ARTICULO ORIGINAL Rev. Methodo 2024;9(2):08-14

https://doi.org/10.22529/me.2024.9(2)03

Recibido 27 Dic. 2023 | Aceptado 24 Nov. 2023 |Publicado 05 Abr 2024

Achieving target blood pressure and LDL Cholesterol does not prevent the progression of atherosclerotic plaque burden in a high-risk population

Alcanzar la presión arterial y el colesterol LDL objetivo no previene la progresión de la carga de placa aterosclerótica en una población de alto riesgo

Hernán Alejandro Pérez1

, Enrique A. Majul2, Ana Laura Oliszynsky3, Delia Agustin3, Delfina Bochetto3, Candela Albrech3, Iara Milena Báez3, Ignacio Foa Torres3, Luz María González Rinaldi3, Sofía Lambrechts3, Sonia Muñoz4, Mariana Carrillo4, David Spence5, Néstor H. García4

1. Universidad Católica de Córdoba. Facultad de Ciencias de la Salud. Catedra Fisiología Medica 2. Universidad Católica de Córdoba. Facultad de Ciencias de la Salud. Maestría Nutrición Médica y Diabetología. Clínica Universitaria Reina Fabiola.

3. Universidad Católica de Córdoba. Facultad de Ciencias de la Salud 4. Instituto de Investigaciones en Ciencias de la Salud (INICSA-CONICET) 5.Robarts Research Institute, Western Ontario University Correspondencia: Hernán Alejandro Pérez E-mail: hernan.perez@ucc.edu.ar

Abstract

BACKGROUND AND AIMS: Atherosclerotic disease is a huge health burden worldwide, and its prevention is largely focused on controlling traditional risk factors, despite limited effectiveness in preventing cardiovascular disease (CVD) events. Improved risk stratification can be achieved by identifying the progression of total plaque area (TPA) using carotid ultrasound, with the risk of CVD events doubling when progression is detected over a 1-year interval. We hypothesize that blood pressure and serum LDL cholesterol control at target values (current clinical guidelines) are insufficient to reduce the progression of atherosclerosis in persons with high CVD risk METHODS AND RESULTS: Prospective, observational study of 742 participants with high cardiovascular risk in a cardiovascular primary prevention program. Two ultrasound measurements of TPA were acquired for each participant for at least one year. We studied only those who maintained a blood pressure below 130/80 mmHg and serum Low-Density Lipoprotein Cholesterol (LDL-C) below 100 mg/dl throughout the study interval (57 participants). Participants with plaque progression of TPA > 5 mm2, were compared to those with TPA changes of 5 mm2 or less (non-progression group) using a multivariable logistic regression controlling for cardiovascular risk factors.

We identified TPA progression in 22 of 57 (38.6%) participants. No differences were detected for any covariate when comparing progression versus non-progression.

CONCLUSION: Progression of TPA occurs in as many as 38.6% of individuals despite maintaining BP

below 130/80 and serum LDL-C below 100 mg/dl. TPA evaluation may help address the limitations of established guidelines for the prevention of CVD events in high-risk individuals.

Keywords: Subclinical Atherosclerosis, Cardiovascular Risk factors, Arterial Hypertension, Lipids

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methodo@ucc.edu.ar / Web: methodo.ucc.edu.ar |ARTICULO ORIGINAL Rev. Methodo 2024;9(2):08-14.

Pérez H, Majul E, Oliszynsky A L, Delia A, Bochetto D, Albrech C, Baez I M, Foa Torres I, González Rinaldi L M, Lambrechts S, Muñoz S, Carrillo M, Spence D, García N . Achieving target blood pressure and LDL Cholesterol does not prevent the progression of atherosclerotic plaque burden in a high-risk population Resumen

INTRODUCION: La enfermedad aterosclerótica es una enorme carga para la salud en todo el mundo, y su prevención está basada en gran medida en el control de los factores de riesgo tradicionales, a pesar de la eficacia limitada en la prevención de eventos cardiovascular (ECV). La mejoría en la estratificación del riesgo se puede lograr a través de la detección de progresión del área total de la placa (TPA) medida por ecografía carotidea, la cual ha demostrado duplicación del riesgo basal en estos pacientes en un intervalo de 1 año. Nuestra hipótesis es que el control de la presión arterial y el colesterol LDL sérico en valores objetivo (según guías clínicas actuales) son insuficientes para reducir la progresión de la aterosclerosis en personas sin eventos previos, con alto riesgo cardiovascular.

METODOS Y RESULTADOS: Estudio observacional prospectivo de 742 participantes con alto riesgo cardiovascular en un programa de prevención primaria cardiovascular. Se determinaron dos mediciones de ultrasonido de TPA para cada participante durante al menos un año. Incluimos en el análisis 57 participantes que mantuvieron una presión arterial por debajo de 130/80 mmHg y un colesterol sérico de lipoproteínas de baja densidad (LDL-C) por debajo de 100 mg/dl durante todo un año. Los participantes con progresión de la placa de TPA definida como aumento sobre el basal mayor de 5 mm2 se compararon con aquellos con cambios de TPA de 5 mm2 o menos (grupo sin progresión) mediante análisis de regresión logística multivariable.

Después de una media de estadía en programa de casi 8 años, con Presión Arterial de 120.4 + 9/68.6 + 8

mmHg y LDL colesterol de 81 + 25 mg/dl, identificamos progresión de TPA en 22 de 57 (39%) participantes. No detectándose diferencias para ninguna covariable al comparar progresión versus no progresión.

CONCLUSIÓN: La progresión de TPA ocurre hasta en el 39% de los individuos a pesar de mantener la presión arterial por debajo de 130/80 y el LDL-C sérico por debajo de 100 mg/dl. La evaluación de TPA puede ayudar a resolver las limitaciones de las pautas establecidas para la prevención de eventos de ECV

en personas de alto riesgo.

Palabras clave: Ateroesclerosis Subclínica, Factores de Riesgo Cardiovasculares, Hipertensión Arterial, Lípidos.

Introduction

score, whereas 84.9% were classified as high-Deaths from cardiovascular disease (CVD) risk by measurement of carotid total plaque area events are a major health problem in the world (TPA)9. The traditional approach to assessing and currently account for about 30% of overall risk has two problems: a low sensitivity to mortality. Every year, more people die from identify patients at high cardiovascular risk10, CVD than from any other cause1,2. More and in clinical studies, no more than 50%

importantly, a substantial proportion of deaths effectiveness in reducing cardiovascular events, (about 50%), occur in people under 70 years of as seen in the biggest multifactorial intervention age, the population's most productive years of in diabetic patients11.

life3. It has been estimated that nearly half of men A significant proportion of this morbidity and and one-third of women will suffer from some mortality could be prevented by targeting manifestation of ischemic heart disease during interventions for people at high risk of CVD, their lifetimes4. Atherosclerosis is the leading both for those with established disease and for cause of these events, but because it is those at high risk of developing the disease12,13,14.

asymptomatic for a long period5, early diagnosis One strategy to classify and treat patients at risk is very difficult. Current guidelines recommend is to use carotid TPA measured by ultrasound, diagnosing and treating patients according to the which reclassifies more patients as high-risk and risk presented by clinical scores (Framingham is very effective in decreasing cardiovascular Risk Score6(FRS), SCORE7, and others, which events in a high-risk cohort through prevention15.

are derived from classic cardiovascular risk TPA is much more predictive of risk than carotid factors). Assman et al. reported that among intima-media thickness (CIMT) and as predictive patients suffering an acute myocardial infarction, as the Coronary Calcium Score16. Furthermore, 45% had a low Prospective Cardiovascular TPA may progress or regress within 3 months, Munster Study (PROCAM) risk score8. In a providing the possibility to assess and adjust prospective study in Germany, among patients preventive therapy in clinically meaningful time who had a myocardial infarction, only 21.2%

frames17. In 2002, Spence et al. found that were classified as high-risk by a PROCAM

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Pérez H, Majul E, Oliszynsky A L, Delia A, Bochetto D, Albrech C, Baez I M, Foa Torres I, González Rinaldi L M, Lambrechts S, Muñoz S, Carrillo M, Spence D, García N . Achieving target blood pressure and LDL Cholesterol does not prevent the progression of atherosclerotic plaque burden in a high-risk population patients whose TPA progressed by 0.05 cm2 in consists of a multidisciplinary team of the first year of follow-up were 2.1 times (95%

physicians, nutritionists, educators, gym trainers, CI, 1.2 to 3.6; p=0.005) more likely to have had psychologists, and health workers.

a stroke, myocardial infarction, or vascular death Also, the follow-up subjects meeting the criteria over 5 years, than patients who had regression or of controlled risk factors were awarded free-of-no change in plaque area18. In high-risk patients charge medication. These criteria were: HbA1c with asymptomatic carotid stenosis in Canada,

<7%, Total Cholesterol <200 mg/dl, and BP <

“treating arteries” as opposed to treating 130/80 mmHg, among others19. The present cardiovascular risk factors was associated with a study was carried out in participants enrolled

> 80% reduction in the two-year risk of stroke between November 2017 and May 2021. In total and myocardial infarction15. Among moderate-there were 742 participants, of these 184

risk patients aged> 65 years attending prevention participants had more than one study and no clinics in Argentina between 2011 and 2015, cardiovascular events. After excluding Diabetic

“treating arteries” was associated with a decline participants, current smokers, and participants in the annual risk of CVD events from 5.8% to with out-of-range blood pressure and cholesterol 2.35%19. We hypothesized that blood pressure values for the analysis, we analyzed 57

and serum LDL cholesterol control at target participants with the inclusion criteria (Blood values (recommended in current clinical Pressure less than 130/80, Serum LDL

guidelines) is not sufficient to reduce the Cholesterol less 100 mg/dl and Framingham progression of atherosclerosis in patients with score at 10 years more than 20%) (Figure 1).

high cardiovascular (CV) risk.

Objectives

1. Evaluate the progression of TPA in high-risk patients whose blood pressure and serum LDL

cholesterol are controlled.

2. Determine if classical cardiovascular risk factors and time between TPA studies are associated with the progression of TPA.

Methods

Figure 1. Block Diagram of the research.

Study design and population: The study The protocol was approved by the Committee on population was composed of patients referred by Independent Institutional Ethics of the National physicians to a Light and Force and Railroad University of Córdoba and the Rusculleda Unions Health Maintenance Organizations (Luz Foundation. Reader reliability was estimated by y Fuerza and Obra Social Ferroviaria), randomly assigning scans of 22 patients to participating in an atherosclerosis prevention interpretation by 2 different readers.

program (LifeQualityA) conducted by Blossom Inclusion and Exclusion criteria: For this DMO Argentina. The program was initiated in analysis, we include participants over 40 years of 2008 and continues at present, with a total of age, with a risk of acute myocardial infarction 4531 participants, white Latin men represent greater than 20% at ten years based on TPA, 41.3%, mean+SD age (58+14 years), and is participants (with or without antihypertensive based in Buenos Aires and Cordoba, Argentina.

medication or Hypertension) with blood pressure The inclusion of a volunteer in the program

< 130 mmHg systolic and < 80 mmHg diastolic started with the stratification of cardiometabolic based on blood pressure determination in clinical risk by using the FRS based on body mass index follow-up,

ambulatory

blood

pressure

(BMI). Those subjects with a 10-year risk score

≤ 6% were assigned to management by a General monitoring or home blood pressure monitoring, LDL-C <100 mg/dl in at least two separate Practitioner (GP), while those with scores> 6%

measurements >3 months apart, and written were re-tested using the Framingham Post-test informed consent given. Excluded were current algorithm. After this stratification with the smokers, participants who had Type I or type II Framingham Post-test algorithm, subjects with diabetes, a history of previous cardiovascular scores <20% were assigned to follow-up by GP

while those with scores ≥ 20% were assigned to events, a history of neoplasm, kidney disease (eGFR less than 60 ml/min), endocrinological the cardiometabolic high-risk group as the High-disease, rheumatological disease, immunological Risk Control Service thereafter. This service Revista Methodo: Investigación Aplicada a las Ciencias Biológicas. Universidad Católica de Córdoba.

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10

Pérez H, Majul E, Oliszynsky A L, Delia A, Bochetto D, Albrech C, Baez I M, Foa Torres I, González Rinaldi L M, Lambrechts S, Muñoz S, Carrillo M, Spence D, García N . Achieving target blood pressure and LDL Cholesterol does not prevent the progression of atherosclerotic plaque burden in a high-risk population disease,

those

medicated

with

clinical guidelines21,22,23,24,25, but focusing on immunosuppressants, and those with a history of TPA evolution criteria. Plaque area regression drug and/or alcohol abuse.

was defined as a decrease of ≥5 mm2 from TPA determination: Measurement of TPA was baseline; progression was defined as an increase performed with a high-resolution ultrasound of ≥5 mm2 from baseline; and stability was machine (Ultrasound system Mindray M5, defined as either an increase or decrease of < 5

Shenzhen, P. R. China) and a linear probe mm2, based on a previous study18. We divided between 5 to 10 MHz. It was performed by a the patients into two groups: progression vs.

single operator, informed of the participant’s sex, non-progression if the plaque regressed or was but blind to the participant’s history of vascular stable.

disease and risk factors (blood pressure, serum lipid levels, glycemia, and HbA1c). TPA was Statistical Analysis

measured as previously described19. “Plaque was defined as a local thickening of the intima >1 mm Descriptive

analyses

include

absolute

in thickness. Measurements were made in frequencies, percentages, the mean and standard magnified longitudinal views of each plaque seen deviation for quantitative variables that follow a in the right and left common, internal, and normal distribution, and median and interquartile external carotid arteries. The plane in which the range for variables with a non-normal measurement of each plaque was made was distribution. Paired or unpaired t-tests were used, chosen by panning around the artery until the as required by the type of analysis appropriate to view showing the largest extent of that plaque the hypothesis to be analyzed. Multiple was obtained. The image was then frozen and regression analysis was used to determine the magnified, and the plaque was measured by factors associated with progression status.

tracing around the perimeter with a cursor on the Reliability was estimated for the entire sample.

screen. The microprocessor in the scanner then The accepted level of statistical significance for displayed the cross-sectional area of the plaque.

rejecting null hypotheses was p<0.05.

The operator then moved on to the next plaque and repeated the process until all visible plaques were measured. The sum of the cross-sectional Results

areas of all plaques seen between the clavicle and the angle of the jaw was taken as total plaque In total 742 participants were followed in this area18.

period, of which 57 people met the criteria for this study (mean age 71 + 8 years, 70% female, Hypertensive patients: Patients with a previous all white Latin). The average Risk post-TPA at diagnosis

of

hypertension

and/or

taking

10 years for Acute Myocardial Infarction was antihypertensive medication.

very high (39.3 +18 %), the blood pressure (120.4/68.6 mmHg) and LDL-C (81 mg/dL) Hypercholesterolemic patients: Patients with a were at target levels during the year of study previous diagnosis of hypercholesterolemia (Table 1 and 2).

and/or medication to treat dyslipidemia.

Blood pressure determination: Blood pressure was taken as the mean of three measurements performed on the left arm in the sitting position after five minutes of rest (OMRON Hem 705

sphygmomanometer, Vermont Hills, IL, USA).

Serum

cholesterol

and

triglycerides

determination: Blood lipids were measured from whole blood samples using routine methods in a central laboratory after a 12-hour fast (LACE

Laboratory, Córdoba, ARG).

Follow-up: Carotid TPA determinations were made at baseline and at least one year later, with three additional visits made during this interval for measuring vital signs and laboratory results.

All patients were treated according to established Revista Methodo: Investigación Aplicada a las Ciencias Biológicas. Universidad Católica de Córdoba.

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Pérez H, Majul E, Oliszynsky A L, Delia A, Bochetto D, Albrech C, Baez I M, Foa Torres I, González Rinaldi L M, Lambrechts S, Muñoz S, Carrillo M, Spence D, García N . Achieving target blood pressure and LDL Cholesterol does not prevent the progression of atherosclerotic plaque burden in a high-risk population therapeutic goals in the management of these patients remain static, irrespective of the effect of the

treatment

on

the

progression

of

atherosclerosis. A meta-analysis reported a reduction in CV events with LDL cholesterol values much lower than the 70 mg/dl suggested presently29. A study in > 4,000 patients reported that renal failure and advanced age were related to “resistant atherosclerosis,” a situation identified in patients who, despite having very low levels of LDL-C, continue to have We found that 22 of 57 participants (38.6%) had progression in their load of atherosclerosis plaque progression (Table 3).

burden30. Plasma levels of toxic metabolites produced by the intestinal microbiome were associated with increased TPA not explained by traditional

risk

factors

(“unexplained

A Multiple regression analysis was performed atherosclerosis”)31. In our study, an association with the evolution of TPA as the response of age or creatinine level with progression as variable and age, sex, systolic blood pressure, independent factors was not reproduced, LDL-C, total cholesterol,Triglyceride/HDL-C

probably because of the small number of ratio, creatinine, and time between studies as patients, and the restricted range of these dependent variables, and we did not find any variables32. The ratio of Tg/HDL-C, recently significant difference in variables, comparing shown to identify metabolic syndrome and progression vs. non-progression (Table 4). To insulin resistance, and an association with high determine if the status of Hypertension or TPA33, was not predictive of progression in our Hypercholesteremia were relevant to these population, perhaps for the same reasons.

findings, a logistic regression model was carried Because factors other than traditional risk factors out, using the evolution (progression/non-account for approximately half of plaque burden progression) at the study as the dependent in linear regression modeling, treating only variable, and age, sex, systolic blood pressure, traditional risk factors to consensus target levels serum

LDLc,

triglycerides-HDL

ratio,

fails approximately half of patients: they have creatinine, time between studies, presence of plaque progression, with twice the risk of those hypertension, presence of hypercholesterolemia with non-progression. Measuring the burden of of the second study as independent variable and atherosclerosis not only permits more precise did not find an association with the occurrence of risk stratification, but also determines the progression (Table 4).

effectiveness of treatment, and identifies patients at higher risk who need more intensive therapy based on “treating arteries” to be sure that the treatment instituted is effective.

Limitations

The selection of our subjects was not based on a random population sample. Our population was derived from a follow-up cohort previously described, and the great majority was older than Discussion

60 years old, which limits the extrapolation of results to the general population. Even when our Current treatment of patients at high CV risk study has few participants, all these had blood continues to be based on control of risk factors, pressure and serum LDL Cholesterol at target even though there are known limitations to that levels, which in real life follow up is very approach. Current diagnostic techniques, such as difficult.

the measurement of TPA, improves risk stratification, as demonstrated by our working Conclusions

group in Argentina26, Fuster et al. in the United States27,

and

Romanens

in

Switzerland.

Our data evaluating a population with high CVD

Regardless of the initial risk level (low, risk, which is representative of patients in real-intermediate, high, very high), the suggested life medical practice, show that controlling blood Revista Methodo: Investigación Aplicada a las Ciencias Biológicas. Universidad Católica de Córdoba.

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Pérez H, Majul E, Oliszynsky A L, Delia A, Bochetto D, Albrech C, Baez I M, Foa Torres I, González Rinaldi L M, Lambrechts S, Muñoz S, Carrillo M, Spence D, García N . Achieving target blood pressure and LDL Cholesterol does not prevent the progression of atherosclerotic plaque burden in a high-risk population pressure and LDL-C target levels does not Outcome

Study.

Cardiol

Res.

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in a substantial proportion of patients. Therapy 10. Cooney MT, Dudina AL and Graham

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for

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Assessment

of

target levels.

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