Clinical and Basic Research on Redegenerative Valvular Heart Disease and Vascular Calcification

20th GW-ICC Geriatric Cardiology symposium

Sponsored by Military “15th” key grant on medical science （ No ： 01Z034 ） &NSFC foundation （ No ： 39770869 ）

Wang Shiwen

Institute of Geriatric CardiologyChinese PLA General Hospital

Background• Retrograde valvular heart disease in the elderly ：

A common valvular disease in the elderly that caused by calcification of heart valves with age. It is the most common reason of valve replacement and mortality

• Vascular calcification ： common lesion in the elderly

indicator of AS degrees

pathological foundation of many Vascular disease

Background

• Mobility of RVHD increases in China along

with advanced elderly population

• Compared with other diseases (CHD,DM, et

al), research on RVHD remains largely

insufficient

Study Contents

• Follow-up study on RVHD • Large scale epidemiologic analysis on RVHD a

nd vascular calcification in the elderly • Further investigation on clinical and molecular

etiology• Statins intervention on RVHD and vascular calc

ification in the elderly

Follow-up Research on Clinical Epidemiology of RVHD

A 6-year follow to 95 cases of valvular calcification and 95 cases of normal patients

• Occurrence of murmur,ventricular enlargement,nodal lesion,A-V block and AF in the elderly patients with RVHD was shown much higher. （ P < 0.05 ）

• Occurrence of congestive heart failure,AMI,cerebral vascular disease and syncopy was also remarkably higher. （ P < 0.05 ）；

RVHD could lead to hemodynamic change,worsen cardiac dysfunction,which turned to be one of the important cause of cardiocerebral disease as well as cardiac arrest. Recognizing the complication on time and early treatment might exert key role in prognosis.

Yuzhen Zhang,Shiwen Wang, Bing Wu, et al. Chinese Gerontology Journal,1994; 13(4):96 － 97

Large scale epidemiologic analysis on RVHD and vascular

calcification in the elderlyStudy was carried on in 8202 elderly retired veterans. 820

were randomized according to age.

• Mobility and proportions of RVHD in the elderly

• Risk factors of RVHD in the elderly

• Correlation between RVHD and carotid athrosclerosis (CAS)

Mobility of RVHD and Relative Risk Factor

Age,hypertension,hyperlipidimia,stroke,cardiovascular family history consist of major risk factors of RVHD in the elderly. Lowering body weight,regular physical exercise as well as adjustment of relative unhealthy life style would prevent and block the pathogenesis of RVHD in the elderly.

CAS ：颈动脉粥样硬化； SDVHD ：退行性心脏瓣膜病； IMT ：颈动脉内膜－中膜厚度

Relationship between Valvular Calcification and CAS

It was shown that valvular calcification was more popular in CAS patients.Doppler examination observing carotid inter-medial thickness would diagnose CAS early and guild the treatment,also effectively block the development of vulvalar calcification and improve the prognosis.

• Alkaline phosphatase might be an initiator of vascular calcification.

• High homocystine level contributes to Ectopic calcipication• MMP-3 protein level was upregulated in aortic calcification,

which might accelerate calcification by certain pathway.• Many factors are involved in the aortic calcification, includi

ng SMC, TGF-β 、 and IGF-1 et al.

• Human KARP-1 –binding protein and KIAA0470 protein might play roles in aortic calcification.

Articles On RVHD and vascular calcification in the elderly

clinical pathology of RVHD

瓣膜内皮下弹力层移位和碎片化。 VvG 染色 X 100

病变内钙盐沉积和胆固醇结晶。茜素红染色 X 400

纤维层内脂质沉积与胶原纤维平行。油红 O 染色 X100

病变瓣膜内单核细胞浸润。CD68 免疫组化染色 X 400

病变瓣膜中新生毛细血管。CD31 免疫组化染色 X 40

骨母细胞标志物表达阳性，OPN 免疫组化染色 X400

The study provide clinical pathology evidences of the hypothesis that RVHD is a arts like pathology, also provide important theoretical foundation of statins interventions on RVHD.

尹彤，王士雯，赵玉生等 . 中华老年多器官疾病杂志 ,2004;4(4):277 － 281张玉珍，王士雯等 .中华心血管病杂志 ,1991;19(6):372 － 376

王从容，王士雯等 .中华内科学杂志 ,1994; 33(10):690王从容，王士雯等 .中华老年医学杂志 ,1995;14(4):220 － 223

Research of Potential prevention and treatment of Statin on RVHD as wel

l as Valvular CalcificationBackgroud ：• Epidemiology research showed hyperlipidemia is an indep

endent risk factor of RVHD.• Clinical pathological research showed RVHD possess simi

lar pathohistological characteristics with AS.• Basic research found RVHD possess similar influence fact

ors and mechanism with AS.

Content ：• The beneficial role of statin on prevention and treatment o

f RVHD was proven by intervention in vivo and in vitro, as well as follow-up to RVHD patients.

Effect of Provastatin on Valvular Calcification and Possible Mechanism

• Provastatin reduced calcium deposion dose-dependently.Also,despite ALP activity didn’t change much, Osteocalcine in supernatant decreased obviously.

The present study proved for the first time provastatin cou

ld reduce calcium deposition,ameliorate in-vivo vascular ca

lcification,suggesting the potency of provastatin on calcific

ation treatment.

50μm ×50μm

500 nm ×500 nm

高脂饮食组 高脂饮食及阿托伐他汀干预组对照组

150 nm ×150

nm

直径 :11－ 19 nm

In-situ observation on ultrastructure changes of arotic Valvular endothelium

In-situ observation shows that statins have protective effect on endo

thelium surface from hyperlidermia. The atom microscope reveale

d changes of nanometer channels and receptor like domains.

This study suggested that hyperlidermia is a risk factot of RVHD an

d statins may be a prospective therapy.

尹彤，王士雯，高磊 , 纪小龙。临床与实验病理学杂志， 2005 ， 21 ： 713 － 717.

Clinical Research of Statin in Early Prevention and HF mortality

• Since 2000 ， 1138 cases of RVHD was diagnosed by UCG in IGC,including 417 cases of aortic valvular disease,310 of mitral valvular disease,385 cases of joint valvular disease.

• In 943 cases of HF in the elderly,about 24% were found to have RVHD. We realized the importance of lipid-lowering therapy from clinical and basic research, reinforced the treating strategy to HF patients. Therefore, the efficiency of HF treatment was elevated to 93.5%.

Typical case 1 ：•male ， 71 years old ， paroxysmal chest compression for 15 years,get severe for 1 day.•Primary diagnosis ： CHD,UAP,HP (2nd Grade),CAS,hyperlipidemia•UCG ： RVHD ； Diminished left ventricular diastolic function.•Anti-platelet,anti-inflammation treatment•Follow-up in outpatient ， strengthening lipid-lowering therapy 、 anti-platelet coagulation 、 coronary dilating,anti-hypertension, no cardiac end point event was found.

This is a typical case of multiple branches coronary

disease.3 main branches was diffusingly invasive an

d stenosized. After lipid-lowering therapy, the AS a

nd calcificating degree didn’t get worse.

Typical case 2 ：

•male ， 54 years old.•Paroxysmal chest pain for 6 months,get strengthened for 1 month•CTA ： stenosis in left coronary artery,calcification.•After strengthened lipid-lowering therapy and anti-platelet therapy for 4 years,the patient’s condition is still stable.

Innovations • This study is the first epidemical survey on RVHD in the

elderly veterans 。

• The first clinical pathology study on RVHD in the elderly in China. Revealed similarities between RVHD and arts 。

• The first systemic study on mechanism of RVHD in China

• The first clinical study and observation about intervention of statins on RVHD and vascular calcification in China 。

Application and social effect

• The results of this study was published total 39 articles,international congress 23 times,3 books,was cited 57 times. Relative therapy and skills were applicated in 14 colleges and educated 2000 medical staff.

• Totally 12 doctors,as well as masters participated the study.

Future steps

• A large scale epidemiologic study is needed to be done among citizens other than veterans to get more precise clinical data

• A multi-center, prospective and larger scale study is needed to justify the statin intervention on RVHD in the elderly