Showing papers by "J. David Spence published in 2018"

Hypertension in Blacks: Individualized Therapy Based on Renin/Aldosterone Phenotyping.

Abstract: The prevalence of hypertension in blacks is higher than in other groups. The following is quoted from the 2015 statistical report of the American Heart Association1: “In 2009 to 2012, the age-adjusted prevalence of hypertension was 44.9% and 46.1% among non-Hispanic black men and women, respectively; 32.9% and 30.1% among non-Hispanic white men and women, respectively; and 29.6% and 29.9% among Hispanic men and women, respectively.” In the national REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke)2, among 27 744 participants followed up for 4.4 years (2003–2010), the overall age- and sex-adjusted black/white incidence rate ratio for ischemic stroke was 1.51, but for ages 45 to 54 years, it was 4.02, whereas for those ≥85 years of age, it was 0.86. This suggests that those who survived to 85 years of age did not have resistant hypertension. Among blacks, compared with whites, the relative risk of intracranial atherosclerotic stroke was 5.85; of extracranial atherosclerotic stroke, 3.18; of lacunar stroke, 3.09; and of cardioembolic stroke, 1.58.3 Similarly, Markus et al4 reported that in South London, United Kingdom, the relative risk of stroke because of small vessel disease in black patients was 2.94 (95% confidence interval, 1.97–4.39; P 20 years of age, the age-adjusted relative risk of intracerebral hemorrhage among blacks compared with white patients was 2.4 for men and 3.2 for women.5 In the Northern Kentucky study, “The greatest excess risk of ICH in blacks compared with whites was found among young to middle-aged (35 to 54 years) persons with brain stem (RR, 9.8; 95% CI, 4.2 to 23.0) and deep cerebral (RR, 4.5; 95% CI, 3.0 to 6.8) hemorrhage.”6 Strokes due to small vessel disease …

How to identify which patients with asymptomatic carotid stenosis could benefit from endarterectomy or stenting

Abstract: Offering routine carotid endarterectomy (CEA) or carotid artery stenting (CAS) to patients with asymptomatic carotid artery stenosis (ACS) is no longer considered as the optimal management of these patients. Equally suboptimal, however, is the policy of offering only best medical treatment (BMT) to all patients with ACS and not considering any of them for prophylactic CEA. In the last few years, there have been many studies aiming to identify reliable predictors of future cerebrovascular events that would allow the identification of patients with high-risk ACS and offer a prophylactic carotid intervention only to these patients to prevent them from becoming symptomatic. All patients with ACS should receive BMT. The present article will summarise the evidence suggesting ways to identify these high-risk asymptomatic individuals, namely: (1) microemboli detection on transcranial Doppler, (2) plaque echolucency on Duplex ultrasound, (3) progression in the severity of ACS, (4) silent embolic infarcts on brain CT/MRI, (5) reduced cerebrovascular reserve, (6) increased size of juxtaluminal hypoechoic area, (7) identification of intraplaque haemorrhage using MRI and (8) carotid ulceration. The evidence suggests that approximately 10%–15% of patents with asymptomatic stenosis might benefit from intervention; this will become more clear after publication of ongoing studies comparing stenting or endarterectomy with best medical therapy. In the meantime, no patient should be offered intervention unless there is evidence of high risk of ipsilateral stroke, from modalities such as those discussed here.

Diet for stroke prevention

Abstract: Lifestyle is far more important than most physicians suppose. Dietary changes in China that have resulted from increased prosperity are probably responsible for a marked rise in coronary risk in the past several decades, accelerating in recent years. Intake of meat and eggs has increased, while intake of fruits, vegetables and whole grains has decreased. Between 2003 and 2013, coronary mortality in China increased 213%, while stroke mortality increased by 26.6%. Besides a high content of cholesterol, meat (particularly red meat) contains carnitine, while egg yolks contain phosphatidylcholine. Both are converted by the intestinal microbiome to trimethylamine, in turn oxidised in the liver to trimethylamine n-oxide (TMAO). TMAO causes atherosclerosis in animal models, and in patients referred for coronary angiography high levels after a test dose of two hard-boiled eggs predicted increased cardiovascular risk. The strongest evidence for dietary prevention of stroke and myocardial infarction is with the Mediterranean diet from Crete, a nearly vegetarian diet that is high in beneficial oils, whole grains, fruits, vegetables and legumes. Persons at risk of stroke should avoid egg yolk, limit intake of red meat and consume a diet similar to the Mediterranean diet. A crucial issue for stroke prevention in China is reduction of sodium intake. Dietary changes, although difficult to implement, represent an important opportunity to prevent stroke and have the potential to reverse the trend of increased cardiovascular risk in China.

Mediterranean Diet Score: Associations with Metabolic Products of the Intestinal Microbiome, Carotid Plaque Burden, and Renal Function

Abstract: Metabolic products of the intestinal microbiome such as trimethylamine N-oxide (TMAO) that accumulate in renal failure (gut-derived uremic toxins, GDUTs) affect atherosclerosis and increase cardiovascular risk. We hypothesized that patients on a Mediterranean diet and those consuming lower amounts of dietary precursors would have lower levels of GDUTs. Patients attending vascular prevention clinics completed a Harvard Food Frequency Questionnaire (FFQ) and had plasma levels of TMAO, p-cresylsulfate, hippuric acid, indoxyl sulfate, p-cresyl glucuronide, phenyl acetyl glutamine, and phenyl sulfate measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Carotid plaque burden was measured by ultrasound; CKD-Epi equations were used to estimate the glomerular filtration rate. In total, 276 patients completed the study. Even moderate renal function significantly increased plasma GDUTs, which were significantly associated with higher carotid plaque burden. There was no significant difference in plasma levels of any GDUT associated with a Mediterranean diet score or with intake of dietary precursors. In omnivorous patients with vascular disease, the intake of dietary precursors of intestinal metabolites or adherence to a Mediterranean diet did not change plasma GDUT. Approaches other than diet, such as probiotics and repopulation of the intestinal microbiome, may be required to mitigate the adverse effects of GDUTs.

Cardioembolic stroke: everything has changed

Abstract: Historically, because of the difficulty of using warfarin safely and effectively, many patients with cardioembolic stroke who should have been anticoagulated were instead given ineffective antiplatelet therapy (or no antithrombotic therapy). With the arrival of new oral anticoagulants that are not significantly more likely than aspirin to cause severe haemorrhage, everything has changed. Because antiplatelet agents are much less effective in preventing cardioembolic stroke, it is now more prudent to anticoagulate patients in whom cardioembolic stroke is strongly suspected. Recent advances include the recognition that intermittent atrial fibrillation is better detected with more prolonged monitoring of the cardiac rhythm, and that percutaneous closure of patent foramen ovale (PFO) may reduce the risk of stroke. However, because in most patients with stroke and PFO the PFO is incidental, this should be reserved for patients in whom paradoxical embolism is likely. A high shunt grade on transcranial Doppler saline studies, and clinical clues to paradoxical embolism, can help in appropriate selection of patients for percutaneous closure. For patients with atrial fibrillation who cannot be anticoagulated, ablation of the left atrial appendage is an emerging option. It is also increasingly recognised that high levels of homocysteine, often due to undiagnosed metabolic deficiency of vitamin B12, markedly increase the risk of stroke in atrial fibrillation, and that B vitamins (folic acid and B12) do prevent stroke by lowering homocysteine. However, with regard to B12, methylcobalamin should probably be used instead of cyanocobalamin. Many important considerations for judicious application of therapies to prevent cardioembolic stroke are discussed.

The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension.

Abstract: TO THE EDITOR: Brown and colleagues (1) report that 46% of study participants in MESA (Multi-Ethnic Study of Atherosclerosis) had markedly suppressed plasma renin activity, which was associated with a higher likelihood of subsequent hypertension. This finding was more common in black participants. The authors focused on primary aldosteronism (PA); neither their article nor the accompanying editorial mentioned Liddle syndrome or its variants. Primary aldosteronism, probably mainly due to bilateral adrenocortical hyperplasia, is certainly more common in black persons. In an African study of resistant hypertension, we found 14 nonsynonymous variants of aldosterone synthase (CYP11B2); 9 of 14 variants were found in all 9 patients sequenced (2). Liddle syndrome, due to variants of the epithelial sodium channel (SCNN1B), is far more common than most physicians suppose. It causes salt and water retention and loss of potassium, with suppression of both plasma renin activity and aldosterone. One variant was found in 5% of black persons with hypertension (mainly from the Caribbean) in London; another was found in 20% of the Khoisan persons of the Kalahari; 9% of Nguni/Zulu persons in South Africa; and 6% of persons with hypertension in Cape Town, South Africa (3). Besides actual variants of SCNN1B, variants of several genes affect the function of the epithelial sodium channel; these include CYP4A11, GRK, NEDD4L, NPPA, and UMOD (2). We found many variants of all but CYP4A11 among participants in our African study (2). Such variants would all result in a Liddle phenotype (low levels of renin and aldosterone). This phenotype was present in 6% of patients attending a hypertension clinic in Louisiana (4). Why does this matter? Because amiloride, a blocker of the epithelial sodium channel, is the specific therapy for Liddle syndrome. In our African study, patients with uncontrolled hypertension were allocated to usual care (UC) versus physiologically individualized therapy (PhysRx) based on plasma renin activity and aldosterone levels (5). The strategy was ineffective in Kenya, where amiloride was not available; however, in the Nigerian and South African sites, 15% of UC versus 78.6% of PhysRx participants achieved systolic control (P< 0.001), 45% of UC versus 71.4% of PhysRx participants achieved diastolic control (P= 0.040), and 15% of UC versus 66.7% of PhysRx participants achieved both (P< 0.001). The greatest change in medication was the use of amiloride. At baseline, 8.3% of UC and 8.6% of PhysRx participants were receiving this agent (P= 0.64); at the end of the study, 2.8% of UC versus 19% of PhysRx participants did so (P= 0.020) (5). Knowing how many MESA participants had a Liddle phenotype, how many of those became hypertensive, and how many were black would be of great interest.

Controlling resistant hypertension

Abstract: Resistant hypertension (failure to achieve target blood pressures with three or more antihypertensive drugs including a diuretic) is an important and preventable cause of stroke. Hypertension is highly prevalent in China (>60% of persons above age 65), and only ~6% of hypertensives in China are controlled to target levels. Most strokes occur among persons with resistant hypertension; approximately half of strokes could be prevented by blood pressure control. Reasons for uncontrolled hypertension include (1) non-compliance; (2) consumption of substances that aggravated hypertension, such as excess salt, alcohol, licorice, decongestants and oral contraceptives; (3) therapeutic inertia (failure to intensify therapy when target blood pressures are not achieved); and (4) diagnostic inertia (failure to investigate the cause of resistant hypertension). In China, an additional factor is lack of availability of appropriate antihypertensive therapy in many healthcare settings. Sodium restriction in combination with a diet similar to the Cretan Mediterranean or the DASH (Dietary Approaches to Stop Hypertension) diet can lower blood pressure in proportion to the severity of hypertension. Physiologically individualised therapy for hypertension based on phenotyping by plasma renin activity and aldosterone can markedly improve blood pressure control. Renal hypertension (high renin/high aldosterone) is best treated with angiotensin receptor antagonists; primary aldosteronism (low renin/high aldosterone) is best treated with aldosterone antagonists (spironolactone or eplerenone); and hypertension due to overactivity of the renal epithelial sodium channel (low renin/low aldosterone; Liddle phenotype) is best treated with amiloride. The latter is far more common than most physicians suppose.

Effect of wine on carotid atherosclerosis in type 2 diabetes: a 2-year randomized controlled trial

Abstract: The progression of carotid-plaque volume in patients with type 2 diabetes is common. Previous observational studies showed an association between moderate alcohol and reduced risk of coronary disease. We examined whether consuming moderate wine affects the progression of carotid atherosclerosis. In the CASCADE (CArdiovaSCulAr Diabetes and Ethanol), a 2-year randomized controlled trial, we randomized abstainers with type 2 diabetes were to drink 150 ml of either red wine, white wine, or water, provided for 2 years. In addition, groups were guided to maintain a Mediterranean diet. We followed 2-year changes in carotid total plaque volume (carotid-TPV) and carotid vessel wall volume (carotid-VWV), using three-dimensional ultrasound. Carotid images were available from 174 of the 224 CASCADE participants (67% men; age = 59 yr; HbA1C = 6.8%). Forty-five percent had detectable plaque at baseline. After 2 years, no significant progression in carotid-TPV was observed (water, −1.4 (17.0) mm3, CI (−2.7, 5.5), white-wine, −1.2 (16.9) mm3, CI (−3.8, 6.2), red wine, −1.3 (17.6) mm3, CI (−3.4, 6.0; p = 0.9 between groups)). In post hoc analysis, we divided the 78 participants with detectable baseline carotid plaque into tertiles. Those with the higher baseline plaque burden, whom were assigned to drink wine, reduced their plaque volume significantly after 2 years, as compared to baseline. Two-year reductions in Apo(B)/Apo(A) ratio(s) were independently associated with regression in carotid-TPV (β = 0.4; p < 0.001). Two-year decreases in systolic blood pressure were independently associated with regression in carotid-VWV (β = 0.2; p = 0.005). No progression in carotid-TPV was observed. In subgroup analyses, those with the greatest plaque burden assigned to drink wine may have had a small regression of plaque burden

Accuracy of Cardiovascular Risk Prediction Varies by Neighborhood Socioeconomic Position.

Abstract: TO THE EDITOR: Dalton and colleagues (1) found a greater underestimation of cardiovascular risk among persons in the most economically disadvantaged neighborhoods. As would be expected, the prevalence of smoking was highest in this population (28.4%) and lowest in the most affluent neighborhoods (9%). This gradient was the most striking among the risk factors and may largely account for the higher prevalence of coronary artery disease and peripheral vascular disease among the most disadvantaged persons. Although the model adjusted for smoking, it did not account for passive smoking (which is understandable considering that this element is difficult to assess). Because there are far more smokers in disadvantaged neighborhoods, it is probable that economically disadvantaged persons would also have more exposure to passive smoke. Bonita and associates reported a 6-fold increase in stroke risk in smokers and a 1.8-fold increase among persons passively exposed to smoke (2). Perhaps at least part of the underestimation of risk may be related to passive smoking. The other major factor that (also understandably) was not assessed was diet. The 2015 American Heart Association statistical report (3) noted that only 0.1% of persons in the United States consume a healthy diet and only 8.3% consume a somewhat healthy diet. It seems likely that there would be a similar socioeconomic gradient of healthy diet scores.

Advances in Stroke Prevention.

Abstract: There have been recent advances in stroke prevention in nutrition, blood pressure control, antiplatelet therapy, anticoagulation, identification of high-risk asymptomatic carotid stenosis, and percutaneous closure of patent foramen ovale. There is evidence that the Mediterranean diet significantly reduces the risk of stroke and that B vitamins lower homocysteine, thus preventing stroke. The benefit of B vitamins to lower homocysteine was masked by harm from cyanocobalamin among study participants with impaired renal function; we should be using methylcobalamin instead of cyanocobalamin. Blood pressure control can be markedly improved by individualized therapy based on phenotyping by plasma renin and aldosterone. Loss of function mutations of CYP2D19 impair activation of clopidogrel and limits its efficacy; ticagrelor can avoid this problem. New oral anticoagulants that are not significantly more likely than aspirin to cause severe bleeding, and prolonged monitoring for atrial fibrillation (AF), have revolutionized the prevention of cardioembolic stroke. Most patients (~90%) with asymptomatic carotid stenosis are better treated with intensive medical therapy; the few that could benefit from stenting or endarterectomy can be identified by a number of approaches, the best validated of which is transcranial Doppler (TCD) embolus detection. Percutaneous closure of patent foramen ovale has been shown to be efficacious but should only be implemented in selected patients; they can be identified by clinical clues to paradoxical embolism and by TCD estimation of shunt grade. "Treating arteries instead of treating risk factors," and recent findings related to the intestinal microbiome and atherosclerosis point the way to promising advances in future.

Decline in the Severity of Carotid Atherosclerosis and Associated Risk Factors From 2002 to 2014.

Abstract: Background and Purpose— Several recent studies suggest declining rates of carotid revascularization for patients with carotid stenosis. We investigated whether carotid atherosclerosis severity has ...

Cardiovascular benefit of egg consumption is most unlikely.

Abstract: To the Editor The conclusion of the recent report that egg consumption reduced cardiovascular risk1 is most unlikely to be valid. It has been clear for many years that dietary cholesterol increases coronary risk, and a single 65 g egg contains 237 mg of cholesterol, more than the 200 mg daily limit that is still wisely recommended in a number of guidelines.2 Besides the very high cholesterol content of egg yolk, phosphatidylcholine (~250 mg in one) leads to the formation of trimethylamine by intestinal …

Homocysteine Lowering with B Vitamins for Stroke Prevention—A History

Abstract: Early trials of B vitamin therapy to lower plasma total homocysteine (tHcy) reported no reduction of stroke with high doses of folate/B6 and cyanocobalamin 400–1,000 μg daily. In patients with diabetic nephropathy, folate/B6 and cyanocobalamin 1,000 μg daily accelerated the decline of renal function and doubled cardiovascular events. Patients with renal failure have high cyanide levels. The French SUpplementation with FOlate, vitamin B6 and B12 and/or OMega-3 fatty acids (Su.Fol.OM3) trial—with the best renal function of the early trials and the lowest dose of cyanocobalamin (20 μg daily)—reported a 43% reduction of stroke. Then the China Stroke Primary Prevention Trial (CSPPT) reported that folic acid alone reduced stroke and was beneficial even in patients with impaired renal function. Patient-level data from the Vitamin Intervention to Prevent Stroke (VISP) and VITAmins TO Prevent Stroke (VITATOPS) trials and meta-analyses stratified by renal function and dose of cyanocobalamin confirmed that harm from cyanocobalamin among participants with renal impairment obscured the benefit of B vitamins in the early trials. It does seem that B vitamins reduce the risk of stroke. In the era of folate fortification, B12 is the main nutritional determinant of tHcy, and metabolic B12 deficiency is very common and usually missed. Therefore, folate alone is not the optimal way to lower tHcy: the use of folate (and possibly B6) with methylcobalamin or oxocobalamin should be considered.

Stroke Prevention: Editorial to accompany June issue of SVN.

Abstract: This issue of Stroke and Vascular Neurology focuses on stroke prevention, a problem that is of paramount importance. Stroke is highly age-related, so prevention of stroke could have a major impact, with the ageing of the population in Western countries. Furthermore, in China the opportunity is particularly important, as the risk of stroke and coronary disease has increased markedly with the dietary changes that have resulted from increased prosperity. Prevention is far more cost-effective …

Diastolic J curve, cuff artefact and low targets for SBP: a need for caution.

Abstract: I read with interest the recent editorial about SBP targets [1]. The authors ended with a note of caution about adverse effects of hypotension; this is well founded. What is missing is an indication of how to identify persons at higher risk from very low systolic targets. Two recent articles describing a diastolic J curve point the way. Very low blood pressure targets for systolic pressure are not safe in people with stiff arteries and a wide pulse pressure. Those with a pulse pressure greater than 60mmHg and a diastolic pressure less than 60mmHg have a significant increase in the risk of coronary artery disease and stroke. McEvoy et al. [2] reported a 2.49-fold increase in coronary risk in such patients, whereas Park and Ovbiagele [3] reported a 5.85-fold increase in the risk of stroke. This probably happens because most of coronary flow and more than half of cerebral blood flow occur during diastole, and in the brain there is a very large drop in pressure from the base of the brain to the small arterioles over the convexity. The base of the brain (the ‘vascular centrencephalon’), is perfused by short straight arteries with few branches, which transmit the pressure straight through from the large arteries to the small resistance vessels. Hypertensive lacunes and intracerebral hemorrhages result from the arteriolar damage; this is why the strokes that are prevented by blood pressure control are lacunar infarctions and intracerebral hemorrhages. In contrast, the cerebral cortex over the convexity is perfused by long arteries with many branches, so that blood pressure drops markedly at the distal end of the arterial bed. Blanco et al. [4] calculated that whenever the blood pressure in the brachial artery is 117/75 mmHg, it is 113/73 mmHg in the lenticulostriate artery, but only 59/ 39mmHg in small branches in the posterior parietal subcortex. A further reason why this may be a particular problem in patients with a wide pulse pressure is that increased arterial stiffness increases the difference between intra-arterial blood pressure and blood pressure measured by a cuff (cuff artefact). In 1978, I reported that among patients aged at least 60 years who had DBP greater than 100mmHg but no endorgan disease, half had a cuff diastolic pressure that was at least 30mmHg higher than the intra-arterial pressure. In 1985, we reported [5] that arterial stiffness increased the difference between intra-arterial pressure and cuff pressure. Thoughtful individualization of blood pressure targets is needed in elderly patients. Whenever patients complain of hypotensive symptoms that do not seem to be explained by cuff blood pressures, it is important to consider that the cuff blood pressure may be overestimating the true blood pressure. ACKNOWLEDGEMENTS

Big Surprise: The Brain Can Recover Many Years After a Stroke

Abstract: Most doctors think that after a patient has a stroke, recovery only happens for 6 months to a year; after that there is no point in continuing with rehabilitation therapy. We described a patient who had a severe stroke at age 15 and was left with a completely useless left hand. Then 23 years later, after he started swimming regularly to lose weight, he had some movement in the fingers of his left hand. He began intensive therapy with exercises using a special glove, and now, 37 years after the stroke, he is still improving. The way his brain “rewired” itself all over both sides of the brain is shown with a special imaging method called functional magnetic resonance imaging. This means that intensive physiotherapy and maybe new approaches to brain recovery including stem cell therapy, need to be tried much longer after the stroke than we used to think.

Letter by Spence Regarding Article, "Serum Potassium Is Positively Associated With Stroke and Mortality in the Large, Population-Based Malmö Preventive Project Cohort".

Abstract: There were 2 key omissions from the report that higher serum potassium predicted higher stroke risk in the Malmo Preventive Project cohort.1 There was no mention of renal function, and no mention of drugs that block the renin/angiotensin axis. Renal function declines linearly with age,2 and impaired renal function markedly increases cardiovascular risk.3 …