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Everyone knows from their own experience that many biological processes follow daily rhythms. These circadian rhythms affect virtually all aspects of human physiological function. Curiously, events such as heart attacks, sudden cardiac death, and stroke are also affected by these daily cycles; these events are more common in the early morning hours than other times of the day. Many physiological processes that might play a role in the risk of heart attack or stroke follow circadian rhythms. Fibrinolytic activity, which dissolves clots that might be forming in a critical artery, is less in the morning. Platelet aggregation, often the first step in clot formation, is most likely to occur in the morning hours. Many hormones that might influence the risk of heart attack, such as norepinephrine, are at their highest levels in the morning. A study was conducted to determine if the muscle tone of blood vessels varies similarly in a daily cycle. The tone of a smaller artery influences the resistance to blood flow. It was found that arterial resistance to blood flow was higher in the morning than in the afternoon or evening. Furthermore, the rate of blood flow was found to be lower in the morning than at other times of the day. This circadian rhythm in the resistance of blood vessels could be eliminated by the infusion of the drug phentolamine. This drug causes blood vessels to relax by interfering with alpha-adrenoreceptors, specific hormone receptors in the sympathetic nervous system, which helps regulate blood pressure. This observation suggests that the alpha-adrenergic mechanisms of the sympathetic nervous system are responsible for the diurnal rhythm. This interpretation is strengthened by the observation that sodium nitroprusside, which causes blood vessels to relax by mechanisms unrelated to the alpha-adrenergic mechanisms, has no effect on the circadian rhythm. Arteries clogged by atherosclerosis are especially sensitive to changes in tone, and these daily rhythms of changing vessel tone may contribute to the increased likelihood of heart attack and stroke in the morning. It should be remembered, of course, that the contribution of vessel tone to the increased morning risk of these events does not rule out participation of other mechanisms such as increased platelet aggregability. (Consumer Summary produced by Reliance Medical Information, Inc.)

Blood vessels are lined with endothelial cells arranged in a sheetlike structure called the vascular endothelium. This layer is known to modulate the activity of the smooth muscle cell layer that surrounds it, whose primary function is contraction, leading to a constricted vessel. Thus, the endothelium is able to affect vascular tone. These effects are exerted on resistance vessels (the smallest arteries and arterioles) that determine peripheral resistance to blood flow and, ultimately, blood pressure. It is possible that vascular endothelium loses its normal ability to affect vessel diameter in some disease states, such as hypertension (high blood pressure). This was tested by evaluating 18 hypertensive patients and 18 nonhypertensive controls with respect to the responses of their blood vessels when vasoactive substances (agents that affect the blood vessels) were infused. The substances were acetylcholine (a vasodilator that acts by inhibiting the release of norepinephrine, a substance that causes constriction, at nerve endings on the blood vessel) and sodium nitroprusside (a direct dilator of smooth muscle in the vessel). Blood vessel responses were measured by plethysmography (a method of measuring size changes) that recorded size changes in the nondominant forearm. Any increase in blood flow would register as increased size. Results showed that blood flow and percent of change in vascular resistance were significantly higher in normal subjects after acetylcholine than in hypertensive patients. At the highest dose, blood flow in the forearm was approximately 20 milliliters per minute for controls, and only nine milliliters per minute for patients. There were no differences between the groups in blood flow after sodium nitroprusside. Other research has shown that acetylcholine cannot induce vasodilation if blood vessel endothelium is damaged, apparently because the endothelium releases a substance that relaxes the smooth muscle (endothelium-derived releasing factor). A discussion of the effects of acetylcholine is provided. An endothelial abnormality in hypertensive people could elevate the blood pressure even more, although whether this effect is the cause, or result, of the hypertension is not known. In any event, endothelium that does not function normally could contribute to hypertension, regardless of the disorder's origin. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abstract Background Fabry disease is an X-linked recessive lysosomal storage disease resulting in the cellular accumulation of globotriaosylceramide particularly globotriaosylceramide. The disease is characterized by a dilated vasculopathy with arterial ectasia in muscular arteries and arterioles. Previous venous plethysomographic studies suggest enhanced endothelium-dependent vasodilation in Fabry disease indicating a functional abnormality of resistance vessels. Methods We examined the mechanical properties of the radial artery in Fabry disease, a typical fibro-muscular artery. Eight control subjects and seven patients with Fabry disease had a right brachial arterial line placed allowing real time recording of intra-arterial blood pressure. Real time B-mode ultrasound recordings of the right radial artery were obtained simultaneously allowing calculation of the vessel wall internal and external diameter, the incremental Young's modulus and arterial wall thickness. By simultaneously measurement of the distal index finger-pulse oximetry the pulse wave speed was calculated. From the wave speed and the internal radial artery diameter the volume flow was calculated by Womersley analysis following truncation of the late diastolic phase. Results No significant difference was found between Fabry patients and controls for internal or external arterial diameters, the incremental Young's modulus, the arterial wall thickness, the pulse wave speed and the basal radial artery blood flow. Further, no significant difference was found for the radial artery blood flow in response to intra-arterial acetylcholine or sodium nitroprusside. Both drugs however, elevated the mean arterial flow. Conclusions The current study suggests that no structural or mechanical abnormality exists in the vessel wall of fibro-muscular arteries in Fabry disease. This may indicate that a functional abnormality downstream to the conductance vessels is the dominant feature in development Fabry vasculopathy.

Aims: This study sought to determine the impact of weight and body mass index (BMI) on the safety and efficacy of direct-acting oral anticoagulants (DOACs) compared with warfarin in patients with non-valvular atrial fibrillation.Methods and Results: A systematic literature search was employed in PubMed, Embase, and Cochrane clinical trials with no language or date restrictions. Randomized trials or their substudies were assessed for relevant outcome data for efficacy that included stroke or systemic embolization (SSE), and safety including major bleeding and all-cause mortality. Binary outcome data and odds ratios from the relevant articles were used to calculate the pooled relative risk. For SSE, the data from the four Phase III trials showed that DOACs are better or similarly effective with low BMI 0.73 (0.56-0.97), normal BMI 0.72 (0.58-0.91), overweight 0.87 (0.76-0.99), and obese 0.87 (0.76-1.00). The risk of major bleeding was also better or similar with DOACs in all BMI subgroups with low BMI 0.62 (0.37-1.05), normal BMI 0.72 (0.58-0.90), overweight 0.83 (0.71-0.96), and obese 0.91 (0.81-1.03). There was no impact on mortality in all the subgroups. In a meta-regression analysis, the effect size advantage of DOACs compared with warfarin in terms of safety and efficacy gradually attenuated with increasing weight.Conclusion: Our findings suggest that a weight-based dosage adjustment may be necessary to achieve optimal benefits of DOACs for thromboembolic prevention in these patients with non-valvular atrial fibrillation. Further dedicated trials are needed to confirm these findings. PROSPERO 2019 CRD42019140693. Available from: https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42019140693. [ABSTRACT FROM AUTHOR]