Case 1: isolated systolic hypertension

Despite the prevalence of isolated systolic hypertension (ISH) in the elderly, many physicians are reluctant to treat the disorder. Recently identified as one of the major health challenges of the new millennium, ISH is the focus of this month's CME-accredited case study in hypertension, featured at www.CardiovascularEd. com.     

优化联合治疗老年单纯性收缩期高血压

目的比较卡托普利单药、左旋氨氯地平（施慧达）单药、卡托普利＋左旋氨氯地平、卡托普利＋左旋氨氯地平＋阿托伐他汀四种治疗方案治疗老年单纯性收缩期高血压（ISH）的临床疗效。方法纳入60岁以上ISH患者264例,平均分为4组。卡托普利组：口服卡托普利（12．5～50）mg（bid）。左旋氨氯地平组：晨起顿服左旋氨氯地平2．5mg（qd）。联合治疗组（联合组）：卡托普利（12．5～50）mg（bid）＋左旋氨氯地平2．5mg（qd）。优化联合组（优化组）：在联合治疗组的基础上加用阿托伐他汀10mg（qd）;共治疗12周。并分别比较治疗前、治疗后1周、3周、6周、12周4组血压、血脂水平及心电图变化。结果四组治疗后收缩压均有不同程度的降低,优化组和联合组与卡托普利组、左旋氨氯地平组比较差异具有统计学意义（P≤0．05）。优化组降压、降脂及心肌供血改善尤其显著,且4组治疗前后肝肾功能变化无明显差异。结论左旋氨氯地平联合卡托普利治疗老年ISH安全有效,可改善心肌缺血、降低血脂,联合阿托伐他汀治疗效果更佳。     

单纯收缩期高血压大鼠模型建立及基质金属蛋白酶-9在其形成中的作用

目的 探讨单纯收缩期高血压(ISH)模型的建立及基质金属蛋白酶(MMP)-9在其形成中的作用.方法 选用8周龄Wistar雄性大鼠20只作为研究对象,随机分成模型组(n=10)和对照组(n=10).应用华法林和维生素K诱导动脉中层钙化,8 w后右侧颈动脉插管进行有创血压和心室内压力的检测.以及取材主动脉,Von Kossa染色分析动脉钙化程度;采用原子吸收光谱法测定血管组织中钙含量.采用弹性纤维染色法观察主动脉组织中弹性纤维形状;应用免疫组织化学和Western印迹检测主动脉组织中MMP-9的表达水平.结果 模型组大鼠血压与对照组相比明显增高(P＜0.01);而各组间平均心室内压无明显变化.模型组大鼠血压变化的同时伴有动脉形态结构的改变,主动脉和颈动脉中层钙化明显,模型组动脉钙含量明显高于对照组(P＜0.01).弹力纤维断裂变直,失去波浪形状.Western印迹分析模型组MMP-9蛋白表达较对照组明显升高.结论 利用法华林和维生素K诱导的ISH大鼠是可重复好,便捷,以及与人体衰老相似较为理想的模型.MMP-9酶表达明显增多可促使大动脉中层弹力蛋白降解和钙在弹力纤维薄层的沉积,从而在ISH形成中发挥重要作用.     

Treatment of isolated systolic hypertension

Isolated systolic hypertension (ISH) is the dominant form of hypertension in the elderly. It is associated with increased arterial pulse pressure, to which an early-returning and magnified pulse-wave reflection makes an important contribution. Treatment of ISH with diuretics, calcium channel blockers (CCBs), and angiotensin II inhibitors is effective in reducing systolic blood pressure, preventing cardiovascular morbid events, and lowering mortality; these agents may have to be used in combination to achieve the systolic blood pressure goal of < 140 mm Hg. Treatment with β-blockers appears to be less effective. The relative efficacy of various classes of antihypertensive drugs for lowering pulse pressure and systolic blood pressure is determined in part by their differing abilities to reduce pulse-wave reflection. In patients with ISH that is refractory to dual or triple therapy, measurement of the reflected wave by applanation tonometry may be useful in determining which additional antihypertensive agent to use.     

硝酸脂类药物治疗老年单纯收缩性高血压分析

目的研究硝酸脂类药物对老年单纯收缩性高血压的治疗效果。方法随机选取我院2009年3月至2012年5月收入的老年单纯收缩性高血压患者68例为研究对象,按入院顺序分为观察组和对照组,各34例。两组均给予非洛地平治疗,观察组在此基础上再加用硝酸异山梨醇酯缓释片。治疗2个月后,观察对比两组的降压效果、血脂变化情况及不良反应的发生率。结果治疗后两组的血压均得到有效控制,较治疗前相比,舒张压变化不大,但收缩压与脉压差改善情况经统计学处理有显著差异（P〈0．05）;治疗后两组相比,观察组收缩压和脉压差较对照组均下降明显,有统计学差异（P〈0．05）。两组血脂水平经治疗均下降,但观察组甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白（HDL）较对照组下降明显（P〈0．05）;对比不良反应的发生率,观察组为11．8％,而对照组为20．6％,经统计学处理,对照组显著高于观察组（P〈0．05）。结论以硝酸异山梨醇酯为代表的硝酸脂类药物对于老年单纯收缩性高血压的治疗效果显著,不仅可以显著改善收缩压和脉压差,缓解临床症状,而且能减少并发症的发生,提高老年患者的生存质量,值得临床推广。     

Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D

The present experiments were carried out to test the hypothesis that arterial calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with osteoprotegerin will inhibit arterial calcification. In the first test, arterial calcification was induced by treating 22-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and causes extensive calcification of the arterial media. Compared with rats treated for 1 week with warfarin alone, rats treated with warfarin plus osteoprotegerin at a dose of 1 mg/kg per day had dramatically reduced alizarin red staining for calcification in the aorta and in the carotid, hepatic, mesenteric, renal, and femoral arteries, and they had 90% lower levels of calcium and phosphate in the abdominal aorta (P<0.001) and in tracheal ring cartilage (P<0.01). More rapid arterial calcification was induced by treating 49-day-old male rats with toxic doses of vitamin D. Treatment for 96 hours with vitamin D caused widespread alizarin red staining for calcification in the aorta and the femoral, mesenteric, hepatic, renal, and carotid arteries, and osteoprotegerin completely prevented calcification in each of these arteries and reduced the levels of calcium and phosphate in the abdominal aorta to control levels (P<0.001). Treatment with vitamin D also caused extensive calcification in the lungs, trachea, kidneys, stomach, and small intestine, and treatment with osteoprotegerin reduced or prevented calcification in each of these sites. Measurement of serum levels of cross-linked N-teleopeptides showed that osteoprotegerin dramatically reduced bone resorption activity in each of these experiments (P<0.001). Therefore, we conclude that doses of osteoprotegerin that inhibit bone resorption are able to potently inhibit the calcification of arteries that is induced by warfarin treatment and by vitamin D treatment. These results support the hypothesis that arterial calcification is linked to bone resorption.     

A comparison of atenolol and nebivolol in isolated systolic hypertension

OBJECTIVES: Some beta-blockers are less effective in reducing central blood pressure than other antihypertensive drugs, which may explain the higher rate of events in subjects randomized to atenolol in recent trials. We hypothesized that nebivolol, a mixed beta-blocker/nitro-vasodilator, would be more effective than atenolol in reducing central blood pressure and augmentation index (AIx). The aim of the present study was to test this in a double-blind, randomized, cross-over study, in a cohort of subjects with isolated systolic hypertension. METHODS: Following a 2-week placebo run-in, 16 never-treated hypertensive subjects received atenolol (50 mg), nebivolol (5 mg) and placebo, each for 5 weeks, in a random order. Seated brachial blood pressure and heart rate were measured. Aortic blood pressure, AIx and pulse wave velocity (PWV) were assessed non-invasively. RESULTS: The placebo-corrected fall in brachial pressure was similar between nebivolol and atenolol, as was the reduction in PWV (mean change +/- SEM: -1.0 +/- 0.3 and -1.2 +/- 0.2 m/s; P = 0.2). However, there was less reduction in heart rate (-19 +/- 2 versus -23 +/- 2 beats/min; P < 0.01) and increase in AIx (+6 +/- 1 versus +10 +/- 1%; P = 0.04), following nebivolol. Aortic pulse pressure was significantly lower (50 +/- 2 versus 54 +/- 2 mmHg; P = 0.02) after nebivolol. N-terminal pro-B-type natriuretic peptide (proBNP) rose on both drugs (100 +/- 33 versus 75 +/- 80 pg/ml; P < 0.01 for both, NS for comparison). CONCLUSIONS: Nebivolol and atenolol have similar effects on brachial blood pressure and aortic stiffness. However, nebivolol reduces aortic pulse pressure more than atenolol, which may be related to a less pronounced rise in AIx and bradycardia. Whether this will translate into differences in clinical outcome requires further investigation.     

The effect of a losartan-based treatment regimen on isolated systolic hypertension

This study was conducted to compare the antihypertensive efficacy and tolerability, over 12 weeks, of a losartan-based treatment regimen and placebo in patients with isolated systolic hypertension. Three hundred eight patients ≥35 years of age with isolated systolic hypertension, defined as trough sitting blood pressure between 140 and 200 mm Hg systolic and between 70 and 89 mm Hg diastolic, were randomized to losartan 50 mg (n=157) or placebo (n=151) once daily, with titration as necessary to achieve a goal trough sitting systolic blood pressure (SBP) <140 mm Hg. At baseline, mean trough sitting SBP was 140–159 mm Hg in 20.5% of patients, 160–179 mm Hg in 62.7%, and 180–200 mm Hg in 16.9%, and was similar in the two groups (losartan, 165.3 mm Hg; placebo, 166.1 mm Hg). At 12 weeks, mean trough sitting SBP decreased significantly (p<0.001) in both the losartan-based treatment group (by 19.2 mm Hg) and in the placebo group (by 7.6 mm Hg). The reduction in sitting SBP was significantly greater for losartan than placebo (−11.6 mm Hg; 95% confidence interval, −14.8 to −8.4). In patients with isolated systolic hypertension, a once-daily losartan-based treatment regimen significantly lowered SBP. The losartan-based regimen exhibited antihypertensive efficacy that was superior to that of placebo, with a similar tolerability profile.     

Candesartan and hydrochlorothiazide in isolated systolic hypertension

AIM: We investigated the efficacy and safety of daily candesartan 8/16mg and hydrochlorothiazide 12.5 mg as monotherapy and in combination in older patients with systolic hypertension. METHODS: The study used a double-blind randomized placebo-controlled crossover design. Treatment phases were of 6 weeks duration. For inclusion, patients were aged 55-84 years with sitting systolic blood pressure (SBP) 160-210 mmHg and diastolic blood pressure (DBP) < 95 mmHg. Nineteen patients (11 male, eight female, median age 68 years) completed the study. MAJOR FINDINGS: Compared with the placebo phase, clinic and ambulatory SBP was significantly reduced with both dose-adjusted candesartan and fixed-dose hydrochlorothiazide as monotherapy, the effect of candesartan being greater than that of hydrochlorothiazide. In combination, the effects of the two drugs were additive. Both drugs were well tolerated either as monotherapy or in combination. CONCLUSION: Both candesartan and a low dose of hydrochlorothiazide are effective and well-tolerated antihypertensive agents in isolated systolic hypertension with additive effects in combination. Candesartan was more effective than hydrochlorothiazide, although it is possible that dose adjustment only of candesartan could have enhanced its relative effectiveness.     

Distinct effects of amlodipine treatment on vascular elastocalcinosis and stiffness in a rat model of isolated systolic hypertension

OBJECTIVE: Medial elastocalcinosis (MEC) contributes to the development of large artery stiffness and isolated systolic hypertension. Since endothelin receptor antagonists can prevent and regress elastocalcinosis, our aim was to determine whether amlodipine, a calcium channel blocker that inhibits endothelin signaling, could likewise influence MEC, or reduce pressure mainly through its vasorelaxing properties. METHODS: Control male Wistar rats were compared with rats receiving warfarin (20 mg/kg per day) with vitamin K1 (15 mg/kg per day) alone (WVK) or in association with amlodipine (15 mg/kg per day) for 4 weeks or during the last week or last 4 weeks of an 8-week WVK treatment (two regression groups). RESULTS: Inactivation of matrix Gla protein by WVK for 4 or 8 weeks increased the calcium content 10-fold in the aorta, inducing a significant elevation of pulse wave velocity and pulse pressure by selective augmentation of systolic blood pressure. Amlodipine prevented aortic MEC, pulse wave velocity and pulse pressure elevation, but reversed only MEC and pulse pressure when administered for 4 weeks. One week of amlodipine administered after 7 weeks of WVK partially decreased pulse pressure without modifying aortic MEC. Amlodipine did not reduce the fibrosis associated with calcified areas in the WVK model during the regression protocols. CONCLUSION: The clinical efficacy of amlodipine in improving hemodynamic variables and reducing cardiovascular events in isolated systolic hypertension could be explained by its beneficial effect on vascular calcification. Amlodipine's lack of effect on pulse wave velocity and collagen deposition, however, suggests that it may reduce pulse pressure by means other than improving arterial stiffness.     

A new rat model of portal hypertension induced by intraportal injection of microspheres

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Extent of cardiovascular risk reduction associated with treatment of isolated systolic hypertension

BACKGROUND: The Systolic Hypertension in the Elderly Program (SHEP) demonstrated the benefit of treating isolated systolic hypertension (ISH) in older adults. However, nearly 20% of older adults remain at high risk of heart disease and stroke from untreated ISH. METHODS: For the Pittsburgh SHEP cohort, 11- to 14-year death or cardiovascular event rates were compared for active (n = 135) and placebo (n = 133) arms plus normotensive controls (n = 187). Carotid ultrasound and ankle blood pressures were used to identify subclinical atherosclerosis at baseline. RESULTS: Fourteen-year Kaplan-Meier event rate estimates were 58% vs 79% for the active vs placebo groups (P =.001). Eleven-year event rates for the control, active, and placebo groups were 35%, 47%, and 65%, respectively. Compared with controls, the relative risk of an event was 1.6 (95% confidence interval, 1.1-2.4) for the active treatment group and 3.0 (95% confidence interval, 2.1-4.4) for the placebo group. Baseline history of cardiovascular disease was present in 19% of SHEP participants vs 15% of controls (P =.32), and subclinical disease (carotid stenosis or low ankle blood pressure) was detected in 33% of SHEP participants vs 10% of controls (P<.001). Among those with no clinical or subclinical disease at baseline, the ISH group assigned to active treatment had 10-year event rates similar to those of the control group (29% vs 27%), whereas the placebo rates were much higher (69%). CONCLUSIONS: Treatment of ISH in older adults results in reduced event rates in 14 years. Treatment before advanced atherosclerosis develops will likely produce the best long-term outcome.     

吲达帕胺治疗老年单纯收缩期高血压疗效观察

目的探讨吲达帕胺对老年单纯收缩期高血压（ISH）的疗效观察。方法以108例老年ISH患者随机分为吲达帕胺治疗组（n=54，吲达帕胺1．25mg／d）和氨氯地平治疗组（n=54，氨氯地平5mg／d）。每周测量坐位血压2次。治疗前和治疗后3个月后分别检测空腹血糖、血脂、血尿酸、血钾、血钠。结果两组治疗前后降压疗效差异均有统计学意义（P〈0．01），但组间相比差异无统计学意义（P〉0．05）。两组治疗前后空腹血糖、血脂、血尿酸、血钾、血钠亦无统计学差异。结论吲达帕胺治疗老年ISH安全、有效。     

The benefit of treating isolated systolic hypertension

Isolated systolic hypertension affects over 15% of all people older than 60 years of age. In the elderly, systolic hypertension is a major modifiable cardiovascular risk factor. Systolic blood pressure is associated with higher risk of an adverse outcome. Diastolic blood pressure is inversely correlated with total mortality, independent of systolic blood pressure, highlighting the role of pulse pressure as risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment in older patients with isolated systolic hypertension have been published: the Systolic Hypertension in the Elderly Program (SHEP), the Systolic Hypertension in Europe (Syst-Eur) Trial, and the Systolic Hypertension in China (Syst-China) Trial. These three trials showed the benefit of antihypertensive drug treatment. A meta-analysis was done by pooling the patients from these three trials with a subset of patients with isolated systolic hypertension from five other trials in the elderly. The pooled results of 15,693 older patients with isolated systolic hypertension prove that antihypertensive drug treatment is justified if systolic blood pressure on repeated clinic measurements is 160 mm Hg or higher.     

吲达帕胺治疗老年单纯收缩期高血压疗效及其对代谢的影响

目的 :探讨吲达帕胺对老年单纯收缩期高血压 (ISH)的疗效及其对代谢的影响。方法 :10 2例老年ISH患者随机分为吲达帕胺治疗组 (n =5 2 ,吲达帕胺 1.2 5～ 2 .5mg/d)和非洛地平治疗组 (n =5 0 ,非洛地平 5～ 15mg/d)。每 1～ 2周测量坐位血压 1次。治疗前和治疗后 2个月后分别检测空腹血糖 ,血脂 ,血尿酸 ,血肌酐 ,血钾、钠和氯。结果 :两组治疗前后降压疗效差异均有非常显著性意义 (P <0 .0 1) ,但组间相比差异无显著性意义 (P 0 .0 5 )。两组治疗前后空腹血糖 ,血脂 ,血尿酸 ,血肌酐 ,血钾、钠和氯亦无统计学差异。结论 :吲达帕胺治疗老年ISH安全、有效 ,对空腹血糖 ,血脂 ,血尿酸 ,血肌酐 ,血钾、钠和氯无明显不良影响 ,是治疗老年ISH的第一线药物     

Benefits of antihypertensive drug treatment in elderly patients with isolated systolic hypertension

Isolated systolic hypertension affects over 15% of all people older than 60 years. In the elderly, systolic hypertension is a major modifiable cardiovascular risk factor. Systolic blood pressure is associated with higher risk of an adverse outcome, whereas diastolic blood pressure is inversely correlated with total mortality, independent of systolic blood pressure, highlighting the role of pulse pressure as risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment in older patients with isolated systolic hypertension have been published: the Systolic Hypertension in the Elderly Program (SHEP), the Systolic Hypertension in Europe (Syst-Eur) Trial and the Systolic Hypertension in China (Syst-China) Trial. These three trials demonstrated the benefit of antihypertensive drug treatment. A meta-analysis was performed by pooling the patients from these three trials with a subset of patients with isolated systolic hypertension from five other trials in the elderly. Antihypertensive treatment based on a calcium-channel blocker may provide additional benefits in diabetic patients and in the prevention of dementia and renal dysfunction. The pooled results of 15693 older patients with isolated systolic hypertension prove that antihypertensive drug treatment is justified if on repeated clinic measurements systolic blood pressure is 160 mmHg or higher.     

The association of vitamin K status with warfarin sensitivity at the onset of treatment

We investigated the association of vitamin K status with warfarin sensitivity among 40 orthopaedic patients beginning perioperative algorithm-dosed warfarin. Baseline vitamin K status was assessed using plasma vitamin K-1 and vitamin K-1 2,3 epoxide concentrations, and a questionnaire-based estimation of usual vitamin K intake. Warfarin sensitivity was assessed as the increase in the International Normalized Ratio (INR) after two doses of 5 mg of warfarin and as the 4-d accumulation of under-gamma-carboxylated prothrombin (PIVKA-II), adjusted for warfarin dose requirement. Multivariate models were used to assess vitamin K variables as predictors of warfarin sensitivity. The mean INR increase was 0.53 U and the mean PIVKA-II increase was 771 ng/ml/mg warfarin. Demographic factors were not associated with warfarin response. For each 1 standard deviation (SD) lower value of plasma vitamin K-1, but not the other vitamin K variables, the INR rose 0.24 U (P < or = 0.01). A higher usual vitamin K intake and plasma vitamin K-1, and lower plasma vitamin K-1 2,3 epoxide, were all associated with a lower PIVKA-II increase over 4 d. Respective differences in PIVKA-II accumulation per SD increase of each variable were -165, -218 and 236 ng/ml/mg warfarin (all P < or = 0.05). We concluded that dietary and biochemical measures of vitamin K status were associated with early warfarin sensitivity.     

Atrial fibrillation and isolated systolic hypertension: the systolic hypertension in the elderly program and systolic hypertension in the elderly program-extension study

We performed a post hoc analysis of the Systolic Hypertension in the Elderly Program database to assess the incidence of atrial fibrillation in the elderly hypertensive population, its influence on cardiovascular events, and whether antihypertensive treatment can prevent its onset. The Systolic Hypertension in the Elderly Program was a double-blind placebo-controlled trial in 4736 subjects with isolated systolic hypertension aged >or=60 years. Atrial fibrillation was an exclusion criterion from the trial. Participants were randomly assigned to stepped care treatment with chlorthalidone and atenolol (n=2365) or placebo (n=2371). The occurrence of atrial fibrillation and cardiovascular events over 4.7 years as well as the determination of cause of death at 4.7 and 14.3 years were followed. Ninety-eight subjects (2.06%) developed atrial fibrillation over 4.7 years mean follow-up, without significant difference between treated and placebo groups. Atrial fibrillation increased the risk for: total cardiovascular events (RR 1.69; 95% CI 1.21 to 2.36), rapid death (RR 3.29; 95% CI 1.08 to 10.00), total (RR 5.10; 95% CI 3.12 to 8.37) and nonfatal left ventricular failure (RR 5.31; 95% CI 3.09 to 9.13). All-cause and total cardiovascular death were significantly increased in the atrial fibrillation group at 4.7 years (HR 3.44; 95% CI 2.18 to 5.42; HR 2.39; 95% CI 1.05 to 5.43) and 14.3 years follow-up (HR 2.33; 95% CI 1.83 to 2.98; HR 2.21; 95% CI 1.54 to 3.17). Atrial fibrillation increased the risk for total cardiovascular events, rapid death, and left ventricular failure. All-cause mortality and total cardiovascular mortality were significantly increased in hypertensives with atrial fibrillation at 4.7 and 14.3 years follow-up.