Hypertension is one of the most important risk factors for cerebral small vessel disease (CSVD). In fact, the majority (70-80%) of all patients had a history of chronic hypertension. CSVD not just affects small arterioles, but also capillaries and veins in the brain. Nearly half of dementia is believed to be caused by CSVD. The hallmark clinical definition of CSVD is white matter lesions found in MRI. However, the link between blood vessel and white matter injuries is not well understood. In this study, the authors investigated an alternative mechanism of actions of CSVD. They found that blood-brain barrier dysfunction, caused by endothelial dysfunction in brain blood vessels, may have important roles in the progression of CSVD. One of the their most important findings was using stroke-prone spontaneous hypertensive rats (SHR-SP), a well-known model of CSVD, that dysfunctional endothelial cells secreted heat shock protein 90, which blocked oligodendroglial differentiation, leading to impaired myelination. As myelination is important structurally and functionally in white matter, impaired myelination may lead to white matter lesions, dementia, and even motor dysfunction, such as gait and balance problems in CSVD. Blood brain barrier disruption and then leakage of unwanted plasma components, including immune cells, is believed to be an early phenomenon of CSVD. In agreement to this idea, the authors found that blood brain barrier dysfunction was found in patients without symptoms of CSVD and rat model of CSVD. The authors further investigated if reversal of endothelial dysfunction would alleviate CSVD. They used drugs reported to reduce endothelial dysfunction, including simvastatin, a cholesterol-lowering drug; perindopril, an angiotensin-converting enzyme inhibitor; or cilostazol, a phosphodiesterase inhibitor and found that these drugs caused less myelin rarefaction in the white matter, supporting the idea that early blood brain barrier breakdown may be an important cause of the progression of CSVD. The investigators further identified a mutation of Atp11b gene that caused endothelial dysfunction in rat model of CSVD. Atp11b is associated with white matter burden and therefore may be an upstream mediator of CSVD. This study provided important novel information concerning a genetic and early component of CSVD. Early endothelial dysfunction and its treatment may provide a novel therapeutic target for the prevention of CSVD in individuals with chronic hypertension.
Cerebral small vessel disease (CSVD) is a chronic disease that affects small arterioles, capillaries, and veins in the brain. CSVD leads to stroke, hemorrhage, and dementia. Hypertension, in addition to aging, is the most important risk factors for CSVD. Sometimes, researchers identify this type as hypertensive CSVD. Despite this, the protective or preventive effects of anti-hypertensive medications on hypertensive CSVD remain not well understood. This study from van Middelaar et al reviewed 4 clinical trials with 1369 participants on hypertensive medications on CSVD. They found that patients with anti-hypertensive medication has less progression in white matter lesions (hyperintensities in MRI) but has no effects on brain atrophy. There were no clinical trials concerning other endpoints, such as lacunes, microbleeds, enlarged perivascular spaces in CSVD. Therefore, anti-hypertensive medications may only be partly effective in treating CSVD. Anti-hypertensive drugs may be effective in preventing CSVD, if starts in the early stages of hypertension.
Collateral perfusion during acute ischemic stroke has been preclinically and clinically shown to be an important predictor of stroke outcomes. Therefore, one would expect that increased collateral perfusion would reduce ischemic injury and improve stroke outcomes. This study explored this possibility by using 4 different therapeutic strategies to increase collateral perfusion in rats having middle cerebral artery occlusion. They found that all 4 strategies improved collateral perfusion. However, only polygeline (increased intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (cerebral blood flow diversion) improved infarct volume. Moreover, only polygeline and head down tilt improved neuroscore. These results showed that improved collateral perfusion may or may not improves stroke outcomes. Other factors, such as whether the drug itself is neuroprotective or affect other hemodynamic parameters, such as heart rate or blood pressure, may also play a role in whether or not the strategy is effective on improving stroke outcome. This study also show that pressor therapy by phenylephrine may not be significantly beneficial in improving stroke outcomes.
Ischemic preconditioning describes a treatment regimen for ischemic stroke that includes brief, repetitive mild ischemic insults to protect the tissue from severe ischemic injury. Ischemic preconditioning has been introduced for more 30 years and has been extensively studied. Interestingly, ischemic preconditioning even in remote tissue, such as limbs, can be beneficial for ischemic stroke and is named remote ischemic preconditioning. Remote ischemic preconditioning has been shown to be neuroprotective that may be related to increased cerebral blood flow, but whether it impacts collateral perfusion is unknown. Ma et al in this study showed that in control rats, collateral blood vessels dilated to increase blood flow initially (measured by open cranial window, laser speckle contrast imaging and two photon laser scanning microscopy), followed by progressive vasoconstriction 60 minutes after stroke onset. In contrast, remote ischemic preconditioning (by bilateral occlusion of the femoral arteries for 3 cycles, 15-minute on/off cycles) prevented the progressive vasoconstriction and significantly reduced ischemic injury (measured by TTC staining) 6 hours after stroke onset. These results provided strong evidence that remote ischemic preconditioning increased collateral blood flow during middle cerebral artery occlusion by a mechanism involving sustained vasodilation in collateral blood vessels. This increased collateral blood flow from the anterior cerebral artery may be able to sustain the penumbra (area that neurons are injured, viable, and therefore salvageable). A recent clinical trial used remote ischemic preconditioning together with tPA in the ambulance. The idea is to increase collateral blood flow and sustain the penumbra (buying time) until further diagnosis and treatment when arrived at the hospital. They found that remote ischemic preconditioning is neuroprotective. Therefore, in addition to preclinical animal studies, remote ischemic preconditioning was shown to be feasible and potentially beneficial in humans. It would be nice if this study also showed whether remote ischemic preconditioning is protective against ischemic injury after a longer period, say 24 hours to show the final infarction. Also, this study did not investigate or discuss any mechanism on how remote ischemic preconditioning works. Previous studies show that the activation of KATP channels or increased nitric oxide production may be the underlying mechanisms for remote ischemic preconditioning. More follow-up studies should be performed to completely understand remote ischemic preconditioning.
TENSION (efficacy and safety of ThrombEctomy iN Stroke with extended leSION and extended time window: a randomized, controlled trial) is a European clinical trial aiming at filling an important knowledge gap: whether endovascular thrombectomy is beneficial in stroke patients who have large lesions and long time after symptom onset. Many previous clinical trials excluded patients with large lesions area because of less or no beneficial effects of thrombectomy. The same reason applied to excluding patients with extended onset time. In fact, only about 5 % of patients were treated after 6 hour of onset time. This trial includes patients with an ASPECTS 3-5 (a scoring system where 10 is no lesions and 0 is the largest lesions) in middle cerebral artery occlusion. Therefore, the trial picks patients who are normally excluded from treatment (ASPECTS 0-4). Primary endpoint is outcome after 90 days, and another follow-up at 12 months. This methodology paper was published in January 2019 and therefore we are all excited to know the outcomes soon.
Hancock and Frostig used a well-known rat model of hypertension (spontaneous hypertensive rats) to study collateral perfusion during M1 permanent middle cerebral artery occlusion. The significance of this study was the use of hypertensive animals to study stroke. The majority of stroke patients are hypertensive and hypertension is one of the most important risk factors for stroke, but the majority of stroke animal models are young male normotensive animals. The authors used a complex open cranial window technique to visualize blood vessels on the surface of the brain. They also used laser spackle to identify the area of increased blood flow, particular where the collateral perfusion occurs. These are the strengths of this study. In addition, the authors used whisker stimulation as a treatment to increase retrograde collateral flow to reduce infarct volume. Whisker stimulation is supposed to increase blood flow to the brain cortex because of neuronal activation. Because of this permanent occlusion model, there was only collateral flow to the penumbra (area that neurons suffer ischemic injury, but still viable and salvable) and no flow from the middle cerebral artery. This whisker stimulation completely removed any infarct in normotensive rats, although I am a bit surprise there was no visual damage at all after 24 hours of ischemia. Whisker stimulation failed to increase collateral flow and reduce infarct volume in hypertensive rats. This may be due to hypertension-induced inward remodeling and endothelial dysfunction, leading to reduced dilation of collaterals to increase blood flow. Results from this study also confirms a few previous studies showing that collaterals are more constricted and may not be dilated as well as normotensive animals when increased blood flow is needed. Previous studies also showed that the number of collaterals were not different between normotensive and hypertensive rats, suggesting that reduced collateral flow may not be due to reduced collateral numbers. This study significantly adds to growing literature on preclinical studies using a variety of animals, including females, animal model of comorbidities, such as hypertension and diabetes.
This report by Khan et al filled an important gap in clinical treatment of high blood pressure. Lower blood pressure in hypertensive patients is essential to lower the risk of cardiovascular diseases (events). However, many healthcare professionals are very careful about lower the systolic pressure to lower than 120 mmHg, as the guideline recommends. This is because aggressively lowering systolic pressure may also lower diastolic pressure to a dangerous level that would increase cardiovascular events. However, this threshold of diastolic pressure is unknown until the article published. This study used a relatively large (n = 9,000) sample population in SPRINT (Systolic Blood Pressure Intervention Trial). The authors found that diastolic pressure lower than 55 mmHg is associated with higher risk of ischemic heart events, such as myocardial infarction and heart failure in patients with or without cardiovascular diseases when compared to patients who had diastolic pressures between 55 to 90 mmHg. Diastolic pressure at 55 mmHg may also be at the edge of the lower threshold in cerebral blood flow autoregulation that may cause ischemic brain events, such as acute ischemic stroke. Therefore, healthcare professionals now have a threshold diastolic blood pressure to look for when aggressively lower blood pressure in patients.
I have a couple of papers published in Journal of Applied Physiology. In my opinion, Journal of Applied Physiology is a good Journal. Journal of Applied Physiology publishes many Sports Science article and therefore, is ranked high in Sports Science. I like Journal of Applied Physiology because they do not require your article to meet their journal format during submission. The editorial office will edit for you if your article is accepted. I also like their generous 6-month time for revision after a first decision. Journal of Applied Physiology may also refer your article to Physiological Report, a newer open access online only journal of the American Physiological Society. This is nice feature to give you a second chance to publish in a Journal published by the Society. However, the review process of Journal of Applied Physiology can take a long time, up to 2 months from my own experience.
Endothelial nitric oxide synthase (eNOS) plays an important role in the health of blood vessels by producing nitric oxide (NO). Two eNOS needs to be coupled, forming a dimer to be functional. Two tetrahydrobiopterin (BH4) bind to each eNOS dimer for electron transfer during l-arginine oxidation. When BH4 is reduced, such as during hypertension, eNOS becomes uncoupled, and superoxide, rather than NO, is produced. Superoxide is very unstable and harmful to the blood vessel. This study by Chuaiphichai et al. used mice deficient in BH4 (as a form of deficient in GTP cyclohydrolase 1 (Gch1-/-), which is essential for the production of BH4) to study the effect of angiotensin II on blood vessels. Angiotensin II, being an effector molecule of the renin-angiotensin system, is regulated in hypertension and causes many adverse effects on blood vessels. The authors found that Gch1-/- mice had reduced levels of BH4, NOx, and increased H2O2, which is considered an oxidative stress. They also found that angiotensin II infusion at a low, sub-pressor dose increased blood pressure in Gch1-/- but not wildtype (WT) mice. In addition, mesenteric artery isolated from Gch1-/- mice had increased constriction to U46619 and reduced dilation to acetylcholine, suggesting endothelial dysfunction. Moreover, increased media thickness, also known as wall hypertrophy, was found in both mesenteric artery and aorta from Gch1-/- mice. These were not found in WT mice. Furthermore, Gch1-/- mice had increased incidence of abdominal aortic aneurysm when compared to WT mice. These results suggest that the presence of BH4 and functional eNOS may be protective against Ang II-mediated changes in blood vessels. This effect may be due to a combination of increased NO production and reduced oxidative stress. This study is impactful because it has done using mesenteric artery, a resistance vessel that controls blood flow and blood pressure. It would be nice to see this group continue their study in other vascular beds, particularly the brain and renal circulations because hypertension (and angiotensin II) is a risk factor for disorders in these two organs.
FASEB Journal is the official journal of the Federation of American Societies for Experimental Biology. Being a good ranking Biology journal, the scope of this Journal is wide. The Journal used to require an "Intention to Submit" before you can submit the full text, but not the case anymore. My own experience was that the review process was efficient, between 3-4 weeks. The editorial office was also very efficient to produce the copy-edited version for final proof. From final proof to publish online was very fast too, within 2 weeks. However, the publication cost is quite high, at $199/published page. The length of the Abstract is rather tight, limits at 200 words.
Journal of Cerebral Blood Flow and Metabolism is one of the better specialized Journal in the brain circulation. This Journal publishes both clinical and basic science research and is quite competitive. Many clinical papers are about brain imaging, such as magnetic resonance imaging. The word limit for Original Articles are 6,000 words excluding references, so you have plenty of room to write. Be aware that the Abstract is rather short, limits at 200 words. You must have an ORCID to submit your manuscript as a corresponding author. You have to strictly adhere to reporting guidelines, including CONSORT and PRISMA for clinical studies or ARRIVE for animal studies. Continuous variables must be reported in dot plot and not bar charts because the distribution of the data is not shown. Standard deviation, but not standard errors, must be used for reporting data. Reviewing process is similar to other Journals. Two to three expert reviewers are invited and the process takes about 4-6 weeks. Be aware that there is page charge, $97/page for members of the International Society of Cerebral Blood Flow and Metabolism and $130/page for non-members.
This study by Ma et al. filled an important gap of knowledge in the stroke field. The majority of stroke research in animal models has been done in young adult male animals, yet the stroke population is disproportionately elderly people. In fact, the average first-ever stroke in men and women are both in their 70s. Therefore, researches in stroke in aged animals are very important. However, to date, studies using aged animals are still rare, partly because first, keeping animals long until aged is very expensive. Second, many aged animals do not survive the stroke that make studying these animals for neuronal injury, behavioral changes, and cognitive deficits more difficult. This study used aged SD rats at 16-18-month old. Because the life span for SD rats is about 24 months, making them appropriate for the study. The authors used a cranial window, where the skull on the top of the head is removed to expose blood vessels for cerebral blood flow monitoring. Cerebral blood flow was measured by two rather new technologies, laser speckle and two-photon laser scanning microscopy. They induced stroke by distal middle cerebral artery occlusion together with bilateral carotid artery occlusion. I believe the investigator use this double occlusion method because they wanted to have a larger drop in cerebral blood flow. They found collateral failure in aged rats during stroke, including reduced collateral vessel diameter and cerebral blood flow when compared to young rats. This collateral failure may be responsible for increased infarct volume found in aged rats after 6 hours of occlusion. Other factors in aging, including increased oxidative stress and inflammation may also play a role. Collateral failure may be due to reduced ability to dilate in collaterals, likely caused by reduced endothelial nitric oxide synthase production and structural inward remodeling in aging. The authors also pointed out the possibility of increased intracranial pressure that was further increase in aged rats during stroke. Increased intracranial pressure decreases perfusion pressure of the brain, but this study did not experimentally address this possibility. The authors did not study reperfusion and therefore, changes in cerebral blood flow dynamics during reperfusion and final infarct were not measured in these rats. Overall, this study provided much needed, valuable information concerning cerebral blood flow dynamics in the collateral circulation during acute ischemic stroke in aging.
I have published 3 articles in Frontiers in Physiology and currently a Review Editor. The Journal is relatively new and is open access. Despite this, the Journal has a respectable impact factor at 3.2. Frontier in Physiology separates into many sub-specialty, therefore, you can find your audience easily. For example, I publish in Frontiers in Vascular Physiology, where I found many researches related to vascular biology and diseases. The review process is a bit different from traditional one. Normally 2 to 3 reviewers are asked to review your paper. Manuscripts are seldom being rejected. Authors and Reviewers are engaged in a forum to send questions and answers back and forth until all Reviewers are satisfied with Authors' response. When the article is published, the Reviewers' name and affiliation are published as well. Therefore, authors will eventually find out who reviewed their manuscript. Before you consider submitting to this Journal, be aware that because it is open access, the cost of publication is a bit high. The Journal do provide a fee waiver program that authors can apply.
Hypertension is led by two well-respected scholars, the Editor-in-Chief Dr. Anna Dominiczak and Deputy Editor Dr. Rhian Touyz, both at University of Glasgow. Hypertension is one of the best specialized journal for studies related to hypertension, both clinical and basic science studies. Generally, two to three reviewers will be asked to review your manuscript. The first decision is normally fast, about 4-5 weeks. The Original Article in Hypertension has a 6,000-word limit, including texts, figures, tables, and references. Therefore, you have to write concisely and sometimes put less important results to supplemental data. The Journal also asks all authors to write a special section call "Novelty and Significance" that will publish at the end of the article. This is a short summary of your study that includes 3 sections: What is New?; What is Relevant?, and Summary.
A few more things I want to mention about the Stroke journal. If your manuscript is reporting a basic science study, you will need a "Visual Abstract". A photo/diagram to summarize your study for the journal website. Also, from January 2020, you will need to obtain an Open Researcher and Contributor Identifier (ORCID) in order to submit to Stroke as a corresponding author. I am an ad hoc reviewer for Stroke so if you have questions concerning submission to this journal, I am more than happy to share with you my experience.
Article