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Acute ischemic stroke (AIS) is the leading cause of disability in adults worldwide and has the second highest mortality of all cardiovascular diseases[1]. The burden of stroke is likely to increase significantly during the next decades, primarily due to population growth and aging[2]. Given the detrimental impact of stroke on healthcare (costs) and patient well-being, it is imperative to explore opportunities for novel therapies to add to the current treatment to further minimize neurological injury. During an ischemic stroke, occlusion of a cerebral artery abrogates cerebral perfusion, causing brain tissue distal from the occlusion to become deprived of oxygen and nutrients, ultimately leading to ischemic injury. Surrounding the ischemic core an area called the penumbra contains potentially reversible injured brain tissue, which may remain viable for several hours. Whilst the time window to attenuate the detrimental impact of an ischemic stroke seems limited to six hours after onset of AIS[3, 4], recent research suggests that subgroups may benefit up to 24 hours[5, 6]. This time window of 6-24 hours offers perspective for hospital-based, additional therapies to reduce ischemic injury and minimize clinical deterioration in AIS patients. This review focuses on remote ischemic conditioning (RIC) as an additive therapy to improve clinical outcomes in AIS patients, both when applied as a single as well as repeated bouts. RIC refers to the application of several cycles of brief ischemia and reperfusion to a limb (using a blood pressure cuff). Pre-clinical work revealed this stimulus to reduce neural damage after reperfusion[7-11], validating the concept that RIC may have clinical potential in AIS. RIC therefore represents a simple, low cost therapeutic strategy that may salvage brain tissue in the penumbral area. In this review, we will summarize (pre)clinical evidence for the efficacy of RIC as an additional therapy in AIS patients.

Contains fulltext : 203303.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Patients with peripheral arterial disease (PAD) have increased risk on future cerebro- and cardiovascular events. Our aim was to examine whether carotid artery reactivity (CAR; a novel, simple procedure to examine endothelial function) predicts cardiovascular events in PAD patients. BACKGROUND: Increased risk for future cardiovascular events in PAD patients is likely related to endothelial dysfunction, highlighting the necessity for simple assessment of endothelial function. METHODS: A total of 172 PAD patients (68 +/- 10 years, 67% male) underwent the CAR, which involves ultrasound measurement of carotid artery diameter during sympathetic stimulation produced by 90-second hand immersion in 4 degrees C ice-water (ie, cold pressor test). CAR-responses were dichotomized into carotid constriction or dilation. We recorded cardiac and cerebrovascular events, mortality, and clinical progression to percutaneous transluminal angioplasty or loss of patency during 12-month follow-up. RESULTS: Eighty-two PAD patients demonstrated carotid constriction and 90 patients demonstrated dilation. PAD patients with carotid constriction showed more cardiovascular events compared to patients with dilation (Kaplan-Meier Log rank; P < 0.05). Cox proportional hazard models showed that patients with carotid constriction continued to show higher risk for cardiovascular events [hazard ratio: 4.1; 95% confidence interval (CI), 1.3-12.5] and clinical progression (hazard ratio: 2.0; 95% CI, 1.2-3.3), even after adjustment for other risk factors. Ankle brachial pressure index and carotid intima-medial thickness alone did not predict (cardiovascular) event or improve risk assessment beyond that provided by CAR. CONCLUSION: Carotid vasoconstriction identifies PAD patients with a 4-fold increased risk for future cardiovascular events and 2-fold increased risk for clinical deterioration. CAR provides a simple, novel strategy to predict cardiovascular events and progression in PAD patients. CLINICAL TRIAL REGISTRATION: www.trialregister.nl/trialreg/index.asp, NTR-4117. 01 april 2019

Background Premenopausal women have a lower incidence of cardiovascular disease, which may partly be due to a protective effect of estrogen on endothelial function. Animal studies suggest that estrogen may also improve the relationship between shear rate ( SR ) and endothelial function. We aimed to explore the relationship between endothelial function (ie, flow‐mediated dilation [ FMD ]) and SR (ie, SR area under the curve [ SRAUC ]) in women versus men, and between pre‐ versus postmenopausal women. Methods and Results Brachial artery FMD and SRAUC were measured in accordance with expert‐consensus guidelines in 932 healthy participants who were stratified into young adults (18‐40 years, 389 men, 144 women) and older adults (>40 years, 260 men, 139 women). Second, we compared premenopausal (n=173) and postmenopausal women (n=110). There was evidence of a weak correlation between SRAUC and FMD in all groups but older men, although there was variation in strength of outcomes. Further exploration using interaction terms (age‐sex× SRAUC ) in linear regression revealed differential relationships with FMD (young women versus young men [β=−5.8 −4 , P =0.017] and older women [β=−5.9 −4 , P =0.049]). The correlation between SRAUC and FMD in premenopausal women ( r 2 =0.097) was not statistically different from that in postmenopausal women ( r 2 =0.025; Fisher P =0.30). Subgroup analysis using stringent inclusion criteria for health markers (n=505) confirmed a stronger FMD ‐ SRAUC correlation in young women compared with young men and older women. Conclusions Evidence for a stronger relationship between endothelial function and the eliciting SR stimulus is present in young women compared with men. Estrogen may contribute to this finding, but larger healthy cohorts are required for conclusive outcomes.

The impact of manipulating shear stress on conduit artery vasodilation has not been comprehensively described in vivo. We hypothesized that manipulation of SR through the brachial and radial arteries would be associated with corresponding changes in diameter. We performed a series of studies involving the following: (1) leg cycle exercise at increasing intensities (≈70 and 85% maximum heart rate [HRmax]) with simultaneous bilateral measurement of SR in the radial arteries; (2) leg cycle exercise for 30 minutes at 80% HRmax with simultaneous bilateral measurement of velocity and diameter in the brachial arteries; and (3) bilateral forearm heating for 30 minutes with simultaneous bilateral measurement of brachial artery diameter and blood velocity. Cycling and forearm heating interventions were performed in the presence of unilateral cuff inflation throughout the experiment, or starting during the intervention (15 minutes), to manipulate SR responses. Cuff placement was associated with lower radial artery SR responses (cuffed versus uncuffed, 248±49 versus 349±105 L/s 85% HRmax; P P P P P

Purpose Studies performed in animals and humans strongly suggest that exercise training and physical activity enhance arterial endothelial function. Studies of athletes have, however, been less definitive. Methods We recruited a range of Olympic and world class athletes who participate in upper or lower limb predominant activities and examined brachial and superficial femoral artery diameter responses to 5-min ischemia (flow-mediated dilation [FMD]) and glyceryl trinitrate, wall thickness (WT) and wall-to-lumen ratio using Doppler and two-dimensional ultrasound. Subjects were elite male canoe paddlers (n = 12), squash players (n = 13), lower limb dominant athletes (i.e., runners/cyclists/triathletes, n = 13), or age- and sex-matched control subjects (n = 16). Results Athletes demonstrated lower superficial femoral artery FMD than controls (P Conclusions Although artery FMD was lower in athletes, artery size was larger and WT smaller than controls. The apparent reduction in artery FMD may relate to the profound structural remodeling in the diameter and WT of the conduit arteries of athletes. These findings have implications for the interpretation of FMD data, particularly as it pertains to the effect of athletic endeavor on cardiovascular health.

Purpose: This study aimed to investigate localized and systemic effects of chronic exercise and inactivity on conduit artery remodeling in humans. Methods: We recruited elite athletes engaged in predominantly lower limb (LL runners/cyclists, n = 10) or upper limb (UL canoe paddlers, n = 12) exercise and matched able-bodied, recreationally active, controls (C, n = 16). We also studied wheelchair controls (spinal cord injury, n = 9) and athletes (spinal cord injury, n = 1; spina bifida, n = 4). Carotid, brachial, and superficial femoral (SF) artery diameter and wall thickness were assessed using high-resolution ultrasound. Results: Brachial diameters were significantly larger in UL and wheelchair users (athletes and controls) compared with C (both P < 0.05). SF artery diameter in wheelchair controls was significantly smaller compared with the other groups, with LL athletes having significantly greater lumen diameter than controls (both P < 0.05). In all arteries, a lower wall thickness was found in able-bodied athletes compared with C, including wheelchair athletes compared with wheelchair controls (P < 0.001). In the SF artery, wall-to-lumen-ratio was significantly lower in able-bodied athletes and higher in wheelchair controls compared with able-bodied controls (P < 0.001). In the brachial and carotid arteries, able-bodied and wheelchair athletes demonstrated lower wall-to-lumen-ratio than less active wheelchair controls and able-bodied controls (P < 0.001). Conclusions: These findings suggest that remodeling of the arterial wall occurs systemically in response to exercise training and is unrelated to exercise type in humans. Conversely, localized effects are evident with respect to the effect of exercise on arterial diameter. These findings have implications for our understanding of the effects of exercise on arterial structure and function in humans.

PURPOSE: Endurance exercise can elevate cardiac troponin (cTn) concentrations in healthy subjects. cTn is preferred biomarker for diagnosing myocardial infarction and indicates cardiac injury. Subjects with cardiovascular disease demonstrate elevated cTn-concentrations at baseline, but it is unknown how cTn concentrations change following endurance exercise. We investigated the impact of cardiovascular (CV) risk and disease (CVD) on exercise-induced cTn elevations. METHODS: We measured baseline and immediate post-exercise cTn-concentrations in 356 subjects who performed 30-50 km of walking. Subjects were classified as healthy (i.e. controls, n=133), having increased CV risk (hypertension, hypercholesterolemia, type 2 diabetes or BMI ≥30 kg/m2, n=131) or having diagnosed CVD (heart failure, myocardial infarction, stroke, n=92). cTn-subunit I (cTnI) was determined using a high-sensitive assay (ADVIA Centaur TnI-Ultra, Siemens) with a detection limit of 6 ng/L and upper reference limit of 40 ng/L. RESULTS: Subjects walked 8.0±1.4 hours at 68±10% of their maximum predicted heart rate. Baseline and post-exercise cTnI concentrations were significantly higher in CVD patients compared to controls (p CONCLUSIONS: Exercise-induced cardiac troponin elevations are significantly larger in subjects with cardiovascular disease, but this difference is small and does not result in a higher incidence of cases exceeding the clinical cut-off value.

Physical activity (PA) protects against future cardiovascular events. Nonetheless, myocardial infarction (MI) has been reported in lifelong athletes. MI typically reduces left ventricular function (LVF), but animal studies suggest that regular PA can reduce the ischemic effects of a MI and therefore preserve LVF. PURPOSE: To examine the impact of lifelong physical activity and myocardial infarction on left ventricular function. METHODS: 68 male subjects (45-75 yrs) were included and divided over four groups: 1) lifelong athletes (>3 h/week PA for>20 years) with a history of MI (active-MI, n=16), 2) lifelong athletes without a history of MI (active-CON, n=17), 3) sedentary subjects ( 20 years) with a history of MI (inactive-MI, n=16), and 4) sedentary subject without a history of MI (inactive-CON, n=19). Physical fitness was assessed by a cardio-pulmonary exercise test, while ejection fraction (EF), E/A ratio, and circumferential wall deformation (CWD) of the left ventricle were measured by echocardiography. RESULTS: VO2max was significantly higher (P 0.05). The E/A ratio was not different across groups (P>0.05). Active-MI (-17.8±3.3%) and active-CON subjects (-19.2±2.5%) demonstrated a better CWD compared to inactive-MI (-13.2±3.6%) (P 0.05). CONCLUSION: Active-MI subjects demonstrate EF and CWD values comparable to active-CON and inactive-CON subjects, while these values are significantly better than those in inactive-MI subjects. These findings suggest that lifelong physical activity may reduce the detrimental effect of myocardial infarction-induced ischemia on left ventricular function in humans.

Lifestyle interventions like aerobic exercise training (“training”) and caloric restriction (“diet”) are frequently prescribed for weight-management in obesity, with studies suggesting a larger effect of diet on weight loss. Importantly, visceral adiposity (VAT) is a stronger and more important predictor for all-cause morbidity and mortality than body weight. Currently, it is not known which of these 2 interventions have superior effects on VAT. PURPOSE: With the use of a meta-analysis, we compared the impact of training versus diet on VAT in overweight/obese humans. Secondly, we examined the correlation between changes in body weight and VAT after both, training and diet. METHODS: Pubmed, Cochrane, Web of Science and Embase were systematically searched for eligible studies. Included studies were clinical or randomized controlled trials in which training and/or diet was implemented for >4 weeks (112 studies, n=4,815). RESULTS: Training and diet caused VAT loss (standard mean difference: 95%CI -0.56/-0.39 and 95%CI-0.71/-0.55, respectively, both P DISCUSSION: Both exercise training and diet reduce VAT. Despite a larger effect of diet on body weight loss, training tends to have superior effects in reducing VAT. Finally, weight loss does not necessarily reflect loss in VAT after lifestyle interventions and may lead to spurious conclusions when evaluating benefits of lifestyle-interventions on body composition.

See related article, pp 1145–1150 In reductionist times, it is refreshing to appreciate the creativity of apparently “simple” technical approaches coupled with clever experimental design. The study of Jiang et al1 evokes Harvey2 in its manipulation of human vascular behavior using a “ligature,” coupled with careful visual appraisal, to examine the impact of pressure on artery diameter responses. They modified a technique introduced by Celermajer et al3 involving inflation of a pneumatic cuff placed around the forearm to high pressure (for ≈5 minutes) to induce distal limb ischemia. Cuff deflation is associated with a large increase in blood flow through the upstream radial or brachial artery,4 which, in turn, induces a “flow-mediated” dilation (FMD).3 This, in turn, has been attributed to the release of vasodilator paracrines such as NO from the endothelium, as a consequence of shear stress–mediated signal transduction.5 The FMD test has become a popular noninvasive test of endothelial function, in part because it predicts future cardiovascular events.6,7 The kinetics of the vasodilator response after cuff deflation in the FMD test have always been quizzical in that the peak blood …

Age is one of the most important risk factors for cardiovascular disease. For example, a 30-year-old male smoker with untreated hypertension, diabetes, dyslipidemia, and a strong family history of premature coronary heart disease (CHD) would have a 10-year coronary heart disease event rate of only 16% (“intermediate risk”) by Framingham criteria; however, given exactly the same risk profile for a 60-year-old, the risk climbs to >50%. Aging, particularly sedentary aging, leads not only to the development of atherosclerosis but also to ventricular and arterial stiffening.1 This reduces functional capacity and contributes to chronic diseases of the elderly, such as systolic hypertension or heart failure with a preserved ejection fraction. In the search for the underlying mechanism for this effect of sedentary aging, one common feature that has been identified universally in older men is an increased baseline vascular tone,2 which has both hemodynamic and metabolic consequences.3 Although this age-related increase in vascular tone is mediated in part by a chronically elevated sympathetic α-adrenergic vasoconstriction,2 endothelial function also plays a critical role in vascular stability and the regulation of vasomotor function. The endothelium regulates vascular tone through the release of dilator and constrictor substances. Endothelin (ET)-1 is the most potent endothelium-derived constricting factor and influences peripheral vascular tone by interacting with ETA and ETB receptors on smooth muscle cells and the endothelium.4 Several animal studies have examined the profound effects of vascular aging on the ET-1 pathway and support a central role for ET-1 to explain the age-related increase in vascular tone.5–7 In the present issue of Hypertension , Van Guilder et al8 present new and important information regarding the role of aging and physical fitness on the vasomotor effects of ET-1. Using a cross-sectional design in a small but carefully studied …