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Posts Tagged ‘SUNY Downstate Medical Center’

Stroke – Ten Big Factors, Heart Rate No Predictor of Second Stroke

Posted in Cardiac & Vascular Repair Tools Subsegment, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Medical and Population Genetics, Medical Devices R&D and Inventions, Pharmaceutical R&D Investment, Population Health Management, Nutrition and Phytochemistry, tagged , , , , , , on August 27, 2012| 4 Comments »

 

Reporter: Aviva Lev-Ari, PhD, RN

Big 10 Risk Factors for Stroke

It’s clear that strokes are a major cause of disability and death throughout the world. But many of the prime risk factors for stroke are within your power to change — something we have long known. A large international study published in the Lancet underscored how far prevention efforts could go. Collecting data from stroke patients and healthy individuals in 22 countries, it found that 10 largely modifiable risk factors account for 90 percent of the risk of stroke worldwide. That means there is much you can do to rein in your personal risk. Here are the Big 10: 

1. High blood pressure. This is the biggest contributor to strokes worldwide. The Lancet study estimated that blood pressure readings of 160/90 mm Hg or higher accounted for up to 52 percent of the “population-attributable risk” of stroke.

2. Sedentary lifestyle. In general, regular exercise is a good move for your cardiovascular health, as it helps lower blood pressure, regulate your weight, boost “good” high-density lipoprotein (HDL) cholesterol and prevent or manage type 2 diabetes. And there’s evidence that even moderate levels of physical activity can curb your risk of stroke.

3. Being “apple-shaped.” We often talk about excess pounds being a risk to your cardiovascular health, but it’s that middle-aged spread around the waist that may be particularly worrisome.

4. Smoking. If you are still a smoker, you need to work on quitting. In the Lancet study, there was no evidence that former smokers were at greater risk of stroke than people who’d never smoked — suggesting that the excess risk declines quickly after you quit.

5. Diet. Diet may be just as important as smoking habits. In particular, the Lancet study found, features of the traditional Mediterranean diet — namely, a high intake of fish and fruit — appeared protective against stroke.

6. Atrial fibrillation. This is the most common form of heart-rhythm disturbance, in which the upper chambers of the heart (atria) do not contract in a rhythmic pattern but instead quiver chaotically. If you have atrial fibrillation, it is critical that you take any anti-clotting medication or other drugs that your doctor has prescribed.

7. Cholesterol. Studies suggest that the relationship between cholesterol and stroke risk is complex. In theLancet study, total cholesterol levels were not associated with strokes, confirming epidemiological evidence, but higher levels of high-density lipoprotein (HDL, or “good”) cholesterol were linked to a lower risk of ischemic stroke.

8. Alcohol. Moderate drinking of alcohol was linked to a reduced risk of ischemic stroke, while any amount more than that was connected to an increased risk versus teetotaling.

9 & 10. Stress and depression. Both chronic stress (related to home or work life) and depression symptoms were linked to an increased risk of stroke. It’s not completely clear why; it could be because mental-health woes make it more difficult to stick to your healthy diet, exercise and medication regimen. Also unclear is whether depression therapy or stress-management classes can help lower your stroke risk.

Takeaway. The overall message here is that there are many steps you can take to help ward off a stroke. If you are not sure which of these risk factors apply to you or what you should be doing about them, talk with your doctor. It could make a substantial difference in the long run.

Posted in Hypertension and Stroke on August 7, 2012

ESC: Heart Rate No Predictor of Second Stroke

By Chris Kaiser, Cardiology Editor,MedPage Today

Published: August 27, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — In patients who had a stroke, a high resting heart rate was not associated with recurrent stroke, but was associated with cognitive and functional decline, according to a pooled analysis of the PRoFESS study.

Of the 20,165 patients evaluated, a high baseline heart rate — 77 bpm and greater — was not significantly associated with recurrent stroke or myocardial infarction (MI) compared with lower heart rates, reported Michael Böhm, MD, of the University of Saarland in Saar, Germany, and colleagues.

However, in patients with a recurrent stroke (n=1,627), a high heart rate had a negative impact on patients’ global disability scale according to the modified Rankin score at baseline and 3 months after the recurrent stroke, Böhm reported here at the European Society of Cardiology (ESC) meeting.

In addition, more patients with high heart rates had Mini-Mental State Examination (MMSE) scores indicative of a greater degree of cognitive decline (≤24) at 1 and 3 months (both were significant atP<0.0001), Böhm said.

“What is most striking is that at 3 months, 15% of those with a heart rate of 77 bpm or greater had signs of dementia,” he said during his presentation.

“This study is a landmark analysis and fills a major knowledge gap,” said study discussant Jeffrey Borer, MD, of SUNY Downstate Medical Center in Brooklyn.

“That heart rate doesn’t predict recurrent stroke, but does predict cognitive decline is a new finding,” he said.

He added that many studies have been conducted looking at heart rate, but none of them involved data because of a stroke. “Whether we can affect outcomes by lowering heart rate is not known and should be the next step in this research,” he said.

The initial PRoFESS (Prevention Regimen for Effectively Avoiding Second Stroke) trial found no evidence that aspirin and extended release dipyridamole were superior to clopidogrel (Plavix) or that telmisartan was superior to placebo to prevent recurrent stroke.

In this post hoc analysis, Böhm and colleagues included 20,165 patients enrolled from 35 countries. They were separated by heart rates, with the top three quintiles representing 71-76 bpm, 77-82 bpm and 82 or more bpm, respectively.

The mean age was 66 and less than half (36%) were women. Those with high heart rates tended to be younger, women, and less likely to drink or smoke.

They also tended to have more large cerebral artery involvement and higher baseline modified Rankin scores and NIH Stroke Scale scores, as well as worse baseline scores for self-care. In addition, there were fewer of them who took protective medications such as beta blockers, statins, and diuretics, Böhm said.

Compared with the lowest quintile, those in the top two quintiles had an increased risk of all-cause death (HR 1.42 and 174, respectively). The difference was significant at P<0.0001.

Patients in the top three quintiles were at an increased risk cardiovascular death (HR 1.39 for the third quintile, P<0.0001) and those in the fifth quintile had an increased risk for non-cardiovascular death (HR 1.66, P=0.0016).

“These findings identify a high-risk group of patients starting at a heart rate of 71 bpm that will die primarily from cardiovascular events,” Böhm said.

Surprisingly, heart rate did not affect the risk for recurrent stroke, MI, or new or worsening heart failure.

Even when researchers included blood pressure in the adjusted analysis, they found no change of risk, “indicating that the effects of heart rate on risk are independent of the blood pressure,” they wrote in the European Heart Journal, which published the study to coincide with the ESC meeting.

The study is limited because it relied only on baseline heart rate measurement, and perhaps variations in heart rate during the trial could explain the failure to predict strokes, Borer said.

Böhm also noted that the study is limited because it is a retrospective post hoc analyses of a randomized trial that did not randomize according to heart rate.

The PRoFESS study was funded by Boehringer Ingelheim.

Böhm reported relationships with AstraZeneca, Bayer AG, Boehringer Ingelheim, Novartis, Pfizer, sanofi-aventis, Servier, Adrian-Medtronic, Daiichi-Sankyo, MSD, AWD Dresden, and Berlin-Chemie. One co-author reported relationships with Boehringer Ingelheim, Lundbeck, Mitsubishi, Phagenesi, and ReNeuron. All other authors reported no conflicts of interest.

Borer reported a relationship with Servier.

 

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Nitric Oxide and Platelet Aggregation

Posted in Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, Nitric Oxide in Health and Disease, Pharmacotherapy of Cardiovascular Disease, tagged , , , , , , , , , , , , , on August 16, 2012| 13 Comments »

Author: Dr. Venkat S. Karra, Ph.D.

Platelets are a natural source of growth factors and they circulate in the blood. They are involved in hemostasis, leading to the formation of blood clots. Platelets, otherwise known as thrombocytes, are small, irregularly shaped clear cell fragments derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is 5 to 9 days. An abnormality or disease of the platelets leads to a condition called thrombocytopathy.

For example:
1. If the number of platelets is too low (called thrombocytopenia), excessive bleeding can occur.

Disorders leading to a reduced platelet count are:
Thrombocytopenia
Idiopathic thrombocytopenic purpura – also known as immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura
Drug-induced thrombocytopenic purpura (for example heparin-induced thrombocytopenia (HIT))
Gaucher’s disease
Aplastic anemia
Onyalai
Alloimmune disorders
Fetomaternal alloimmune thrombocytopenia

2. If the number of platelets is too high (called thrombocytosis), blood clots (thrombosis) can form. Such clots in the blood may obstruct blood vessels and result in events like stroke, myocardial infarction, pulmonary embolism or the blockage of blood vessels to other parts of the body (e.g., arms, legs).

Disorders featuring an elevated count are:
Thrombocytosis, including essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease).

3. Thrombasthenia is a condition in which a decrease in function of platelets is observed.

Disorders leading to platelet dysfunction or reduced count are:
HELLP syndrome
Hemolytic-uremic syndrome
Chemotherapy
Dengue

Platelets play a significant role in the repair and regeneration of connective tissues. They release a multitude of growth factors, which have been used as an adjunct to wound healing, include:

Platelet-derived growth factor (PDGF), a potent chemotactic agent,
TGF beta, which stimulates the deposition of extracellular matrix.
Fibroblast growth factor,
Insulin-like growth factor 1,
Platelet-derived epidermal growth factor,
Vascular endothelial growth factor.

As said earlier, the function of platelets is the maintenance of hemostasis (the opposite of hemostasis is hemorrhage). This is achieved primarily by the formation of thrombi. When a damage to the endothelium of blood vessels occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor which initiate the maintenance of hemostasis after injury.

Hemostasis has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a clot that seals the hole until tissues are repaired.

The platelets get activated when a damage occurs to the blood vessel and the platelets clump at the site of blood vessel injury as a protective mechanism – a process that precedes the formation of a blood clot. This is the case if there is a damage to the endothelium otherwise thrombus formation should be considered seriously and must be inhibited immediately.

Vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost during the injury to the blood vessel. In the second step – platelet plug formation – platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a “molecular glue”

Disorders of platelet adhesion or aggregation are:
Bernard-Soulier syndrome
Glanzmann’s thrombasthenia
Scott’s syndrome
von Willebrand disease
Hermansky-Pudlak Syndrome
Gray platelet syndrome

In normal hemostasis a thin layer of endothelial cells, that are lined with the inner surface of blood vessels, act to inhibit platelet activation by producing nitric oxide, endothelial-ADPase (which clears away the platelet activator, ADP – this activator otherwise can be blocked by the famous blockbuster clopidogrel), and PGI2 (also known as prostacyclin or eicosanoids, like PGD2, PGI2 is an inflammatory product that inhibits the aggregation of platelets). Intact blood vessels are central to moderating blood’s tendency to clot because the endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with
1. Nitric oxide (NO), and
2. Prostacyclin (PGI2) – a member of eicosanoids family.

In this post, nitric oxide role in inhibiting platelet aggregation will be presented. Similarly Interaction of NO and prostacyclin (PGI2) in vascular endothelium will be presented as a separate post.

Nitric oxide (NO) and its role in inhibiting platelet aggregation:

Nitric oxide (NO) is known as the ‘endothelium-derived relaxing factor’, or ‘EDRF’. The endothelium (inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. NO is biosynthesized endogenously from L-arginine, oxygen and NADPH by various nitric oxide synthase (NOS) enzymes. Nitric oxide is highly reactive and yet diffuses freely across membranes that makes it ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.

This is an important cellular signaling molecule involved in many physiological and pathological processes. It is a powerful vasodilator with a short half-life of a few seconds in the blood. Low levels of nitric oxide production are important in protecting organs such as the liver from ischemic damage. Nitric oxide is considered an antianginal drug as it causes vasodilation, which can help with ischemic pain, known as angina, by decreasing the cardiac workload. By dilating the veins, nitric oxide lowers arterial pressure and left ventricular filling pressure. This vasodilation does not decrease the volume of blood the heart pumps, but rather it decreases the force the heart muscle must exert to pump the same volume of blood.

Chronic expression of NO is associated with various carcinomas and inflammatory conditions including Type-1 diabetes, multiple sclerosis, arthritis and ulcerative colitis.

Endothelium-derived relaxing factor (EDRF), the best-characterized is nitric oxide (NO), is produced and released by the endothelium to promote smooth muscle relaxation. EDRF was discovered and characterized by Robert F. Furchgott, a winner of the Nobel Prize in Medicine in 1998 with his co-researchers Louis J. Ignarro and Ferid Murad.

According to Furchgott’s website at SUNY Downstate Medical Center, “…we are investigating whether the endothelium-derived relaxing factor (EDRF) is simply nitric oxide or a mixture of substances”.

Although there is strong evidence that nitric oxide elicits vasodilation, there is some evidence tying this effect to neuronal rather than endothelial reactions. http://www.nature.com/jhh/journal/v15/n4/abs/1001165a.html.

The article says that “The possibility that neuronal rather than endothelial production of NO might play a significant role in the aetiology of essential hypertension is a promising area for future human research”.

Mechanism of Platelet Aggregation:

Platelets aggregate, or clump together, using fibrinogen and von Willebrand factor (vWF) as a connecting agent. The most abundant platelet aggregation receptor is glycoprotein IIb/IIIa (gpIIb/IIIa) which is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin, and vWF. Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).

Activated platelets will adhere, via glycoprotein (GP) Ia, to the collagen that is exposed by endothelial damage. Aggregation and adhesion act together to form the platelet plug. Myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. Platelet aggregation is stimulated by ADP, thromboxane, and α2 receptor-activation, and further enhanced by exogenous administration of anabolic steroids.

In an injury to the blood vessel, once the blood clot takes control of the bleeding, the aggregated platelets help the healing process by secreting chemicals that promote the invasion of fibroblasts from surrounding connective tissue into the wounded area to completely heal the wound or form a scar. The obstructing clot is slowly dissolved by the fibrinolytic enzyme, plasmin, and the platelets are cleared by phagocytosis.

Possible usefulness of measuring GP IIb-IIIa content as a marker of increased platelet reactivity is discussed in the following very recent (2011) reveiw article: “Glycoprotein IIb-IIIa content and platelet aggregation in healthy volunteers and patients with acute coronary syndrome”. http://www.ncbi.nlm.nih.gov/pubmed/21329420

Further readings:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134593/?tool=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/2620689

http://pharmaceuticalintelligence.com/2012/07/25/nitric-oxide-production-in-systemic-sclerosis/

http://pharmaceuticalintelligence.com/2012/08/10/nitric-oxide-chemistry-and-function/

http://pharmaceuticalintelligence.com/2012/08/05/nitric-oxide-a-short-historic-perspective-7/

http://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

http://pharmaceuticalintelligence.com/2012/07/16/nitric-oxide-in-bone-metabolism/

http://pharmaceuticalintelligence.com/2012/06/22/bone-remodelling-in-a-nutshell/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717403/?tool=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/7605019

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