心率 ——心脏保护的新靶点 张福春 北京大学第三医院.

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1 心率 ——心脏保护的新靶点 张福春 北京大学第三医院

2 目 录 心率与心血管疾病预后密切相关 β受体阻滞剂降低心率对临床的获益 β受体阻滞剂使用现状及原因 高选择性β1受体阻滞剂的临床优势

3 Framingham心脏研究表明： 人类心血管疾病死亡率随心率增加而增加
女性 心血管疾病死亡率（每1000人/年） 心 率 n=11,334例 心血管死亡率（每1000人/年） 男性 心 率 n=10,519例 Am Heart J Jun;113(6):

4 多项研究证明： 心率是心血管疾病预后的重要预测因子
随访时间 入组例数 基础疾病 结 论 研究 随访时间 入组例数 基础疾病 结 论 Framingham研究 36年 4530 高血压病 校正年龄和收缩压后，心血管事件发生率和死亡率随心率增加而增加 Syst-Eur研究 2年 4682 单纯收缩性 心率是死亡的独立危险因素 CASS研究 15年 1.5万 冠心病 在校正高血压、糖尿病、吸烟等危险因子后，心率仍是死亡的强预测因子 TNT研究 4.9年 9580 心率增快是引起主要心血管事件增加的重要原因 CIBIS-Ⅱ研究 1.3年 2647 慢性心衰 基础心率和治疗后心率的改变均与生存率显著相关 1. Gillman MW, et mal.A Heart J.1993;125(4): ; 2. Palatini P, et al.Arch Intern Med. 2002;162: ; 3. Lancet. 1999;353(9146):9-13; 4. Diaz A, et al. Eur Heart J. 2005;26(10): ; 5. Ho JE, et al.Am J Cardiol.2010;105:

5 NHEFS研究表明： 心率增加使心血管疾病患者病死率也随之增加
心率（次/分） 影响 入选人群 >84 冠心病危险上升 白种男性65-74岁 白种女性45-74岁 住院期间50-69 15%总病死率在心肌梗死后1年 心肌梗死患者 住院期间≥90 41%总病死率在心肌梗死后1年 住院期间>110 48%总病死率在心肌梗死后1年 <90 5%-7%发生严重心力衰竭 24%发生严重心力衰竭 在12h内降低14次/分 25%-30%心肌梗死面积减少 每分钟增加5次 冠状动脉事件发生可能增加1.14倍 包括女性和男性平均年龄81岁 心率（次/分） 影响 入选人群 Am Heart J Jan;121(1 Pt 1):172-7

6 急性心肌梗死后 心率持续性增高与死亡率增高密切相关
Hjalmarson分析1807例急性心肌梗死患者入院时与出院后1年内心率与死亡率的关系，结果显示，入院时心率50～69次/min者，一年后总死亡率为15%；≥90次/min者，一年后总死亡率为41%。同时发现，急性心肌梗死后心率持续性增高与死亡率增高密切相关。 中华心血管病杂志2006年6月第34卷第6期Chin J Cardiol，June 2006．Vo1．34 No.6:

7 心率是冠心病患者发病和死亡的强预测因子 心率既是一个独立的冠心病的预测因子 也是冠心病患者死亡的强预测因子
Diaz A, et al. Eur Heart J. 2005;26(10):

8 心衰患者死亡风险随心率增快而增加 Kjekshus & Gullestad . Eur Heart J, 1999, h64-h69

9 INVEST研究表明：心率控制在一定范围心血管事件最少
心率控制需在一定的范围内， 方可获得最大收益 INVEST研究表明：心率控制在一定范围心血管事件最少 HR每增加 5 bpm，心血管事件风险提高6% HR >75 bpm及HR<60 bpm，均与心血管事件增加相关 Kolloch et al. Eur Heart J. 2008;29:

10 国内外指南同样指出： 控制心率在心血管疾病治疗中占重要地位
2006年ESC 《稳定性心绞痛管理指南》： 心率需控制在50-60次/分才能较好控制心绞痛的发作 2007年中国 《慢性心力衰竭诊断治疗指南》： 2007年中国 《慢性稳定性心绞痛诊断与治疗指南》： 2006ESC《稳定性心绞痛管理指南》; 2007中国《慢性心率衰竭诊断治疗指南》; 2007中国《慢性稳定性心绞痛诊断与治疗指南》

11 静息心率和心血管事件 Paolo Palatini Hypertension. 2011;58:745-750; 11
Role of Elevated Heart Rate in the Development of Cardiovascular Disease in Hypertension Paolo Palatini That elevated heart rate (HR) is a risk factor for cardiovascular morbidity and mortality in healthy people as well as in patients with cardiac diseases is supported by numerous epidemiological association studies.1–4 Increased HR has been recognized as a negative prognostic factor independent of many other clinical parameters that can influence the HR, including physical activity scores, left ventricular function, or use of -blockers. Thus, HR appears to satisfy all epidemiological criteria for being considered as a true risk factor, and its predictive value for cardiovascular disease appeared to be as strong as that of most important cardiovascular risk factors. This is particularly true for the results obtained in hypertensive patients. Elevated HR is a common feature among hypertensive individuals.1 Among the young hypertensive subjects participating in the HARVEST study, 15% had a baseline resting HR 85 bpm and 27% had a HR 80 bpm.5 According to the Tensiopulse study, which evaluated patients cared for by 2000 general practitioners all across Italy, 30% of the hypertensive patients had a resting HR 80 bpm.6 In a large French population, untreated hypertensive subjects had approximately a 6-bpm faster HR than normotensive individuals.7 Elevated HR is frequently associated with high blood pressure (BP) and metabolic disturbances and increases the risk of new onset hypertension and diabetes.1 Many experimental data obtained both in animals and in human beings support the importance of HR as a true risk factor for atherosclerosis and cardiovascular disease, providing convincing evidence for this pathogenetic mechanism.1–3 The pathogenetic connection between HR and cardiovascular disease has been discussed in several reports1–3,8,9 and is beyond the scope of this review. Paolo Palatini Hypertension. 2011;58: ; 11

12 静息心率和心血管事件（接上） Paolo Palatini Hypertension. 2011;58:745-750; 12
Role of Elevated Heart Rate in the Development of Cardiovascular Disease in Hypertension Paolo Palatini That elevated heart rate (HR) is a risk factor for cardiovascular morbidity and mortality in healthy people as well as in patients with cardiac diseases is supported by numerous epidemiological association studies.1–4 Increased HR has been recognized as a negative prognostic factor independent of many other clinical parameters that can influence the HR, including physical activity scores, left ventricular function, or use of -blockers. Thus, HR appears to satisfy all epidemiological criteria for being considered as a true risk factor, and its predictive value for cardiovascular disease appeared to be as strong as that of most important cardiovascular risk factors. This is particularly true for the results obtained in hypertensive patients. Elevated HR is a common feature among hypertensive individuals.1 Among the young hypertensive subjects participating in the HARVEST study, 15% had a baseline resting HR 85 bpm and 27% had a HR 80 bpm.5 According to the Tensiopulse study, which evaluated patients cared for by 2000 general practitioners all across Italy, 30% of the hypertensive patients had a resting HR 80 bpm.6 In a large French population, untreated hypertensive subjects had approximately a 6-bpm faster HR than normotensive individuals.7 Elevated HR is frequently associated with high blood pressure (BP) and metabolic disturbances and increases the risk of new onset hypertension and diabetes.1 Many experimental data obtained both in animals and in human beings support the importance of HR as a true risk factor for atherosclerosis and cardiovascular disease, providing convincing evidence for this pathogenetic mechanism.1–3 The pathogenetic connection between HR and cardiovascular disease has been discussed in several reports1–3,8,9 and is beyond the scope of this review. Paolo Palatini Hypertension. 2011;58: ; 12

13 静息心率和心血管事件（接上） VALUE 研究 N=15245
Tachycardia predicts CV events in VALUE Baseline and in-trial tachycardia are strong, independent predictors of cardiovascular events in patients with high-risk hypertension, a new analysis of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial has shown [1]. Risk seems to be particularly increased in those with a heart rate (HR) of >80 beats per minute (bpm), Dr Stevo Julius (University of Michigan Cardiovascular Center, Ann Arbor), told a late-breaking clinical-trials session at the American Society of Hypertension (ASH) 2010 Scientific Meeting last week. The time has come to test whether HR lowering in tachycardic high-risk hypertension is beneficial, said Julius. Hypertension guidelines should also "recommend tachycardia as a potent and clinically relevant risk factor," he noted. ASH president Dr George Bakris (University of Chicago Pritzker School of Medicine, IL), who was a chair of the late-breaking session, commented: "I want to publicly thank you." Bakris explained that he had argued some time ago to specifically add heart rate to the algorithm for predicting risk in chronic-kidney-disease patients but had been ridiculed "by all my nephrology colleagues." Dr Franz Messerli (St Luke Roosevelt Hospital, New York), who was not involved with this new analysis, told heartwire that ever since Framingham, "We have known that resting heart rate is a powerful risk factor for cardiovascular morbidity and mortality. Julius has extended this observation in the VALUE study." But Messerli stresses the most important next step is to figure out why heart rate is elevated in some patients and how this links pathophysiologically to increased morbidity and mortality. Until then, any attempts to lower heart rate pharmacologically would merely be "Band-Aid therapy," he says. Baseline and annual HR were strong predictors of primary end point The VALUE trial, first reported almost six years ago, showed that valsartan-based and amlodipine-based therapy were essentially equal in reducing the primary end point of cardiac morbidity or mortality in patients with hypertension and at least one high-risk factor. The new analysis included almost all the original 15 245 participants, bar a few who were excluded because no ECGs were available for them or because they had "unreasonable" heart rates of <45 bpm or >130 bpm, Julius told heartwire. He explained that while it is known that heart rate is a risk factor for cardiovascular events and for total mortality, it is not clear whether that risk still prevails in high-risk hypertension, and "that is the question we set out to answer." He and his colleagues examined both baseline HR and HR during the trial (obtained yearly from ECGs), "and both proved to be very strong predictors of the primary end point, cardiac morbidity and mortality," even after adjustment for multivariate confounding factors. The adjusted hazard ratio for the primary end point for a 10-bpm increment of the baseline HR was 1.22 (p<0.0001). There was always an excess of events in patients with a fast heart rate . . . [so this] is a true clinical predictor. "There was always an excess of events in patients with a fast heart rate," indicating that this "is not related to subclinical events but is a true clinical predictor," Julius said. Two particular components of this end point appeared to be strongly related to heart rate—heart failure and sudden death—Julius explained, whereas "the findings were less impressive with regard to myocardial infarction and stroke." Most of risk in those with HRs of 79 bpm or higher The researchers also identified that most of the risk occurred in those trial participants with heart rates of 79 bpm or more: there was a striking increase of the primary end point in the highest quintile of heart rate (>79 bpm) compared with the pooled lower four quintiles. Annual incidence of new primary-end-point events in the highest quintile (compared with the lower four) was 30% higher in the first year of the study, 55% higher in the second, 55% higher in the third year, 52% more in the fourth, and 46% greater in the fifth year of the study. A similar trend was seen throughout the trial for the HF and sudden-death components of the end point. And the negative effect of the in-trial tachycardia was not modified by the blood-pressure control achieved in the study, Julius explained. The relative increase of the primary end point in the tachycardic group was 68% in the BP-controlled and 63% in the BP-uncontrolled groups (p<0.0001). HR reduction does not need to be dramatic, but beta blockers no good Julius believes the time has come to examine the effects of lowering heart rate with appropriate drugs to see whether this would further lower the cardiovascular risk in patients with high-risk hypertension and tachycardia. "Heart rate may well be a legitimate target for treatment," he stated. He added that such reductions in heart rate "would not need to be dramatic. We are talking about getting HRs down from around 80 and above to somewhere in the region of 60 to 70 bpm." But beta blockers are "not the way to go," he maintains; they are inappropriate because of their tendency to increase central pressure and cause diabetes—hence, the reason there was no benefit seen with beta blockers in tachycardic patients in a recent analysis of the ASCOT study, Julius noted. Other potential agents that could be tested are the calcium-channel blocker verapamil as well as ivabradine (Procoralan, Servier), he said. The latter is a pure heart-rate-lowering agent that acts by selective inhibition of the cardiac pacemaker current. It is available in the EU for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta blockers. Messerli agrees that beta blockade has been unsuccessful in this regard, adding that the only outcome study with ivabradine, the BEAUTIFUL trial, was disappointing. In any case, seeking to lower the heart rate by pharmacological means is merely "cosmetic, until we know exactly why the heart rate is elevated," he stressed. N=15245 Julius S, et al. American Society of Hypertension 2010 Scientific Meeting; May 1-4, 2010; New York, NY. Abstract LB-OR-01 13

14 糖尿病静息心率和心血管并发症的关系 14

15 心率升高与冠脉斑块破裂显著相关 Left Ventricular Muscle Mass and Elevated Heart Rate Are Associated With Coronary Plaque Disruption Ulrich E. Heidland, MD; Bodo E. Strauer, MD Background—Plaque disruption is the central pathophysiological mechanism underlying acute coronary syndromes and the progression of coronary atherosclerosis. There exists only scant information about the factors that are associated with its development. The aim of the current study was to analyze the contribution of hemodynamic forces in the pathogenesis of plaque disruption. Plaque disruption was diagnosed by coronary angiography of stenosed but not completely occluded coronary arteries. Methods and Results—This study retrospectively analyzed 106 patients who underwent 2 coronary angiography procedures within 6 months. We investigated 53 patients with initially smooth stenoses who developed plaque disruption by the time of the second coronary angiogram and compared these patients with 53 age- and sex-matched individuals with smooth stenoses without angiographic signs of plaque disruption. The 2 groups were compared by analyzing central hemodynamics, echocardiographic measurements, and cardiovascular medication use. Logistic regression analysis identified positive associations between plaque disruption, left ventricular muscle mass .270 g, and a mean heart rate .80 bpm and a negative association with the use of b-blockers. Conclusions—The associations documented by our investigation indicate that hemodynamic forces may play a crucial role in the pathogenesis of plaque disruption. These findings may help to identify patients who are at an increased risk of plaque disruption and who might gain benefit from pharmacological interventions aimed at reducing heart rate, for example, by the use of b-blockers, or a reduction of left ventricular hypertrophy. (Circulation. 2001;104: ) Ulrich E, et al. Circulation. 2001;104: 15

16 β受体阻滞剂通过抑制交感活性，降低心率 中枢交感神经系统效果 外周交感神经系统效果 心脏交感神经系统效果 中枢交感神经系统效果
 β受体阻滞剂 ↓↓ ↓ ↓ 减少 ↓↓ 显著减少 Grassi G. Am J Hypertens. 2010;23:

17 TIBBS研究: 比索洛尔显著减少冠心病患者终点事件
*终点事件包括死亡、心梗和住院 von Arnim, et al. JAAC. 1996; 28:20-24.

18 CIBIS II 研究： 比索洛尔显著降低心衰患者全因死亡率
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

19 CIBIS III 研究： 比索洛尔有效降低心衰患者心源性猝死发生率
Emilio ,et al. Heart International .2006; 2(2):73-77

20 β受体阻滞剂抑制交感亢进、有效控制心率和降低死亡率，在CHD、心衰治疗中具有不可取代的地位
BB临床使用情况如何？

21 β受体阻滞剂在冠心病患者中 使用率和剂量均远远不够
我国通过对13078例高危冠心病患者进行调查（均有服用β受体阻滞剂的适应症），但服用β受体阻滞剂比例仅60%。 《β受体阻滞剂在中国高危冠心病患者中的应用现状调查》 临床治疗应用的平均剂量仅相当于有效剂量的1/4左右 J Clin Cardiol (china), 2011;6; 27(6) : ;中国处方药 (5):50-52

22 β受体阻滞剂在我国慢性心衰患者中 使用情况仍不理想
虽呈逐年上升趋 势，但使用率仍低 2002年中华医学会心血管病学分会对我国部分地区42家医院1980、1990、2000年住院病历进行回顾分析显示：三个年度的β受体阻滞剂使用率分别为8.5％、9.5％、19％，使用率低(不及20％)； 靶剂量使用率极低 研究显示：无禁忌证及不良反应住院患者中应用β受体阻滞剂者仅4.0％达到指南所要求的靶剂量，24.9％达到50％靶剂量；无禁忌证及不良反应的门诊患者中仅2.5％达到指南规定的靶剂量，26.6％达到50％靶剂量。 基层医院β受体阻滞剂使用率低与经济文化水平有相关性 国内一项研究显示：在我国一些经济和文化比较发达的地区，如湖南、山东两省β受体阻滞剂使用率为50％，高于全国的平均水平；而在我国相对落后的地区如青海省为30％，贵州省为33％。 我国β受体阻滞剂治疗慢性心力衰竭的临床现状仍让人担忧！ Adv Cardiovasc Dis, 2011,1 (1)：

23 心梗病人出院时 β受体阻滞剂使用明显剂量不足
1971例平均年龄为63岁的急性心梗病人出院时及出院后3周BB使用情况调查 50% Jeffrey J Goldberger, et al. Am Heart J。 2010；160(3),

24 出院后3周大部分病人 β受体阻滞剂剂量未调整
绝大部分病人心梗3w后日服用β受体阻滞剂的剂量并没有调整，而是保持原剂量 β受体阻滞剂剂量改变 Jeffrey J Goldberger, et al. Am Heart J。 2010；160(3),

25

26 COMET研究亚组分析： BB达到目标剂量更好改善CHF患者死亡风险
β受体阻滞剂剂量 治疗4个月后 高剂量 vs 低剂量* 563/1980 vs 249/615 0.78 (0.661, 0.921) 0.0034 减少风险 增加风险 死亡/患者数量 风险比(95%CI) P值 死亡相对风险(95%CI) * 高剂量：卡维地洛日剂量≥50mg/d；美托洛尔日剂量≥100mg/d 低剂量：卡维地洛日剂量<50mg/d；美托洛尔日剂量<100mg/d Metra M, et al. European Heart Journal 2005;26:2259–2268.

27 BB剂量达标相比剂量不足更好保护心脏 康可5-7．5mg／d治疗组较康可2．5mg／d组，心衰恶化及再住院显著减少，NYHA心功能和EF显著改善，对血压和心率控制更理想。 吴树贵, 中华临床医学研究杂志 2008;14(9):

28 影响β受体阻滞剂使用的原因 担心心动过缓的风险 担心药物的其他不良反应

29 3-5%患者因低血压和心动过缓不能耐受BB Erdmann E, et al. European Heart Journal Supplements (2009) 11 (Supplement A), A21–A25

30 比索洛尔出现心动过缓的几率较小 窦性心动过缓发生比例
从1996 年2 月至12 月, 使用比索洛尔对228 例高血压病患者进行临床观察,试验过程出现窦缓共11例, 仅占4.82% , 因窦缓退出试验4 例,且停药后很快恢复。 刘国树等. 心肺血管病杂志, 1999, 18(3):

31 β受体阻滞剂的不良反应 主要由阻断β2受体所引起
选用高β1选择性的β受体阻滞剂 可减少不良反应发生 β肾上腺素能受体阻滞剂的规范使用.人民卫生出版社.

32 -阻滞剂长期治疗对死亡率的影响 糖尿病患者 vs 非糖尿病患者
研究 例数 药物 非糖尿病患者 糖尿病患者 安慰剂 -阻滞剂 Gunderson 1884 噻吗洛尔 138 (15.5) 92 (10.3) 14 (30.5) 6 (11.3) BHAT 3837 普萘洛尔 155 (9.2) 116 (6.9) 33 (14.4) 22 (9.3) Kjekshus 1670 103 (12.8) 42 (6.5) 33 (23.4) 13 (10.2) 合计 7391* 396 (11.7) 250 (7.8) 80 (19.2) 41 (9.9) -阻滞剂降低死亡率 33% 48% * 非糖尿病患者6559例，糖尿病患者832例 32

33 BB更有效降低T2DM合并高血压全因死亡率 ——UKPDS研究20年随访结果
ACEI较之BB全因死亡率风险增加23% (RR 1.23 (1.00–1.51)) 全因死亡率 时间（年） Holman RR, et al. N Engl J Med 2008;359:

34 β 受体阻滞剂治疗缺血性心脏病 合并糖尿病患者非常有效
研究 非糖尿病患者 糖尿病患者 急性心肌梗死使用β受体阻滞剂降低早期死亡率（相对危险性降低，%） 哥德堡美托洛尔试验 MIAMI研究 ISIS研究 Malmberg et al 急性心肌梗死使用β受体阻滞剂降低长期死亡率（相对危险性降低，%） BHAT研究 Gundersen et al Kjekshus et al Sawicki PT J Int Med 2001;250:11 34

35 比索洛尔不引起高血压患者糖脂代谢紊乱 N=12 P=NS P=NS
Angiotension converting enzyme (ACE) inhibitors and β-blockers have been reported to possess disparate effects on insulin sensitivity. The aim of this study was to study the effects of the selective β-1 blocker bisoprolol and of the ACE inhibitor captopril on cellular insulin action in hypertensive individuals. After washout, 12 mild to moderate essential hypertensives were randomized in a double-blind manner to 5 mg bisoprolol daily or 25 mg captopril twice daily for 8 weeks. Erythrocyte insulin binding and insulin-stimulated tyrosine kinase (TK) activity were measured before and after therapy. Both agents decreased diastolic blood pressure significantly (bisoprolol 96.5 ± 0.9 to 87.8 ± 3.1 mm Hg; captopril 96.5 ± 0.9 to 91.5 ± 1.8 mm Hg; P < .05). Fasting plasma glucose, insulin, and insulin/glucose indices remained unchanged after both therapies, as did lipid profiles. Maximal insulin-stimulated TK activity, assessed by phosphorylation of the exogenous substrate poly-Glu80Tyr20, was significantly higher (P < .05) after bisoprolol treatment, but not after captopril treatment, when compared to placebo (bisoprolol 8.5 ± 1.8; captopril 7.3 ± 1.5; placebo: 6.4 ± 1.3 pmol 32P-ATP/fmol bound insulin). However, captopril, but not bisoprolol, increased the sensitivity of the receptor TK activity, as measured by the half-maximal activity concentration (ED50). Specific insulin binding was not affected by these two agents. Thus, both captopril and bisoprolol may have favorable but different effects on TK activity and insulin action at the cellular level. Ligia J. Dominguez,et.al. American Journal of Hypertension, 1997;10:1349–1355

36 比索洛尔对CHF合并T2DM患者糖脂代谢 无明显影响
基线 卡维地洛 (达最大剂量) P值 比索洛尔 两组间 基线 卡维地洛 (达最大剂量) P值 比索洛尔 两组间 血糖控制 ns HbA1c 7.7 ± 1.5 7.2 ± 1.2 0.02 7.0 ± 1.2 6.9 ± 1.3 0.92 血脂谱 TC/HDL 4.1 ± 1.0 3.7 ± 1.1 0.07 3.1 ± 1.0 3.0 ± 1.2 0.67 LDL/HDL 2.2 ± 0.9 2.0 ± 0.9 0.08 1.5 ± 0.7 1.5 ± 1.0 0.83 TG 1.9 ± 1.2 2.0 ± 1.5 0.66 1.6 ± 1.2 1.5 ± 0.9 0.52 The mean peak dose of carvedilol was 26.5 ± 21.1 mg/day and bisoprolol was 5.8 ± 3.0 mg/day. n = 80 carvedilol, n = 45 bisoprolol Wai et al. Cardiovascular Diabetology 2012, 11(1):14

37 比索洛尔对血脂谱影响小 Frithz G. 5th Internat Symposium on Cardiovascular Pharmacotherapy,Minneapolis, Abstract 1993

38 BB可能导致支气管收缩的原因 与非选择性β受体阻滞剂相比， 高选择性β1受体阻滞剂较少引起支气管收缩
β-受体阻滞剂导致支气管收缩——多见于非选择性β-受体阻滞剂，因为： β2受体主要分布于支气管平滑肌 β1受体仅10% & 30%分布于粘膜下腺和肺泡壁 高选择性β1 受体阻滞剂对β1受体的亲合力比β2受体高75倍 与非选择性β受体阻滞剂相比， 高选择性β1受体阻滞剂较少引起支气管收缩

39 比索洛尔对肺功能影响小 合并慢阻肺的冠心病患者，比索洛尔对气道阻力无显著影响 b 2 1 小时 3 6 12 4 8 24 安慰剂组
比索洛尔组 阿替洛尔组 50 70 90 7 9 b = 用药前 n = 12 S± SEM 气道阻力(cmH2O/l/s) 心率（次/分钟） 合并慢阻肺的冠心病患者，比索洛尔对气道阻力无显著影响 Dorow P. Eur J Clin Pharmacol. 1986;31:143–147

40 Adapted from Dzau V. Braunwaid E.Am Heart J 1991:121:1244-1263
导致心血管死亡事件之链 心肌梗死 心律失常 冠脉血栓 肌肉丢失 猝死 心肌缺血 神经激素 激活 重塑 CAD 动脉硬化 LVH 心室扩大 心力衰竭 危险因素 高脂蛋白血症 高血压 糖尿病 胰岛素抵抗 死亡 Adapted from Dzau V. Braunwaid E.Am Heart J 1991:121:

41 谢谢！