Effect Of Diabetes On Endothelial And Plateletts 2019 Pdf
- and pdf
- Wednesday, April 28, 2021 11:11:36 PM
- 5 comment
File Name: effect of diabetes on endothelial and plateletts 2019 .zip
Thank you for visiting nature. You are using a browser version with limited support for CSS.
- Pathological effects of ionizing radiation: endothelial activation and dysfunction
- Platelets Are at the Nexus of Vascular Diseases
- Coagulatory Defects in Type-1 and Type-2 Diabetes
Pathological effects of ionizing radiation: endothelial activation and dysfunction
The mean P2Y 12 reaction units PRU on empagliflozin was significantly less than without empagliflozin at baseline The mean difference in PRU was No patients experienced any serious adverse events SAEs. Significantly attenuated platelet reactivity was observed on empagliflozin as compared to without empagliflozin. Further studies are required to confirm these exploratory findings. Funded by the University of the West Indies, St. This article is published with digital features to facilitate understanding of the article.
SGLT2 inhibition decreases hyperglycemia by inducing glucosuria [ 1 ]. Additionally, diuresis, natriuresis, weight loss, and antihypertensive effects also occur [ 4 ]. The mechanistic effects of SGLT2 inhibition have not been fully elucidated, and other postulated mechanisms include alterations in myocardial energetics and prevention of cardiac fibrosis, among others [ 5 ].
To our knowledge, the question of whether SGLT2 inhibition also resulted in pleiotropic antiplatelet effects remained unanswered. Therefore, we conducted this exploratory pilot study to assess the antiplatelet pharmacodynamic PD effect of empagliflozin in a Trinidadian subpopulation with stable coronary artery disease CAD and T2DM. Augustine, Trinidad [ 6 ].
Patients were screened and enrolled between May and August at the cardiology outpatient clinic at our institution Eric Williams Medical Sciences Complex, Trinidad and Tobago. Samples were processed by laboratory personnel blinded to ongoing study data. The assays were performed according to standard protocols, as previously described [ 7 , 8 , 9 ]. A PRU greater than was considered high on-treatment platelet reactivity HPR according to the last consensus [ 10 ]. No adjustments for multiple comparisons were made.
Missing data were not imputed none. Statistical analysis was performed using SPSS version The mean age was Just less than half of the patients were female and all bar one patient was South Asian in ethnicity. The mean body mass index BMI was No patients were on mineralocorticoid receptor antagonists MRA. Nearly one-third of patients were on insulin therapy, while half were on metformin and sulfonylureas.
The mean PRU on empagliflozin was significantly less than that without empagliflozin at baseline No patients experienced any serious adverse events. Diabetes is associated with a complex neurohormonal milieu that accentuates platelet reactivity [ 11 ]. Several factors contributing to this phenomenon include hyperglycemia, dyslipidemia, insulin resistance with resultant oxidative stress, inflammation, and endothelial dysfunction [ 11 ].
Recently, SGLT2is have gained robust traction as a novel class of antidiabetic agents with a unique mechanism of decreasing hyperglycemia by inducing glucosuria [ 12 ]. In addition to its primary effect, natriuresis, weight loss, antihypertensive, and antilipidemic effects also occur [ 4 ].
Other postulated extraglycemic mechanisms include alterations in myocardial energetics and attenuation of fibrosis [ 5 ]. Several putative mechanisms to explain these cardioprotective effects have been proffered but not yet formally proven nor refuted.
For example, glycemic control with a similar reduction in HbA 1c with other pharmacotherapies such as DPP4is does not necessarily equate to comparable CV benefit. This is in contrast to SGLT2i CV outcome trials in which there is an early and clear-cut divergence of the event-free survival curves. Interestingly, enhanced glycemic control has been associated with attenuated platelet reactivity [ 20 ]. BMI and specifically overweight and obesity have been associated with increased platelet reactivity [ 23 ].
SGLT2i treatment is associated with an average 2-kg to 4-kg reduction of body weight [ 24 ]. Also, obesity can induce and exacerbate insulin resistance. Insulin antagonizes the effect of platelet agonists such as collagen, ADP, epinephrine, and platelet-activating factor PAF [ 25 ].
Thus, resistance by the platelet to the effects of insulin attenuates insulin-mediated antagonism of platelet activation and thereby promotes platelet reactivity. Oxidative stress accentuates platelet reactivity and induces endothelial dysfunction [ 30 , 31 , 32 ]. Superoxide can lead to intracellular calcium release and attenuates the biologic activity of nitric oxide [ 33 , 34 ].
Impaired endothelial function results in decreased prostacyclin and nitric oxide concentrations [ 35 ]. We postulate that SGLT2i-mediated attenuation in platelet reactivity occurs via the aforementioned multifaceted pathways of decreased hyperglycemia, dyslipidemia, obesity, insulin resistance, oxidative stress, inflammation, and endothelial dysfunction with the potential clinical sequelae of an overall reduction of MACE.
This pilot study was adequately powered for PD PRU outcomes and achieved its target enrollment of 20 patients. However, this study was not designed to evaluate clinical endpoints, and therefore, no safety or efficacy conclusions can be affirmed.
Composite testing with other platelet function assessment modalities such as flow cytometry and thromboelastography would have been informative; however, these are not currently available in Trinidad. Empagliflozin achieved a greater antiplatelet effect and led to significantly lower platelet reactivity than in Trinidadian patients with CAD and T2DM without empagliflozin.
This mechanistic pilot study can be clinically relevant because of an improved efficacy and safety profile. Das SR, et al. J Am Coll Cardiol. Zinman B, et al. N Engl J Med. Nassif ME, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.
SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Seecheran NA, et al. Open Heart. Seecheran N, et al. Cardiol Ther.
The effect of low-dose ticagrelor on platelet function profiles in patients with stable coronary artery disease in Trinidad: the TWIST pilot study. Tantry US, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding.
Schneider DJ. Factors contributing to increased platelet reactivity in people with diabetes. Diabetes Care. Ali A, et al. Diabetes Ther. Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose cotransporter 2 inhibitors. Clin Exp Pharmacol Physiol.
Extraglycemic effects of SGLT2 inhibitors: a review of the evidence. Diabetes Metab Syndr Obes. Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ratio in isolated platelet membranes from diabetic and control subjects. Thromb Haemost. Effects of increased concentrations of glucose on platelet reactivity in healthy subjects and in patients with and without diabetes mellitus.
Am J Cardiol. Assert R, et al. Regulation of protein kinase C by short term hyperglycaemia in human platelets in vivo and in vitro. Platelet function in patients with familial hypertriglyceridemia: evidence that platelet reactivity is modulated by apolipoprotein E content of very—low-density lipoprotein particles. Diabetes Vasc Dis Res. Scheen AJ. Diabetes Metab. Storgaard H, et al. PLoS One. Ranucci M, et al. Platelet reactivity in overweight and obese patients undergoing cardiac surgery.
Vasilakou D, et al. Ann Intern Med. Westerbacka J, et al. Inhibition of platelet-collagen interaction. Arterioscler Thromb Vasc Biol. Hammoudi N, et al.
Cardiovasc Drugs Ther. Xu L, et al.
Platelets Are at the Nexus of Vascular Diseases
The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases. For many years after its discovery in the s, the vascular endothelium was believed to be a mere inert, semipermeable barrier between circulating blood and underlying subendothelial tissues. Numerous subsequent studies have led to the current view of the endothelium as a dynamic heterogeneous and distributed organ with essential secretory, synthetic, metabolic, and immunologic functions [ 1 ]. In the presence of irritant stimuli, such as dyslipidemia [ 2 , 3 ], hypertension [ 4 , 5 , 6 , 7 ], and pro-inflammatory agents [ 8 , 9 , 10 , 11 ], the normal physiological functions of the arterial endothelium are adversely affected [ 12 , 13 ], starting a chain of molecular changes that leads to atherosclerosis and cardiovascular diseases CVDs , including coronary artery disease, carotid artery disease, peripheral artery disease, and ischemic stroke [ 14 , 15 , 16 ].
Diabetes both type-1 and type-2 affects millions of individuals worldwide. A major cause of death for individuals with diabetes is cardiovascular diseases, in part since both types of diabetes lead to physiological changes that affect haemostasis. Those changes include altered concentrations of coagulatory proteins, hyper-activation of platelets, changes in metal ion homeostasis, alterations in lipid metabolism leading to lipotoxicity in the heart and atherosclerosis , the presence of pro-coagulatory microparticles and endothelial dysfunction. In this review, we explore the different mechanisms by which diabetes leads to an increased risk of developing coagulatory disorders and how this differs between type-1 and type-2 diabetes. In , combined occurrences of type-1 diabetes mellitus T1DM and type-2 diabetes mellitus T2DM were estimated at million individuals worldwide [ 1 ]. This number is predicted to rise to million by [ 1 ].
The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 GSTM1 gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55—70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion ppb filtered air , 70 ppb, and ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. There were no effects of ozone on the three primary markers of systemic inflammation and a prothrombotic state: C-reactive protein, monocyte-platelet conjugates, and microparticle-associated tissue factor activity.
Although, effects of intensive glycemic control were well profound for prevention of micro-vascular complications as compared to macro-vascular.
Coagulatory Defects in Type-1 and Type-2 Diabetes
Metrics details. The incidence and prevalence of diabetes mellitus is rapidly increasing worldwide at an alarming rate. Besides affecting the ability of body to use glucose, it is associated with micro-vascular and macro-vascular complications. Augmented atherosclerosis is documented to be the key factor leading to vascular complications in T2DM patients. The metabolic milieu of T2DM, including insulin resistance, hyperglycemia and release of excess free fatty acids, along with other metabolic abnormalities affects vascular wall by a series of events including endothelial dysfunction, platelet hyperactivity, oxidative stress and low-grade inflammation.
Box , Al-Ahsa, Saudi Arabia. Box , Doha, Qatar. Microparticles MPs are small vesicles shed from the cytoplasmic membrane of healthy, activated, or apoptotic cells. Virtually, all cells can shed MPs, and therefore, they can be found in all body fluids, but also entrapped in tissues.
Diabetes mellitus is associated with an enhanced risk for cardiovascular disease and its prevalence is increasing. Diabetes induces metabolic stress on blood and vascular cells, promoting platelet activation and vascular dysfunction. The level of vascular cell activation can be measured by the number and phenotype of microparticles found in the circulation.