Lan Wei. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 260-301). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Photocopy. Ann Arbor, Mich. : UMI Dissertation Services, 2002. xx, 301 p. : ill. ; 22 cm. / Abstracts in English and Chinese.

A Hipercolesterolemia Familiar (HF) é uma doença caracterizada por aterosclerose precoce. Contudo, o curso clínico da doença coronária na HF é variável. A detecção da aterosclerose subclínica, pela espessura íntima média (IMT) carotídea, calcificação da artéria coronariana (CAC) e da rigidez arterial pela velocidade de onda de pulso (VOP) em portadores de HF pode ser útil na estratificação do risco cardiovascular. O objetivo primário deste estudo foi avaliar se existe correlação da CAC, IMT e VOP em portadores de HF. Como objetivos secundários, comparar estes marcadores de aterosclerose subclínica nos HF em relação a controles pareados por idade e sexo (CTRL) e avaliar quais são os principais fatores que influenciam a VOP carotídeo-femoral a IMT carotídea e a CAC, em pacientes com HF. Material e Métodos: Analisamos 89 HF (39±14 anos, 38% homens, LDL-c médio de 279 mg/dL) e 31 controles pareados para sexo e idade (CTRL) (LDL-c médio de 102mg/dL). Determinamos o IMT pela ultra-sonografia de alta definição tipo \"echotracking\" (Wall-Track System2), a VOP pelo método Complior®, CAC pela tomografia de múltiplos detectores, perfil lipídico e variáveis bioquímicas como Lp(a), PCR as, apoA1 e apoB. Foram calculados respectivamente o risco de DAC em 10 anos e a carga de exposição ao colesterol pelos escore de Framingham (ERF) e pelo índice LDL-c x idade (LYS). Resultados: Os HF apresentaram maior ERF (%) (7 ± 3 vs. 3 ± 3, p=0,002), maior prevalência de CAC (34% vs. 12%, p=0,024), maior IMT (micra m) (653 ± 160 vs 593 ±111, p=0,027), maior VOP (m/s) (9,2 ±1,5 vs. 8,5 ± 0,9, p=0.007) e glóbulos brancos mais elevados (x109 células/L) (7,2 ± 2,0 vs 6,4 ± 1,5, p=0,046) do que CTRL. Não foram observadas diferenças de PCR as respectivamente 1,7 (0,2-3,4 mg/L) e 1,3 (0,2-8,0 mg/L), p=n.s. para HF e CTRL. Na análise multivariada os determinantes da IMT foram: pressão arterial sistólica. (r2=0,36, p=0,045), ERF (r2=0,26, p=0,0001) e Apo B (r2=0,32, p=0,02). A idade foi o único determinante da VOP (r2=0,37, p=0,0001). Os determinantes independentes da CAC como variável contínua foram: sexo masculino (r2=0,36, p=0,0027) e LYS (r2=0,29, p=0,0001). Os determinantes da presença ou ausência de CAC foram: estimativa de risco de DAC em 10 anos do ERF (P=0,0027) e o produto LDL-c X Idade (p=0,0228). Conclusão: Não foram encontradas correlações entre CAC, como variável continua ou categórica, IMT, VOP, na população com HF. Pacientes com HF têm maior prevalência de aterosclerose subclínica que os CTRL. / Familial hypercholesterolemia (FH) is associated with early onset of coronary heart disease (CHD). Detection of subclinical atherosclerosis (SCA) could be useful for risk stratification in FH subjects. The relationship among carotid, aortic and coronary SCA was not yet explored in FH. We studied the correlation among common carotid intima-media thickness (IMT), coronary artery calcification (CAC) and arterial stiffness (carotid-femoral pulse wave velocity-PWV) and their determinants in FH subjects. Methods: 89 FH subjects (39±14 Years, 38% male, median LDL-c = 279 mg/dL) and in 31 normal matched controls (NL) (median LDL-c 102mg/dL) were studied. IMT was determined by the Wall-Track System2, aortic stiffness (PWV) with the Complier® method, CAC prevalence and severity were measured by multidetector computed tomography. Clinical and laboratory variables (lipids, apolipoprotein AI and B, Lp(a), glucose, hsCRP and WBC) were determined. The 10-year CHD risk was calculated by Framingham scores (FRS) and the age-cholesterol burden by the LDL-cholesterol year score (LYS=LDL-c x age). Results: FH subjects had a greater FRS (%) (7 ± 3 vs. 3 ± 3, p=0.002), higher prevalence of CAC (34% vs. 12%, p=0.024), greater IMT values (micra m) (653 ± 160 vs 593 ±111, p=0.027), higher PWV (m/s) (9.2 ±1.5 vs. 8.5 ± 0.9, p=0.007) and white blood cels (x109 cels/L) (7.2 ± 2.0 vs 6.4 ± 1.5, p=0.046) than NL. No difference were found in median hsCRP levels (mg/L) respectively 1.7 (0.2-3.4) and 1.3 (0.2-8.0) p=n.s. for FH and NL. By multivariate analyses the following variables were independent determinants of: 1)IMT: systolic blood pressure (r2=0.36, p=0.045), FRS (r2=0.26, p=0.0001) and apolipoprotein B (r2=0.32, p=0.02). 2)PWV: age (r2=0.37, p=0.0001). 3)CAC as a continuous variable: male gender (r2=0.36, p=0.0027) and LYS (r2=0.29, p=0.0001). 4)Presence of CAC as a dichotomous variable: FRS (P=0.0027) and LYS (p=0.0228). Conclusions: No correlations was found among CAC either as a continuous or a dichotomous category, IMT, PWV, in FH subjects and clinical parameters poorly explained their variability, however subclinical atherosclerosis is more prevalent in FH than NL.

Abstract Increased plasma cholesterol is a well-known risk factor for cardiovascular diseases in middle and early old age. At older ages, this association seems to disappear. Very few studies have assessed the impact of the lifelong cholesterol burden on old age, the purpose of this thesis. Study populations consisted of 1) old persons with familial hypercholesterolemia (FH), a genetic disorder associated with an increased risk of coronary heart disease (CHD) if untreated, and 2) initially healthy men (The Helsinki Businessmen Study, HBS) followed-up from midlife to old age. A population-based FH cohort, aged ≥ 65 years (n=37, aged 65 to 84 years) agreed to participate in this study. All but one of them had been using statin therapy for approx. 15 years. Variables studied were: health-related quality of life (HRQoL) with questionnaires (RAND-36, 15D), a brain magnetic resonance imaging (MRI) scan and cognitive tests (CERAD). These older FH patients enjoyed a similar HRQoL as controls in the general population. Only two (6%) of the older FH patients had clinically silent brain infarcts detected by MRI and those aged 65 to 74 years did not have more white matter hyperintensities (WMHIs) when compared to middle-aged controls. In the cognitive assessments, FH patients, especially those with duration of statin therapy longer than median, even expressed better episodic memory than population controls. HBS consists of a cohort of men (3277 men) who at baseline (1964–1973) were healthy and in their 40s. They were subdivided into seven groups according to baseline total cholesterol value at 1 mmol/L intervals starting from ≤  4 mmol/L. In 2000, at a mean age of 73 years, they filled a postal questionnaire including RAND-36. Cumulative mortality data were collected up to January 2010. A strong and graded relation was found between the cholesterol level and total mortality, those men with a cholesterol level ≤  4 mmol/L exhibiting the lowest mortality. A low cholesterol value at midlife also predicted a better score in the Physical functioning scale of RAND-36 in old age. In conclusion, in initially healthy men, a low cholesterol value at midlife was associated with better survival and better physical function in old age. Despite their genetic risk, FH patients on long-term statin medication seemed to enjoy a health and cognitive status similar to the general population. / Tiivistelmä Suurentunut plasman kolesterolipitoisuus on tunnettu valtimotautien riskitekijä keski-iässä, mutta vanhuusiässä kolesterolin merkitys näyttää vähentyvän. Hyvin harvassa tutkimuksessa on tutkittu elämänaikaisen kolesterolitason vaikutuksia vanhuusiän terveydentilaan, kuten tässä väitöskirjatyössä. Tutkimuskohteina olivat 1) iäkkäät, joilla on familiaalinen hyperkolesterolemia (FH) eli perinnöllinen sairaus, johon hoitamattomana liittyy lisääntynyt sepelvaltimotaudin riski, sekä 2) alun perin terveet miehet (Helsingin Johtajatutkimus), joita seurattiin keski-iästä vanhuuteen. Väestöpohjainen, 65 vuotta täyttänyt (65–84 vuotta, 37 henkilöä) FH-potilaiden ryhmä oli yhtä lukuun ottamatta käyttänyt keskimäärin 15 vuoden ajan statiinilääkitystä. Heille tehtiin seuraavat tutkimukset: terveyteen liittyvän elämänlaadun kyselyt (RAND-36- ja15D-mittarit), aivojen magneettitutkimus (MRI) ja kognitiota tutkivat testit (CERAD). FH-potilaiden elämänlaatu ei eronnut väestöverrokeista. Aivojen MRI tutkimuksessa vain kahdella (6 %) FH-potilaalla oli todettavissa kliinisesti hiljainen aivoinfarkti ja 65–74-vuotiailla FH-potilailla ei ollut enempää valkean aineen muutoksia kuin keski-ikäisillä verrokeilla. Kognitiotutkimuksissa FH-potilailla oli parempi episodinen muisti kuin väestöverrokeilla, etenkin niillä FH-potilailla, joiden statiinihoidon kesto oli mediaania pidempi. Helsingin Johtajatutkimukseen kuului alun perin 3 277 lähtötilanteessa (1964–1973) tervettä keski-ikäistä miestä. Heidät jaettiin lähtövaiheen kolesterolitason perusteella seitsemään ryhmään yhden millimoolin välein siten, että alin ryhmä oli alle 4 mmol/l. Vuonna 2000 (keski-ikä 73 vuotta) lähetettiin postikysely, johon kuului myös RAND-36. Kokonaiskuolleisuutta seurattiin tammikuuhun 2010 asti. Kokonaiskuolleisuuden ja keski-iän kokonaiskolesterolin välillä oli vahva ja asteittainen suhde siten, että niillä miehillä oli pienin kuolleisuus, joilla oli alin kolesteroli (alle 4 mmol/l). Pienin kolesterolipitoisuus keski-iässä oli myös yhteydessä RAND-36-mittarin Fyysinen toimintakyky -osion parempaan pistemäärään. Yhteenveto: Alun perin terveillä miehillä pieni kolesterolipitoisuus keski-iässä ennusti pitempää elämää ja myös parempaa fyysisistä toimintakykyä vanhalla iällä. Huolimatta perinnöllisestä riskistä oli pitkäaikaista statiinilääkitystä käyttäneiden FH-potilaiden terveydentila muuta väestöä vastaava.

A Hipercolesterolemia Familiar (HF) é uma doença caracterizada por aterosclerose precoce. Contudo, o curso clínico da doença coronária na HF é variável. A detecção da aterosclerose subclínica, pela espessura íntima média (IMT) carotídea, calcificação da artéria coronariana (CAC) e da rigidez arterial pela velocidade de onda de pulso (VOP) em portadores de HF pode ser útil na estratificação do risco cardiovascular. O objetivo primário deste estudo foi avaliar se existe correlação da CAC, IMT e VOP em portadores de HF. Como objetivos secundários, comparar estes marcadores de aterosclerose subclínica nos HF em relação a controles pareados por idade e sexo (CTRL) e avaliar quais são os principais fatores que influenciam a VOP carotídeo-femoral a IMT carotídea e a CAC, em pacientes com HF. Material e Métodos: Analisamos 89 HF (39±14 anos, 38% homens, LDL-c médio de 279 mg/dL) e 31 controles pareados para sexo e idade (CTRL) (LDL-c médio de 102mg/dL). Determinamos o IMT pela ultra-sonografia de alta definição tipo \"echotracking\" (Wall-Track System2), a VOP pelo método Complior®, CAC pela tomografia de múltiplos detectores, perfil lipídico e variáveis bioquímicas como Lp(a), PCR as, apoA1 e apoB. Foram calculados respectivamente o risco de DAC em 10 anos e a carga de exposição ao colesterol pelos escore de Framingham (ERF) e pelo índice LDL-c x idade (LYS). Resultados: Os HF apresentaram maior ERF (%) (7 ± 3 vs. 3 ± 3, p=0,002), maior prevalência de CAC (34% vs. 12%, p=0,024), maior IMT (micra m) (653 ± 160 vs 593 ±111, p=0,027), maior VOP (m/s) (9,2 ±1,5 vs. 8,5 ± 0,9, p=0.007) e glóbulos brancos mais elevados (x109 células/L) (7,2 ± 2,0 vs 6,4 ± 1,5, p=0,046) do que CTRL. Não foram observadas diferenças de PCR as respectivamente 1,7 (0,2-3,4 mg/L) e 1,3 (0,2-8,0 mg/L), p=n.s. para HF e CTRL. Na análise multivariada os determinantes da IMT foram: pressão arterial sistólica. (r2=0,36, p=0,045), ERF (r2=0,26, p=0,0001) e Apo B (r2=0,32, p=0,02). A idade foi o único determinante da VOP (r2=0,37, p=0,0001). Os determinantes independentes da CAC como variável contínua foram: sexo masculino (r2=0,36, p=0,0027) e LYS (r2=0,29, p=0,0001). Os determinantes da presença ou ausência de CAC foram: estimativa de risco de DAC em 10 anos do ERF (P=0,0027) e o produto LDL-c X Idade (p=0,0228). Conclusão: Não foram encontradas correlações entre CAC, como variável continua ou categórica, IMT, VOP, na população com HF. Pacientes com HF têm maior prevalência de aterosclerose subclínica que os CTRL. / Familial hypercholesterolemia (FH) is associated with early onset of coronary heart disease (CHD). Detection of subclinical atherosclerosis (SCA) could be useful for risk stratification in FH subjects. The relationship among carotid, aortic and coronary SCA was not yet explored in FH. We studied the correlation among common carotid intima-media thickness (IMT), coronary artery calcification (CAC) and arterial stiffness (carotid-femoral pulse wave velocity-PWV) and their determinants in FH subjects. Methods: 89 FH subjects (39±14 Years, 38% male, median LDL-c = 279 mg/dL) and in 31 normal matched controls (NL) (median LDL-c 102mg/dL) were studied. IMT was determined by the Wall-Track System2, aortic stiffness (PWV) with the Complier® method, CAC prevalence and severity were measured by multidetector computed tomography. Clinical and laboratory variables (lipids, apolipoprotein AI and B, Lp(a), glucose, hsCRP and WBC) were determined. The 10-year CHD risk was calculated by Framingham scores (FRS) and the age-cholesterol burden by the LDL-cholesterol year score (LYS=LDL-c x age). Results: FH subjects had a greater FRS (%) (7 ± 3 vs. 3 ± 3, p=0.002), higher prevalence of CAC (34% vs. 12%, p=0.024), greater IMT values (micra m) (653 ± 160 vs 593 ±111, p=0.027), higher PWV (m/s) (9.2 ±1.5 vs. 8.5 ± 0.9, p=0.007) and white blood cels (x109 cels/L) (7.2 ± 2.0 vs 6.4 ± 1.5, p=0.046) than NL. No difference were found in median hsCRP levels (mg/L) respectively 1.7 (0.2-3.4) and 1.3 (0.2-8.0) p=n.s. for FH and NL. By multivariate analyses the following variables were independent determinants of: 1)IMT: systolic blood pressure (r2=0.36, p=0.045), FRS (r2=0.26, p=0.0001) and apolipoprotein B (r2=0.32, p=0.02). 2)PWV: age (r2=0.37, p=0.0001). 3)CAC as a continuous variable: male gender (r2=0.36, p=0.0027) and LYS (r2=0.29, p=0.0001). 4)Presence of CAC as a dichotomous variable: FRS (P=0.0027) and LYS (p=0.0228). Conclusions: No correlations was found among CAC either as a continuous or a dichotomous category, IMT, PWV, in FH subjects and clinical parameters poorly explained their variability, however subclinical atherosclerosis is more prevalent in FH than NL.