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Isradipine improves impaired endothelium-mediated vasodilation in patients with hyperlipidemia independent of changes in cholesterol
ASH XII ABSTRACTS
ISRADIPINE IMPROVESIMPAIREDENDOTHELIUM-MEDIATEDVASODILATION INPATIENTS WITHHYPERLIPIDEMIA INDEPENDENT OFCHANGESINCHOLESTEROL W. Kiowski, C, Bracht, X. Yan, G. Siitsch, P. Poget, H. Brmrner Div. of Cardiology, University Hospital, Zitrich, Switzerland Isradipine (Isr) has antiatherosclerotic effects in animals and improves nitric oxide (NO) -dependent vasodilation in vitro. We investigated whether Isr would also improve NO-mediated vasodilation in humans and studied 30 normotensive patients (pts; age 55.4+10.5 years) with angiographicafly proven coronary artery disease and elevated (> 6 mmol/1) total cholesterol (Chol) or a Chol/ HDL-Chol ratio of >5 and 10 healthy, age matched control subjects. Forearm blood flow responses (FBF; ml/mirr/100 ml) to graded brachial artery infusions of acetylcholine (Ach; 10 - 1600 ~g/1000 ml/ min for 3 min each), to the NO-synthaae blocker L-NMMA (2500 vg/1000 ml/min for 5 rein) and to the endothelium-independent vasodilator sodium nitroprrrsside (SNP; 10 ~g/ 10CS3ml/min for 3 rein) were measured. Pts were restudied after double blind, randomized therapy with Isr 5 mg/d or placebo (Pla) for 3 months. No dietary advice was given and no pt received a lipid lowering drug. Isr/Pla were withheld for 2 days prior to the repeat study. Mean blood pressure (BP) was similar in pts and control subjects (85 vs 90 mmHg) and total Chol was elevated in pts (6,7 vs 5.0 mmol/1). While FBF responses to SNP and LNMMA were similar in both groups the response to Ach was attenuated in pts (AFBF: 10.9 vs 14.1 for the highest Ach dose, p<.05). After 3 months, BP was unchanged in both groups on the day of study but Chol levels decreased similarly in both groups (Isr: 6,7 vs 6.1 mmolll, n.s,; Pla: 6.6 vs 5.9 mmol/1, p
A]H-APRIL 1997-VOL. 10, NO. 4, PART 2
EFFECTS OF 4 WEEKS OF AMLODIPINE THERAPY ON MUSCLE SYMPATHETIC NERVE ACTIVITY, ~ Caltroun*,VascularBiology amdHypcrtmaion Prcgram, Univcraityof Alabama at B-gbam, Birmmgham,AL. ‘f%eprcwrrtstudy was designedto dctcrmieefhc effcots of short-tarn arnlodipinstherapy on periphed sympathetic nerve activity. A&r withdrawingarrtibypertenaivetherapy for a mirrimmnof2 wks, resting hamodynanricvafues and muscle symP~~c n~e acdtity (MSNA) recordedby microneurographyfrom the Ml pcrorzeafnerve were determined in 10 subjexts (5 African-Americazssand 5 wlrk). AUsubjects were thcrrbegun on amodipirre5 rrrgqday. A&r 2 wka, the doac ofamfodipine was inweeacdto 10 mg qday irr8 subjects whoaeblood pM33u7Srcmaincdin the bypatcnsive range, After an additional 2 wka, rcatinghcrncdyrramicaed MSNA values at trough (24-26 bra post-dosieg) were determinedad compared to baactincvalues by ANOVA formpestcdrneauq. ‘f%emean ageofsubjectawaa 4725 years andweight was 95ti kg. Vatusa (mean+SEM)at baseline arrdatlcr4-wks of fhexapy were: DBP MAP HR SBP MSNA (mnrI-fz) hrrrf-k) (EnmHx) (bAnin) (trur3ts/EEde) 35+c4.8 92 &ZO l13fl,4 6%3.0 BasAirre 156+4.7 4-wk3 14M3.6* 85*1.2* 103*1.7* 71i3,2 49+3.7* * Stadaticslly ~ ffornbeaalina, ~o.05. Thcabovedata &mmtmtefhat aRer4-wka of andodipinetherapy arrdwhen aasmsed at trough serum levels, pcripberat aympabdc nerve activity is increaaed. UnknmvrEia the cffactofkmg-term arrdodipincuaeor the efl’ectofother cfascs ofartihypcrbmaive agents on mstirrgMSNA,
mic~b> Key Words:
‘c activity, celcium SYM@I@
antagonist
Kay words: Endothelium, hypercholesterolemia, calcium antagonists, forearm circulation
ANTIHYPERTENSIVE MEDICATIONS AND CARDIOVASCUmR DISEASE IN A IARGE COHORT OF U.S. WOMEN. K,B, Michels, B.A. Rosner, J.E, Manson, M.J. Stampfer, A.M. Walker, W,C, Willett, C.H. Hennekens. Charming Laboratory, Harvard Medical School, Brigham and Women’s Hospital, Boston. Cardiovascular morbidity and mortality (CVD) were studied among 14,476 hypertensive women in a prospective cohort study, the Nurses’ Health Study, who reported intake of one or more of the following medications in 198S: thiszide diuretics (TD), beta-blockers (BB), (short-acting) calcium channel blockers (CCBI, or ACE inhibitors. CVD was followed prospectively from 19BB through 1S94. The relative risks of documented fetel and nonfatal myocardial infarction and of total cardiovascular events according to medication status and 95% confidence intervals are given in the table below. Covariate-adjuated relative risks are adjusted for history of angina pectoris end diabates prior to 19SB, as well as reported alcohol intake, smoking, body mass index, menopausal status, postmenopausal hormone use, aspirin intake, cholesterol level, and exercise. Cardlwrmc.lar Event. W...,diel I.farcrmn Excluding priorMl Excluding priorCW) A9,C..ariate. AwC.variat.. adjusted adiusted’ adjusted adjusted 14,053 No,of women 14,1a9 22a 37a No. of TD 1,00(referent) 100 1 CQ(referent] 1.00 1:27 1:2a[0.e6.1.e5) 1.11 1.13(0.a3-1.54) 8B 2.43 1.76 1,35i0.aa.2.Oa) 1.6610 .9e.2.62) CCB 1.14(0.75-1.74) 1,61 1.40(0,83-2,39) 1.2e ACE 1.4eil,w2.16) 1 24(0 92-1.67) 1.70 137 To&6B 1.53(1:03-2,27) 1.96[1,22-3.15} 2:30 cca&TDoraa 3,53 1.12[0.62-2.01) 1.45 1.29{0.a5-1.e4) ACE&TO oraa 1.34 ~tov ofstrokeprior to 19!s9, These resulta may suggaat an increased risk of cardiovascular diseaae among patiente prescribed CCB, hut neither chance nor confounding by indication cen be completely excludad. These findings may not be relevant to longer-acting forms of CCB which are more commonly used at present. Randomized trials to address these issuea ara currently underway. Kay WOKIS: Calcium channel blockers, hypertension,
events
cardiovascular
diseese, myocardial infarction
TREATMENT WITH CALCIUM CHANNEL BLOCKERS OOES NOT INCREASE THE RISK OF FATAL AND NON-FATAL CANCER IN AN ELDERLY EUROPEAN POPULATION: RESULTS FROM STEPHY Il. ~forthe STEPHY Investigators, Stsmbsfg Hospital, Ludwig Maximilian University Munich, Stsmberg, Gentrsny. Recently, expsrimentsl data - linking phsmtseological blockade of calcium ef’fsnnels snd inhibition of spoptoaie - snd s cohort study from the US postulated sn incmsead risk of cancer with use of caloium channel blockerx (CCBS). The aim of the present study wss to aeeses the relstionehip bafwaan the 3-year inddencs of fstal or non-fetsl cancer snd the use of CCBsin the STEPHY (Sfambsfg Study on Epkfemiology of Psddneonism and Hypertension in the Elderly) population. In 1992 STEPHY inveefigatad (queetionnske snd examination st home) the totsl population z65 yeere (n=l182) of 2 villages in Bavaria, Germany. A total of 982 Inhebitsnfe psrtio@tted (sge 6599 years). The prsvslencs of “sdusl” hypertension (blood pressure z160/95 mmHg or sntihypeftensive treetment) was 53%. Of sII hypertensive S4% were treated, 26% (n=137) wfth CCBS (sseeaead by showing the mntsiners of scfually prescribed drugs during the interview). Partitipanta (IT) with s history of canoer or msnifeet cancer ware excluded from furiher analysis. In 1995 STEPHY 11,a 3-yesr follow-up, seseeaad mortality (Including fatal cenc8re) ecconiing to offtcial death csftificates, catiiovsecular events snd non-fatal cancers, both sccording to a second interviaw and case raccmls of hoepitsls snd GPa. The incidence of fstal and non-fatal csncar was calculstsd for PT on CCBS and not on CCSS. Total moriality waa 12,1% (n=l19). There were 22 deaths due te carmar and 75 cease of newly diagrmead non-fatal cancer. The incidence of fatal cancer waa 2.2% (n =3) for PT on CCBS and 2.1% (n=19) for those not on CCBS, the incidence of non-fatal csmcsr was 12% (n=12) for those on CCSS and 11% (n=63) forthees not on CCBS (both differences not slgniflcent). Conclusion: In a European population ?65 yearn of age CCSS do not incmses the risk of fatal or non-fatal cencarover 3 yeats.
Key Worda:
celdum channel blockers - side effects - drug safety osneer - antihyperfensive treatment
ISRADIPINE IMPROVESIMPAIREDENDOTHELIUM-MEDIATEDVASODILATION INPATIENTS WITHHYPERLIPIDEMIA INDEPENDENT OFCHANGESINCHOLESTEROL W. Kiowski, C, Bracht, X. Yan, G. Siitsch, P. Poget, H. Brmrner Div. of Cardiology, University Hospital, Zitrich, Switzerland Isradipine (Isr) has antiatherosclerotic effects in animals and improves nitric oxide (NO) -dependent vasodilation in vitro. We investigated whether Isr would also improve NO-mediated vasodilation in humans and studied 30 normotensive patients (pts; age 55.4+10.5 years) with angiographicafly proven coronary artery disease and elevated (> 6 mmol/1) total cholesterol (Chol) or a Chol/ HDL-Chol ratio of >5 and 10 healthy, age matched control subjects. Forearm blood flow responses (FBF; ml/mirr/100 ml) to graded brachial artery infusions of acetylcholine (Ach; 10 - 1600 ~g/1000 ml/ min for 3 min each), to the NO-synthaae blocker L-NMMA (2500 vg/1000 ml/min for 5 rein) and to the endothelium-independent vasodilator sodium nitroprrrsside (SNP; 10 ~g/ 10CS3ml/min for 3 rein) were measured. Pts were restudied after double blind, randomized therapy with Isr 5 mg/d or placebo (Pla) for 3 months. No dietary advice was given and no pt received a lipid lowering drug. Isr/Pla were withheld for 2 days prior to the repeat study. Mean blood pressure (BP) was similar in pts and control subjects (85 vs 90 mmHg) and total Chol was elevated in pts (6,7 vs 5.0 mmol/1). While FBF responses to SNP and LNMMA were similar in both groups the response to Ach was attenuated in pts (AFBF: 10.9 vs 14.1 for the highest Ach dose, p<.05). After 3 months, BP was unchanged in both groups on the day of study but Chol levels decreased similarly in both groups (Isr: 6,7 vs 6.1 mmolll, n.s,; Pla: 6.6 vs 5.9 mmol/1, p
A]H-APRIL 1997-VOL. 10, NO. 4, PART 2
EFFECTS OF 4 WEEKS OF AMLODIPINE THERAPY ON MUSCLE SYMPATHETIC NERVE ACTIVITY, ~ Caltroun*,VascularBiology amdHypcrtmaion Prcgram, Univcraityof Alabama at B-gbam, Birmmgham,AL. ‘f%eprcwrrtstudy was designedto dctcrmieefhc effcots of short-tarn arnlodipinstherapy on periphed sympathetic nerve activity. A&r withdrawingarrtibypertenaivetherapy for a mirrimmnof2 wks, resting hamodynanricvafues and muscle symP~~c n~e acdtity (MSNA) recordedby microneurographyfrom the Ml pcrorzeafnerve were determined in 10 subjexts (5 African-Americazssand 5 wlrk). AUsubjects were thcrrbegun on amodipirre5 rrrgqday. A&r 2 wka, the doac ofamfodipine was inweeacdto 10 mg qday irr8 subjects whoaeblood pM33u7Srcmaincdin the bypatcnsive range, After an additional 2 wka, rcatinghcrncdyrramicaed MSNA values at trough (24-26 bra post-dosieg) were determinedad compared to baactincvalues by ANOVA formpestcdrneauq. ‘f%emean ageofsubjectawaa 4725 years andweight was 95ti kg. Vatusa (mean+SEM)at baseline arrdatlcr4-wks of fhexapy were: DBP MAP HR SBP MSNA (mnrI-fz) hrrrf-k) (EnmHx) (bAnin) (trur3ts/EEde) 35+c4.8 92 &ZO l13fl,4 6%3.0 BasAirre 156+4.7 4-wk3 14M3.6* 85*1.2* 103*1.7* 71i3,2 49+3.7* * Stadaticslly ~ ffornbeaalina, ~o.05. Thcabovedata &mmtmtefhat aRer4-wka of andodipinetherapy arrdwhen aasmsed at trough serum levels, pcripberat aympabdc nerve activity is increaaed. UnknmvrEia the cffactofkmg-term arrdodipincuaeor the efl’ectofother cfascs ofartihypcrbmaive agents on mstirrgMSNA,
mic~b> Key Words:
‘c activity, celcium SYM@I@
antagonist
Kay words: Endothelium, hypercholesterolemia, calcium antagonists, forearm circulation
ANTIHYPERTENSIVE MEDICATIONS AND CARDIOVASCUmR DISEASE IN A IARGE COHORT OF U.S. WOMEN. K,B, Michels, B.A. Rosner, J.E, Manson, M.J. Stampfer, A.M. Walker, W,C, Willett, C.H. Hennekens. Charming Laboratory, Harvard Medical School, Brigham and Women’s Hospital, Boston. Cardiovascular morbidity and mortality (CVD) were studied among 14,476 hypertensive women in a prospective cohort study, the Nurses’ Health Study, who reported intake of one or more of the following medications in 198S: thiszide diuretics (TD), beta-blockers (BB), (short-acting) calcium channel blockers (CCBI, or ACE inhibitors. CVD was followed prospectively from 19BB through 1S94. The relative risks of documented fetel and nonfatal myocardial infarction and of total cardiovascular events according to medication status and 95% confidence intervals are given in the table below. Covariate-adjuated relative risks are adjusted for history of angina pectoris end diabates prior to 19SB, as well as reported alcohol intake, smoking, body mass index, menopausal status, postmenopausal hormone use, aspirin intake, cholesterol level, and exercise. Cardlwrmc.lar Event. W...,diel I.farcrmn Excluding priorMl Excluding priorCW) A9,C..ariate. AwC.variat.. adjusted adiusted’ adjusted adjusted 14,053 No,of women 14,1a9 22a 37a No. of TD 1,00(referent) 100 1 CQ(referent] 1.00 1:27 1:2a[0.e6.1.e5) 1.11 1.13(0.a3-1.54) 8B 2.43 1.76 1,35i0.aa.2.Oa) 1.6610 .9e.2.62) CCB 1.14(0.75-1.74) 1,61 1.40(0,83-2,39) 1.2e ACE 1.4eil,w2.16) 1 24(0 92-1.67) 1.70 137 To&6B 1.53(1:03-2,27) 1.96[1,22-3.15} 2:30 cca&TDoraa 3,53 1.12[0.62-2.01) 1.45 1.29{0.a5-1.e4) ACE&TO oraa 1.34 ~tov ofstrokeprior to 19!s9, These resulta may suggaat an increased risk of cardiovascular diseaae among patiente prescribed CCB, hut neither chance nor confounding by indication cen be completely excludad. These findings may not be relevant to longer-acting forms of CCB which are more commonly used at present. Randomized trials to address these issuea ara currently underway. Kay WOKIS: Calcium channel blockers, hypertension,
events
cardiovascular
diseese, myocardial infarction
TREATMENT WITH CALCIUM CHANNEL BLOCKERS OOES NOT INCREASE THE RISK OF FATAL AND NON-FATAL CANCER IN AN ELDERLY EUROPEAN POPULATION: RESULTS FROM STEPHY Il. ~forthe STEPHY Investigators, Stsmbsfg Hospital, Ludwig Maximilian University Munich, Stsmberg, Gentrsny. Recently, expsrimentsl data - linking phsmtseological blockade of calcium ef’fsnnels snd inhibition of spoptoaie - snd s cohort study from the US postulated sn incmsead risk of cancer with use of caloium channel blockerx (CCBS). The aim of the present study wss to aeeses the relstionehip bafwaan the 3-year inddencs of fstal or non-fetsl cancer snd the use of CCBsin the STEPHY (Sfambsfg Study on Epkfemiology of Psddneonism and Hypertension in the Elderly) population. In 1992 STEPHY inveefigatad (queetionnske snd examination st home) the totsl population z65 yeere (n=l182) of 2 villages in Bavaria, Germany. A total of 982 Inhebitsnfe psrtio@tted (sge 6599 years). The prsvslencs of “sdusl” hypertension (blood pressure z160/95 mmHg or sntihypeftensive treetment) was 53%. Of sII hypertensive S4% were treated, 26% (n=137) wfth CCBS (sseeaead by showing the mntsiners of scfually prescribed drugs during the interview). Partitipanta (IT) with s history of canoer or msnifeet cancer ware excluded from furiher analysis. In 1995 STEPHY 11,a 3-yesr follow-up, seseeaad mortality (Including fatal cenc8re) ecconiing to offtcial death csftificates, catiiovsecular events snd non-fatal cancers, both sccording to a second interviaw and case raccmls of hoepitsls snd GPa. The incidence of fstal and non-fatal csncar was calculstsd for PT on CCBS and not on CCSS. Total moriality waa 12,1% (n=l19). There were 22 deaths due te carmar and 75 cease of newly diagrmead non-fatal cancer. The incidence of fatal cancer waa 2.2% (n =3) for PT on CCBS and 2.1% (n=19) for those not on CCBS, the incidence of non-fatal csmcsr was 12% (n=12) for those on CCSS and 11% (n=63) forthees not on CCBS (both differences not slgniflcent). Conclusion: In a European population ?65 yearn of age CCSS do not incmses the risk of fatal or non-fatal cencarover 3 yeats.
Key Worda:
celdum channel blockers - side effects - drug safety osneer - antihyperfensive treatment