VEGF) and endothelial progenitor cells (EPCs) number in plasma were also tested at the endpoint. Demographic data were consistent between experimental groups. At the endpoint, the scores of the FMA, MBI, and SF-36 were significantly higher than that at baseline. As compared to the Control group, the score of FMA and SF-36 in PIT group was significantly higher, while no significant difference was detected between groups in terms of MBI. Both groups had significantly higher cerebral blood flow (CBF) level at endpoint as compared to that at baseline. Moreover, the CBF level was even higher in the PIT group as compared to that in the Control group after 4 weeks of training. The same situations were also found in the plasma VEGF and EPCs assessment. In addition, positive correlations were found between FMA score and CBF level (r = 0.686, p < 0.01), CBF level and VEGF concentration (r = 0.675, p < 0.01), and VEGF concentration and EPC number (r = 0.722, p < 0.01). PIT may be effective in increasing the expression of VEGF and recruitment of EPCs and in turn promote the formation of brain collateral circulation. The positive correlations may demonstrate a potential association between biological and functional parameters, and PIT may be able to improve the motor function, activity of daily living, and quality of life in patients with stroke.

Impact of remote physiological ischemic training on vascular endothelial growth factor, endothelial progenitor cells and coronary angiogenesis after myocardial ischemia

ObjectiveThis experimental study investigates the potential role of physiological ischemic training (PIT) of remote limbs on vascular endothelial growth factor (VEGF), endothelial progenitor cells (EPCs) and myocardial angiogenesis after myocardial ischemia. MethodsForty-two rabbits were assigned into six groups at random: sham-operated (SO), training only (TO), myocardial ischemia (MI), PIT, EPC promoter (PIT+), and EPC inhibitor (PIT−). MI was experimentally induced by implanting a constrictor around the left ventricular branch. The PIT procedure included three 3-min cycles of cuff inflations on the hind limbs followed by a 5min reperfusion. VEGF mRNA, protein and EPC numbers were measured in plasma and myocardium. Capillary density (CD), coronary blood flow (CBF) and coronary collateral blood flow (CCBF) were also determined. ResultsGroups were compared using non-parametric statistics and associations between agents were explored with fractional polynomial regression. VEGF-mRNA and -protein levels were highest in PIT+ and PIT. PIT differed significantly from SO, TO, MI, and PIT− regarding VEGF-mRNA and -protein in plasma and VEGF-protein in myocardium. EPCs were highest in PIT+ followed by PIT. PIT differed significantly from SO, TO, MI, and PIT− regarding plasma EPCs. CD, CCBF and CCBF/CBF were significantly increased in PIT+ and PIT as compared to controls. PIT− did not differ significantly from SO and TO. VEGF explained up to 43% of variance in EPCs. EPCs explained up to 87% of variance in CD. CD explained up to 97% of variance in CCBF and CCBF/CBF. ConclusionPIT stimulates VEGF-mediated mobilization of EPCs as well as angiogenesis and might be proven as a new treatment strategy for patients with coronary heart disease.

GW25-e0151 Role of Endothelial Progenitor Cells and Nitric Oxide in Collateral Circulation Formation in Ischemic Myocardium Induced by Physiological Ischemic Training

GW25-e0151 Role of Endothelial Progenitor Cells and Nitric Oxide in Collateral Circulation Formation in Ischemic Myocardium Induced by Physiological Ischemic Training

Physiologic ischaemic training induces endothelial progenitor cell mobilization and myocardial angiogenesis via endothelial nitric oxide synthase related pathway in rabbits

Ischaemia-induced angiogenesis promises to improve neovascularization by delivery of angiogenic factors or endothelial progenitor cells (EPCs) to cardiac ischaemic areas. In order to avoid the risk of excessive myocardial ischaemia, therefore, we hypothesized that physiological ischaemic training (PIT) of normal skeletal muscle might contribute to myocardial angiogenesis via nitric oxide mediated mobilization of EPCs from the bone marrow in the established rabbit model of controllable myocardial ischaemia. The rabbits were grouped by sham-operation, myocardial ischaemia without PIT, PIT and PIT with pretreatment with the endothelial nitric oxide synthase (eNOS) inhibitor L-nitroarginine methyl ester (L-NAME). Controlled myocardial ischaemia was modelled by a water balloon constrictor implanted on the left ventricular branch in a rabbit. The PIT procedure included three cycles of 3 min of cuff inflation followed by 5 min of deflation on hind limbs of the rabbits for 4 weeks. At the endpoints, circulating EPCs (CD34/Flk-1) were measured by fluorescence-activated cell sorter; capillary density, by immunohistochemistry; blood flow, by a microsphere technique; endothelial nitric oxide synthase (eNOS) mRNA and protein, by real-time reverse transcriptase (RT)-PCR and Western blotting. The mRNA levels of eNOS were significantly higher in the PIT and L-NAME groups than in the sham-operation group (P < 0.05). Phospho-eNOS protein expression was higher in the PIT group than in the sham-operation and myocardial ischaemia without PIT groups (P < 0.05), and the effect was inhibited by L-NAME pretreatment (P < 0.05). Compared with sham-operation and myocardial ischaemia without PIT groups, the PIT group had the highest EPC count (P < 0.001), and the increase of capillary density (P < 0.01) and collateral blood flow (P < 0.05) in the ischaemic myocardium was consistent with the finding of EPC count. These effects were also inhibited by pretreatment with the eNOS inhibitor L-NAME. Capillary density and collateral blood flow were highly correlated with the increase of EPC count (r = 0.913 and r = 0.929, respectively, P = 0.000). PIT improved EPC mobilization and contributed to compensatory neovascularization via eNOS-related pathway. These results might support the future development of strategies for therapeutic neovascularization.

Improving Angiogenesis and Muscle Performance in the Ischemic Limb Model by Physiological Ischemic Training in Rabbits

The aim of this study was to test the effects of physiologic ischemic training on the performance of skeletal muscle in a pathologically ischemic limb models. Twenty-seven New Zealand white rabbits were randomly assigned to three groups: (1) those in the ischemia with cuff inflation training group received right femoral artery ligation and occlusion of blood flow in the left limb by 3 mins of cuff inflation followed by 5 mins of deflation, repeated three times; (2) those in the ischemia with isometric exercise training group received right femoral artery ligation and 4 mins of isometric contraction exercise ischemic training in the left limb followed by 10 mins of rest, repeated twice; (3) those in the sole ischemia group received right femoral artery ligation and no intervention in the left limb. Five weeks later, muscle endurance, resting blood flow, and collateral angiogenesis were examined. Capillary supply, types and cross-sectional areas of muscle fibers and cellular oxidative potential were also evaluated. Gastronomic endurance of rabbits in the cuff inflation training group was the best among the three groups (P < 0.01). Collateral circulation (P < 0.05), distribution of type I fibers (P < 0.01), and cross-sectional area of type IIB fibers (P < 0.05) were also significantly higher in the cuff inflation training group than in the sole ischemia group. Similar differences were recorded between the isometric exercise training and sole ischemia groups. The distribution of type IIA fibers was lower (P < 0.01) in the cuff inflation training group than in the isometric exercise training group. Distribution of type IIB was found to be significantly different between these two groups (P < 0.01). Physiologic ischemic exercise training can promote remote angiogenesis in the pathologic ischemic skeletal muscle and thus improve performance.

Physiological ischemia training enhanced circulating EPCs and neovasculation

BackgroundRecently researches showed that physiological ischemic training increased VEGF and capillary density (CD) in the remote regions. Physiological ischaemic training was referred to the ischemic isometric contraction on the normal...