2007 년년년춘 춘 계대 계 한 순 환 기 학 회 Apr 20-21 2007

New Concept of Calcium Channel Blocker In The Improvement of Cardiovascular Function

Myung Ho Jeong , MD, PhD, FACC, FAHA, FESC, FSCAI

Chonnam National University Medical School, The Heart Center of Chonnam National University Hospital, Gwangju , Korea 사망자 / 100 만 심혈관질환은 심혈관질환은 심혈관질환은 심혈관질환은 10 8 0 2 4 6 8.0 E D C B A 4.0 A B C 심혈관심혈관 암암암 사고사고 심혈관심혈관 암 사고사고 3.4 남자 남자 남자 남자 질환질환 질환질환 1.8 1.5 전세계 전세계 전세계 전세계 0.4 F D F E HIV/AIDS 사망원인 사망원인 사망원인 사망원인 8.6 E D C B A 당뇨병당뇨병 당뇨병당뇨병 호흡기호흡기 호흡기호흡기 3.2 질환질환 질환질환 1.7 여자 여자 여자 여자 1.7 1.3 111위 1 위 위 위 (2001 0.5 F 년 WHO) 우리나라에서는 사망률 222위2위 성인 사망률 111위는1위는 순환기질환

70,000 25.0%

60,000

50,000

40,000

30,000 사망자수 사망자수 사망자수 사망자수

20,000

10,000

0

기타 질환 질환 질환 질환 질환 질환 질환 질환 질환 질환

감염 정신 신경 ,종양 순환기 호흡기 소화기 내분비 비뇨기 혈액 근육골격 2002년 통계청 Atherosclerosis: A Progressive Disease Arrhythmia & Loss of muscle Coronary Thrombosis Sudden Death Myocardial Infarction Silent Myocardial Remodeling Angina Ischemia Hibernation Ventricular dilatation

CAD Congestive Heart Failure

Atherosclerosis, LV Hypertrophy End Stage Heart Disease Risk Factors (smoking, HL, HT, DM, insulin resistance, arterial stiffness…) Progressive Development of Cardiovascular Disease

Risk Factors Prevention or Early Treatment Endothelial Dysfunction at Initial Stage is more Important Atherosclerosis CAD Myocardial Ischemia Coronary Thrombosis Myocardial Infarction Arrhythmia & Loss of Muscle Remodeling Ventricular Dilation Congestive Heart Failure Endstage Heart Disease Hypertension and Cardiovascular Disease

▶ For persons over age 50 , SBP is a more important than DBP as CVD risk factor

▶ Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range

▶ Persons who are normotensive at age 55 have a 90 % lifetime risk for developing HTN

▶ Those with SBP 120–139 or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD

JNC VII report. JAMA 2003;289:2573-2575 Hypertension and Cardiovascular Disease

▶ Benefits from BP control

Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50%

JNC VII report. JAMA 2003;289:2573-2575 Hypertension and Cardiovascular Disease

Stroke MI HF All CV end points

-5%

-15%

-25% P<0.001

-29% -30% -31% -35% P=0.003

Reduction withReduction active treatment (%) -42% -45% Subjects are elderly persons with ISH

Syst-Eur Trial. Staessen et al. Lancet 1997 Korea Acute Myocardial Infarction Registry (KAMIR) STUDY – 위험 인자

STEMI (n=4149) NSTEMI (n=2724) 고혈압 Yes (%) 1829(44.1) 1432(52.6) No (%) 2032(55.9) 1292(47.4) 당뇨병 Yes (%) 1012(24.4) 830(30.5) No (%) 3137(75.6) 1894(69.5) 고지혈증 Yes (%) 261(6.3) 275(10.1) No (%) 3888(93.7) 2449(89.9) 흡연 Yes(%) 1904(45.9) 980(36.0) No(%) 2245(54.1) 1744(64.0)

2006 년년년 10 월월월 대한순환기학회대한순환기학회 7,164 명명명 분석분석 결과 Hypertension and CAD: Beyond BP Lowering

▶▶▶ BP is strongly linked to the risk for CAD and CVA : caused by atherosclerosis associated with endothelial dysfunction and stiffening of artery

▶▶▶ Incidence of CAD : higher in treated hypertensive patients than in matched controls, despite similar BP levels : cardiovascular function may be more important than BP reduction Furberg et al. Ann Intern Med 2001 Calcium Channel and Cardiovascular System

▶ Various types calcium channels are present in human body ▶ BP regulation and calcium channel : About 6 types of calcium channels are involved : L-type

: T-type Main target of pharmacologic treatment (CCB) : N-type CCB and Cardiovascular Diseases

▶ Developed as vasodilators ▶ Widely used in various cardiovascular diseases : Hypertension : Symptomatic relief of stable angina : Stabilized UA/NSTEMI : Symptomatic relief of diastolic heart failure : Rate control of persistent atrial fibrillation Characteristics of Ca ++ Channel

▶▶▶ Require strong depolarization (high activation threshold) ▶▶▶ Long Lasting (slow activation rate) L-type ▶▶▶ Main currents recorded in muscle and endocrine cells ▶▶▶ Blocked by organic CCB (DHP, Phenylalkylamines, benzothiazepines)

▶▶▶ Activated at weak depolarization potential

T-type ▶▶▶ Transient (fast inactivation)

▶▶▶ Resist to L-type and N- and P/Q-type blockers

▶▶▶ Require strong depolarization for activation ▶▶▶ Resistant to L-type blockers N-type ▶▶▶ Found primarily in neurons: initiate neurotransmission ▶▶▶ Blocked by specific polypeptide toxins Main Functions of Ca ++ Channel

Main Functions of L-Type Ca ++ Channels in the CV System

Cadiac action Excitation-contraction potential generation & coupling in the heart propagation (AV- conduction)

Vascular contaction

Regulation of pacemaker activity

Main Functions of T-Type Ca ++ Channels in the CV System Classes of Calcium channel blocker

Tissue Chemical Group 1st Generation 2nd Generation 3rd Generation Selectivity Vascular > Nifedipine Nifedipine Amlodipine Myocardium Nicardipine SR/GITS Lacidipine Nicardipine SR Cilnidipine Felodipine Lercarnidipine Dihydropyridines Isradipine Nimodipine Nisoldipine Nitrendipine Vascular = Diltiazem Diltiazem SR Benzothiazepines Myocardium Vascular Verapamil Verapamil SR Phenylalkylamines < Myocardium Gallopamil First Generation CCBs

▶ Inhibit voltage-dependent L-type calcium channel : Vascular smooth muscle relaxation (vasodilator) : Negative chronotropic and inotropic effects in the heart ▶ Vasodilation-triggered, baroreceptor-mediated reflex increase in sympathetic tone : Indirect cardiostimulation : Associated with adverse events Classical Effects of First Generation CCBs

CCB

Mason RP & Hintze TS. ATVB 2003;23:2155-63 Clinical Trials with 1 st generation CCBs

Nifedipine may paradoxically exacerbate the frequency of angina pectoris!!! Am Heart J 1983;1066(4 pt 1):644-52

Short acting nifedipine increases mortality in patients with CAD!!! Circ 1995;92:1326-31

Diltiazem associated with 63% increase in rate of MI in hypertensive pts!!! J Am Geriatr Soc 1995;274:620-5

Diltiazem increases the risk of ADHF and death in pts with post-MI Circ 1991;83:52-60 Clinical Problems of First Generation CCBs

▶ Rapid onset and short duration of short-acting formulations : Lead to neurohormonal activation : Can be detrimental in CAD and CHF ▶ Reflex-mediated increase in sympathetic tone : Reflex tachycardia : Worsening angina, CHF or increased risk of mortality ▶ Coronary steal to non-ischemic myocardium via collaterals : Arterioles are more affected by CCB than larger epicardial coronary arteries Second and Third Generation CCBs

▶▶▶ Slower onset and longer duration of action ▶▶▶ Less pronounced increase in sympathetic tone : Reduced reflex tachycardia ▶▶▶ Reduced likelihood of negative inotropic effects ▶▶▶ Beneficial cardiovascular effects beyond BP lowering : So called “pleiotropic effects” of CCB 2nd & 3 rd Generation CCBs

▶ Meta-analysis of placebo controlled trials with longer-acting CCB suggest mortality benefit in treated patients (HTN, post- MI, CHF, CAD) Opie LH. JACC 2000 ▶ RCTs with amlodipine & felodipine in patients with LV dysfunction revealed equivalent (if not improved) mortality rates Packer et al. NEJM 1996

Cohn et al. Circ 1997 Pleiotropic Effect of 2 nd & 3 rd Generation CCBs

Inhibition of Enhancement SMC Migration of Endothelial and NO production Proliferation

2nd or 3 rd Lipid Endothelial Antioxidant Generation Cell Activity Calcium Channel Cytoprotection Blocker

Remodeling of Modulation of Atherosclerotic ECM Membrane Metabolism Structure Endothelial Function and CCB

▶ Lacidipine restores endothelium dependent FMD of brachial artery in patients with HT Taddel et al. Hypertension 1997

▶ Combination of nifedipine and cerivastatin improves coronary endothelial function measured by QCA change of coronary diameter after intracoronary infusion of acetylcholine

ENCORE Investigators. Circulation 2003 Endothelial Function and CCB

▶▶▶ Benidifine improves endothelium dependent FMD of brachial artery in patients with HT

Mikino et al. Blood Press 2005

▶▶▶ Calcium channel blocker not only protect the endothelium through their blood pressure lowering action but also improve endothelial function through the stimulation of NO

production Yasuda et al. Clin Calcium 2005 Endothelial Function and CCB: NO Biology

CCB

Mason RP & Hintze TS. ATVB 2003;23:2155-63 VSMC Growth/Proliferation and CCBs

CCB

Mason RP & Hintze TS. ATVB 2003;23:2155-63 Ant-oxidant Effect of CCBs

CCB

CCB blocks free radical propagation in the lipid bi-layer

Mason RP & Hintze TS. ATVB 2003;23:2155-63 Anti-atherogenic Properties of CCB

▶ Anti-oxidant properties ▶ Small animal studies suggest that some CCBs : Reduce influx of LDL into arterial wall : Suppress progression of atherosclerosis in aorta

: Decrease thromboxane A2 production ▶ Human studies (limited, less compelling) : Some evidence suggests decrease in new plaque formation : Enhanced effect when given with statins : Stronger evidence for carotid plaque regression

Hernandez et al. Am J of Therap 2003 Carotid IMT Regression: Clinical trials with CCB

Study name No Pts Duration Comparative Results drugs

Lacidipine vs. Significantly less carotid ELSA (1998) 2259 4 yrs atenolol progression in lacidipine group

Isradipine vs. No difference in rate of carotid MIDAS (1996) 883 3 yrs hydrochloroth IMT progression between iazide treatment group

Regression of larger lesions Verapamil vs. VHAS (1998) 498 4 yrs significantly greater in chlorthalidone verapamil group

Amlodipine vs. Less carotid IMT progression PREVENT (2000) 825 3 yrs Placebo in amlodipine group CAD and CCB: CAMELOT Study

▶ To evaluate the effect of antihypertensive agents on CV events in patients with CAD and normal BP

: CCB (Amlodipine) or ACEI (Enalapril) vs. Placebo

▶ 1991 patients with documented CAD and DBP < 100 mmHg ▶ Study endpoints : Incidence of CV events (CV death, MI, cardiac arrest, coronary revascularization, hospitalization) : Anti-atherosclerotic effects measured by IVUS

Nissen SE et al. JAMA 2004;292:2217-25 CAD and CCB: CAMELOT Study

Placebo Enalapril Amlodipine Cumulative event proportion event Cumulative

Months Nissen SE et al. JAMA 2004;292:2217-25 Changes of Percent Atheroma Volume: CAMELOT

All randomized patients (n=274) Patients with BP > mean (n=136)

Nissen SE et al. JAMA 2004;292:2217-25 Cilnidipine: Cinalong ® H HHH CCC NNN 333 CHCHCH 333

CHCHCH OCH CHCHCH OCOCOC = 333 222 222 COOCH 222CH=CHCH=CH---- OOO cinnamyl

▶▶▶ Newer 3 rd generation long-acting CCB ▶▶▶ Dual mechanism of action : Block both L-type and N-type calcium channel Cilnidipine: Mechanism of Dual Action

N-type Ca channel

SympatheticSympathetic NerveNerve ++ Ca NE MyocardiumMyocardium

ααα1-receptor βββ1-receptor L-type Ca channel Vasoconstriction Inotropic Chronotropic VSMCVSMC Soft on the heart !! Cilnidipine: Clinical Characteristics

▶▶▶ Effective BP lowering CCB without HR change ▶▶▶ Long duration of action: stable and steady BP control ▶▶▶ Favorable effects on lipid metabolism ▶▶▶ Favorable effects on glucose metabolism ▶▶▶ Improve LVH and diastolic function BP Lowering Effect: Cilnidipine vs. Amlodipine

Hoshide et al. Hypertens Res 2005 Changes in HR: Cilnidipine vs Amlodipine

Hoshide et al. Hypertens Res 2005 Cilnidipine: Lipid and Fibrinolytic Parameters

mmol/L mmol/L TTT-T---cholesterolcholesterol Triglyceride 6 2

4 ttt-t---PAPAPAPA----PAIPAIPAI----11 Complex1

2 0 6 0
Trend of changes in lipid and lipoprotein levels Before After Before After

: TC ↓↓↓mmol/L, HDLC ↑↑↑, HDLC/TC ↑↑↑, TG ↓↓↓,mmol/L LDLC ↓↓↓ 3 4 LDL HDL
Trend of changes in fibrinolytic parameters2 3 ↑↑↑ ↓↓↓ : tPA , tPA-PAI-1 complex0 2 Before After1
Beneficial lipid change and enhanced fibrinolysis 1 : important in anti-atherogenic actions in hypertensive patients Before After Before After

Drugs Exptl. Clin Res 2000 Cilnidipine: Catecholamine and C-peptide

㎍㎍㎍/day ㎍㎍㎍/day 25 250 UUU-U---EPEPEPEP UUU-U---NENENENE 20 32% 200 47% 15 150 10 100

5 50 0 0
N-type calciumBefore channel NVP CNP Before NVP CNP ㎍㎍㎍/day ㎍㎍㎍/day : 1500More important in pancreatic βββ-cell insulin secretion than L-type UUU-U---DADADADA 150 UUU-U---CPRCPR
Improve insulin resistance47% 36% 1000 100 : By inhibition of hyper-secretion of NE, dopamine (U-DA)

L,500 N-type CCB cilnidipine 50 : More effectively reduced the urinary levels of catecholamines and C-peptideBefore (U-CRP) NVP than CNP L-type CCB nilvadipineBefore (NVP) NVP CNP Diabetes Research & Clinical Practice 1999 Cilnidipine: LVH and Diastolic Function

Effective decreasing of SBP, DBP
Without changing HR -> heart protective effects
LVMI : significantly decreased
LV Wall motion velocity patterns : significantly improved
LV diastolic function : improved
Conclusion CCB (esp. cilnidipine) has an important myocardial-protecting action in addition to its antihypertensive effect Cilnidipine, * p<0.05, ** p<0.01, ***p<0.0001 Yukiko et al. Jpn Circ J 2001. FMD

101010 P=0.010 999 888 FMD (%) 777 666 555 444 333 6.21 8.10 222 111 000 4 weeks afterBefore CCB Treatment After in stageAfter I or II HT

CNUH Data. Korean Hypertension J 2006;1:13-18 Arterial Stiffness and CAD cm/s CAD (n=547) 1600 No CAD (n=256) ▶▶▶ Heart-femoral pulse wave velocity 1500 : significantly correlated with CAD

1400 : 1033.0 ±±±247.4 vs. 930.0 ±±±212.3 cm/s (p<0.001) 1300 ▶▶▶ Brachial-ankle PWV 1200 : significantly associated with CAD 1100 : 1542.0 ±±±340.4 vs. 1463.6 ±±±288.1

1000 cm/s (p<0.001)

900 haPWV baPWV

CNUH data, 2006 Korean Society of Internal Medicine, 2007 TCT-Asia Arterial Stiffness in Angina Following Cilnidipine (Cinalong ®) and Captopril (Capril ®)

(%) CCB and ACEI (n=39) (%) CCB and ACEI (n=39) CCB only (n=41) CCB only (n=41) 1100 2000

P=0.04 P=0.09 1900 P=0.004 P=0.006 1050 1800

1700

1000 1600

1500

950 1400

1300

900 1200 Heart-femoral PWV Brachial-ankle PWV

CNUH data, 2007 ACC 김계훈 홍영준 Lerman Schwartz 정명호 안영근 조장현 Conclusion

▶ Not all CCBs are created equally ▶ First generation, short-acting formulations may be detrimental in CAD, CHF ▶ Second and third generation, long-acting formulations are generally safer ▶ Well-established role in treating HTN and angina ▶▶▶ Additional clinical benefits with combined ACEI (esp. Cinalong + Capril) - improve endothelial dysfunction, arterial stiffness, vascular inflammation and renal dysfunction Perspectives

▶ Promising anti-atherogenic effects (Pleiotropic effects) : Enhancement of endothelial function and arterial stiffness : Anti-oxidant activities : Favorable effects on lipid and glucose metabolism : Enhanced fibrinolytic activity : Inhibition of VSMC growth and proliferation : Slowing of the progression of atheroma volume/IMT 황금황금 돼지돼지 해를해를 맞이하여맞이하여 순환기학회순환기학회 회원회원 모든모든 분들의분들의 건강과건강과 행복을행복을 기원합니다기원합니다 LLLLLL------&& N& NN& N ------typetype CaCa ++++++++++++ ChannelChannel BlockerBlocker

R CINAL NG

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