March, 2012

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Efectos Pleiotropicos de las estatinas

Las estatinas (inhibidores de la hidroximetilglutaril Co enzima A reductasa) son los fármacos mas utilizados en el control de dislipidemia sin embargo sus efectos van mas allá del poder hipolipemiante, estos efectos adicionales a la reducción del colesterol se denominan efectos pleiotropicos y serán mencionados a continuación.

Mecanismo: Inhibición de formación de isoprenoides lo cual implica reducción del estrés oxidativo al disminuir la producción de NADPH. Ademas tiene efecto antinflamatorios al disminuir la proteína C reactiva y factor nuclear K B (NF-KB).

Síndromes Coronarios Agudo.    Mejora la función endotelial , aumenta la oxido nítrico sintetasa, disminuye la inflamación  de la placa lo que le confiere mayor estabilidad. Existen varios estudios de estatinas en este contexto y un metanalisis  de ellos demostró reducción de la mortalidad total y cardiovascular en 26% (p=0.003) la recurrencia de angina en un 19% (p=0.027) y la tasa de revascularización coronaria en un 14% ( p=0.006)

Insuficiencia cardiaca   Disminuyen la inflamación ocasionada por la falla cardiaca. Reducen el riesgo de hospitalización por insuficiencia cardiaca en un 33% (p=0.008), aumento de la FEVI en 4.6% (( p=0.004) y con atorvastatina una reducción de la mortalidad en 61% (p=0.004).

Fibrilación auricular. Desensibiliza los miocitos cardiacos a la estimulación adrenérgica. Acorta la conducción interatrial y aumenta el periodo refractario. En pacientes con cardiopatía isquémica crónica reduce 59% ( p=0.0006) la incidencia de FA. Durante la fase aguda reduce en 10% la incidencia de FA  así como taquicardia y/o fibrilación ventricular.

Estenosis aortica. Resultados contradictorios, no se ha comprobado de forma robusta su utilidad en estos pacientes.  

Angioplastia Coronaria Percutánea.  Estabiliza la placa, mejora la perfusión microvascular. Reducción de eventos cardiovasculares en 50% ( p=0.039).

Cirugía de Revascularización Coronaria. Disminuyen la inflamación sistémica y disminuye moléculas de adhesión. Metanalisis  mostró reducción del 43% de mortalidad a 30 días (p=0.0001),  disminución de la incidencia de FA en 33% (p=0.004)y 26% el riesgo de EVC (p=0.004)

Hipertensión arterial sistémica esencial.  Disminuye receptores de angiotenisna II , aumenta la sensibilidad de los baroreceptores lo que disminuye el tono simpático. Solamente existió disminución de 1.9 mmHg y 0.9 mmHg en las presiones sistólica y diastólica respectivamente.

Aneurisma aórtico abdominal. Inhibe las metaloproteinasas y disminuye la apotosis. Disminuye la mortalidad por esta enfermedad en un 79% (p=0.01) .

Evento vascular cerebral isquémico o hemorrágico.   Se demostró reducción del riesgo de EVC de un 21% (p=0.009). En hemooragia subaracnoidea el uso de estatina redujo el riesgo de vasoespasmo en 27% y la mortalidad en 82%.

Nefropatía por contraste.  Aumenta la producción de oxido nítrico y disminuye los radicales libres. Disminución del riesgo de nefropatía inducida por contraste y depuración de creatinina mayor posterior al  uso de contraste .

Trombosis venosa. Disminución de factores procoagulantes . Metanalisis mostró reducción del riesgo de trombosis venosa profunda del 41% (p<0.05) siendo el efecto mayor en pacientes con cáncer.

Lecturas recomendadas.

Mihos,C. The Pleiotropic Effects of the Hydroxy-Methyl-Glutaryl-CoA Reductase Inhibitors in Cardiovascular Disease A Comprehensive Review. Cardiology in Review • Volume 18, Number 6, November/December 2010

Palaniswamy, Ch.  Mechanisms Underlying Pleiotropic Effects of Statins. American Journal of Therapeutics: January/February 2010 – Volume 17 – Issue 1 – pp 75-78

Luis Eduardo Rodriguez Castellanos

@LuisERodCas

Obesity

Obesity during childhood has been associated with numerous adverse effects including a variety of health complications such as hypertension, dyslipidemia, left ventricular hypertrophy, atherosclerosis, metabolic syndrome, type 2 diabetes, sleep disorders, and non-alcoholic fatty liver disease as well as psychological effects such as stigmatization, discrimination, depression and emotional trauma. Obesity in childhood also substantially increases the risk of being an obese adult. In addition, adults who were obese during childhood have higher risk of developing hypertension, dyslipidemia, metabolic syndrome, diabetes, and coronary heart disease than those who were not obese during childhood. I would like to share this assay that barely depicts the burden of disease related to obesity.

Overweight and obesity is an epidemic that affects individuals of all ages, sexes, races and latitudes, regardless of the socioeconomic status. Not long ago the rich were obese, poor people were thin and the concern was how to feed the malnourished population. Today, the rich are thin and the poor are well nourished, overweight and obesity is now the concern (World Health Organization, 2008). The obesity epidemic is not restricted to developed societies; in fact, their increase is often faster in developing countries, which face a double challenge with its problems of malnutrition.

Mexico is a republic of 31 states and a federal district in which Mexico City is located. Mexico City is the political and economic center of the country and is in turn, the second largest metropolis in the world only after Tokyo, Japan. The country is divided in three regions (Northern, Central, and Southern) of 10 states each. A fourth region is the Metropolitan area with about 20 million people comprising Mexico City and 10 adjacent counties of the State of Mexico (Arroyo et al, 2000).

Data from Mexico come either from urban populations or regional studies and show a prevalence of obesity of, 20% in Mexico. The preobesity prevalence is very high in most Latin American countries (even higher than in the USA): 40.3% in Mexico (Filozof et al, 2001).

In the analysis of the National Survey of Chronic Diseases (NSCD) carried out in 1993, Arroyo and colleagues reported high prevalence of overweight and obesity in both sexes and all age groups. In the analysis of the National Health Survey of 2000 (NHS 2000), showed increases in the rates of obesity with respect to the NSCD done in 1993 of 5% and 4% for men and women respectively (Del Rio et al, 2004 ).

In Latin America, Mexico is among the highest prevalence of overweight in children. In Mexico, the National Nutrition Survey 1988 and 1999 showed a slight increase in the prevalence of overweight and obesity in children under five years of 4.7% and 5.5% respectively (Del Rio et al, 2004).

One study (Sanchez et al, 2001) in children in ages of 5 to 17 years conducted in rural Mexico where we the international definition of the International Obesity Taskforce (IOTF) was used to assess overweight, showed that 17% of boys and 19% girls were overweight (including those with obesity).

Obesity in children is of extreme importance. It is known that if a child enters to adulthood with obesity and in the course has a small weight gain, the risk of developing diabetes is significantly higher than if it enters into adulthood with normal weight (Whitaker et al, 1997). By itself, childhood obesity is an independent risk factor for obesity in adults.

Mexico, traditionally a country with a population undernourished, is not free from this epidemic. Perhaps one of the factors that explain the nutrition transition is the apparent improvement in the socioeconomic status of Mexicans in the last decade, even though Mexicans are far from achieving an optimal situation, probably because of the uneven distribution of wealth extremely in some regions of Mexico. According to Perichart et al “obesity is an emerging public health problem in Mexico, and its prevalence has increased among all age groups, including children.” Data from the Mexican National Nutrition Survey showed that 27.2% of school-aged children are overweight or obese and that Mexico City has among the highest prevalence of overweight children (26%) (Perichart et al, 2007, P81).

Mexico is facing deep political and social changes associated with clear changes in the conduct and behavior of Mexicans. Mexicans are changing their eating habits, leaving aside the traditional diet, rich in grains such as corn, which makes “tortillas” and legumes such as beans, to adopt a new culture of fast food with high energy value, but poor in some essential nutrients.

An increase in portion sizes and in the consumption of energy-dense foods, fast foods, and soft drinks are important etiological factors for obesity that have been recognized worldwide. Mexico is not an exception: An increase in obesigenic factors and inexpensive energy sources occurred between 1992 and 2000 (Rivera et al, 2004). The Mexican Urban Food Survey reported that 32% of energy intake is provided by fat and that 80% of the population does not practice exercise on any day of the week. Schools have been proposed as a good environment for achieving a healthful lifestyle in children (Perichart et al, 2007, p82).

With regard to lifestyles, the boom of television and video games has been another factor of great influence. Hernandez et al in 1999, studied 7112 Mexican children between 9 and 16 years old and found a clear association between obesity, physical activity and time spent watching television, while those who watched more television had a higher risk of developing Obesity (Hernadez et al, 1999). Mexicans read very little, but in contrast watching television is very common practice. In this sense, television not only changes behaviors and habits, it promotes the consumption of certain products which are advertised. Frequently these television advertisements are for food and these ads promote soft drinks, cakes and fried foods intake.

The findings of Perichart and colleagues (2007) underscore the poor health conditions and health behaviors evident among low-income Mexican children living in Mexico City. The high obesity rate evident in their sample of school-age children may be a consequence, in part of the nutritional transition and Westernization that this country is experiencing. The investigators report anthropometric, dietary, and physical activity data in children ages 6 to 13 assessed through self-report. Their findings show that 48.5% of all of the children in the school were either overweight (27.1%) or obese (24.1%), which, according to the investigators, is higher than the national average that has been reported over the past 5 years.

OBESITY PREVENTION PROGRAM

One of the major concerns of Mexican society is the need to adopt adequate healthy lifestyles since childhood to ensure the development of a full and healthy life. The high prevalence of obesity that is suffering Mexico is generated by many factors, but the most important are related to technological progress, social and labor conditions and the current lifestyle. These changes have altered dietary habits and inactivity was triggered.

Schools offer countless opportunities to provide information on healthy eating habits and encourage the practice of regular physical activity and sports, therefore schools are one of the most effective ways for changing bad lifestyles in children and adolescents because they come daily to the schools. However, experience shows that the results are scarce when it acts only on the school, without involving their families and without simultaneous action on the environment in which they live.

“Environmental influences can promote excess energy and fat intake which are a potential factor in this secular upward trend in obesity. Furthermore, the school food environment can have a significant impact on adolescents food choices, because 35% to 40% of youths’ total daily energy is consumed at school “(French et al, July 2003).
It is for this reason that I have decided to launch a program for childhood obesity that could be implemented in primary schools in Mexico City. The present program for the prevention of obesity in schools includes the implementation of strategies to improve education in students and in the family and the installation of vending machines that contain fruit and salads.

The program that I propose in this trial must begin with a pilot-test and includes simple interventions that can be easily carried out in different centers and in the future serve as a model for larger-scale studies.

The initiative aims to achieve both personal and social changes in eating habits and physical activity in the school community. To achieve this, a team of experts in education and public health are needed to design in detail the prevention program on a pilot-test basis, targeting the students of primary schools.

The program will be developed in collaboration with the Mexican Government and probably with non-governmental organization interested in the project. As I mentioned previously, an initial pilot phase will be developed and if the program is successful, it will be extended to successive phases.

The program on prevention of obesity will last for 1 year and aims to be implemented in all public primary schools in Mexico City. The target groups for this obesity control program are students and parents of students who are enrolled in public primary schools of Mexico City.

The activities of this program are set for all public primary schools regardless of socio-demographic differences that exist between the elementary schools. At the end of the pilot program, the results will be analyzed paying special attention to those schools that show higher percentage of risk factors and behaviors related to unhealthy diet and physical activity.

General objectives of the prevention program in obesity includes:

- Promote the acquisition of healthy eating habits and encourage the practice of regular physical activity among schoolchildren.
- To detect early and prevent obesity progression with clinical evaluations by health professionals in primary care.
- To sensitize the society in general, and especially the school environment, of the importance that educators have in this field.
- Create a school environment that promotes a balanced diet and frequent practice of physical activity.
- Reduce intake of unhealthy fats and sugars.
- Increase the daily consumption of fruits and vegetables.
- Promote the use of water as a beverage of choice.
- Reduce the time spent on television, video games or computers.
- Providing schools with vending machines that contain fruit or salads.

The implementation of a program with these characteristics in a school context requires institutional support and efforts of coordination by the various stakeholders involved in the project.

A randomized controlled trial done by Gortmaker (1999) was a behavioral choice intervention and concentrated on the promotion of physical activity, modification of dietary intake and reduction of sedentary behaviors using educational material (with a strong emphasis on reducing television viewing). Gortmaker reports that the intervention reduced television hours among both girls and boys. In addition, the authors report an increased fruit and vegetable consumption in girls, resulting in a smaller daily increment in total energy intake among girls. These results highlight the importance of education while implementing a new strategy for obesity control in scholars.

The intervention program will provide educational materials to students and families to inform how to prevent childhood obesity and especially promote healthy lifestyles that protect the health of schoolchildren. The students of primary schools will be measured and weighed by medical professionals in order to obtain anthropometric measurements. With this action we can have an initial registry of weight and height from the students at the time that the program starts. To estimate the overweight or obesity in students, an indicator body mass index (BMI) will be used. This measure will be calculated by dividing weight in kilograms measured over height measured in squared meters. Students will be considered obese or overweight if they are above the cutoff points specific to their age and sex proposed by the International Obesity Task Force (Cole et al, 2000).

At the end of the pilot test we will retake anthropometric measurements of the same students who participated in the program in order to estimate the effect of the intervention proposed.

The families of school students will receive monthly information to raise awareness about the problem of obesity and how to reduce risk factors that can contribute to the presentation of this disease in their children. The information will focus on promoting healthy eating behaviors and increase physical activity in children and recommend that children spend less time in front of the TV.

The government of Mexico City will provide a vending machine that will offer only healthy foods like fruits and salads with a low cost. The food of the vending machines will be elaborated by a private company which provides food low in fats, sugars and carbohydrates. A study done by Wechsler H et al (2001, p313) found that vending machines are available in 88% 61% and 14% of secondary schools, middle schools, and elementary schools, respectively. These findings highlight the importance of controlling these automatic vending machines because frequently the products offered by these machines are junk foods high in fats and sugars. Therefore, I believe that the introduction of vending machines containing fruit and vegetables might reduce levels of obesity among school children because these foods are nutritious and healthy for the body.

According with the availability of schools, it will be given space and time to comment on the information that schoolchildren receive and encourage physical activity in school activities. The activities to be undertaken while implementing this program will require the development of educational materials that could be elaborated by experts in nutrition and public health professionals. It also requires special training to teachers working in primary schools to have a better understanding with regard to the obesity epidemics.

Finally, obesity is an epidemic in Mexico that requires preventive strategies and consistently management. In Mexico and other rapidly developing countries coexist malnutrition and obesity, this represents a double disadvantage. The populations in development are more likely to develop obesity and for this reason it is necessary to develop strategies that attack the obesity issue. Children are a population vulnerable to the adverse effects of the environment that surrounds them, that is why programs that promote education in schools, families and changes in the environment surrounding children such as vending machines could reduce the rates of obesity in Mexico.

It is necessary to establish preventive rather than remedial measures and promoting the traditional diet and implement actions that will correct the unhealthy lifestyles in the community. There is evidence in the literature that educational programs that promote healthy eating and healthy lifestyles can help to decrease the rates of obesity in the community.

By Oscar Millán-Iturbe, MD/MPH
@ozkr_millan

References:

Arroyo, Pedro, Alvar Loria, Victoria Fernandez, Katherine M. Flegal, Pablo Kuri-Morales, Gustavo Olaiz, and Roberto Tapia-Conyer. Prevalence of pre-obesity and obesity in urban adult Mexicans in comparison with other large surveys. Obesity Research. 2000;8:179 –185.

Cole TJ, Bellizzi M, Flegal KM, Dietz W. Establishing a standard definition for child overweigth and obesity worldwide: international survey. British Medical Journal 2000; 320:1240-1243.

Del Río-Navarro B, Velázquez-Monroy O, Sánchez- Castillo C, Lara-Esqueda A, Berber A, Fanghanet G, Violante R, Tapia-Conyer R, James P, The Encuesta Nacional de Salud (ENSA) 2000 Work Group. The high prevalence of overweight and obesity in Mexican children. Obesity Research. 2004;12:215-223.

Filozof C, C. Gonzalez, M. Sereday, C. Mazza and J. Braguinsky. Obesity prevalence and trends in Latin-American countries. Obesity reviews (2001) 2, 99–106

Gortmaker SL, Peterson K,Wiecha J, SobalAM,Dixit S, FoxMK, et al. Reducing obesity via a school-based interdisciplinary intervention among youth. Archives of Pediatrics and Adolescent Medicine 1999; 153(4):409–418

Hernández B, Gortmakers SL, Coldietz GA. Association of obesity with physical activities, television programs and other forms of video viewing among children in Mexico City. Int J Obesity 1999;23:845-54.

Perichart-Perera O, et al. Obesity Increases Metabolic Syndrome Risk Factors in School-Aged Children from an Urban School in Mexico City. Journal of the American Dietetic Association. January 2007;107:81-91.

Rivera J, Barquera S, González-Cossío T, Olaiz G, Sepúlveda J. Nutrition transition in México and in other Latin American countries. Nutr Rev. 2004; 62(suppl II):S149-S157.

Sánchez-Castillo CP, Lara JJ, Villa AR, Aguirre J, Escobar M, Gutiérrez H, Chávez A, James WPT. Unusual high prevalence rates of obesity in four Mexican rural communities. Eur J Clin Nutr 2001;55:833-40.

Wechsler H, Brener ND, Kuester S, Miller C. Food service and foods and beverages available at school: results from the School Health Policies and Programs Study 2000. J School Health 2001;71:313–24.

Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH. Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med 1997;337(13):869-873.

World Health Organization. Obesity and overweight. http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/ (Oct 2008)

Lisinopril, nitratos o ambos Vs controles de forma temprana posterior a un SICA (GISSI-3)

Lisinopril, nitratos o ambos Vs controles de forma temprana posterior a un SICA

Vista rápida El Lisinopril cuando se inicia dentro de las primeras 24 hrs posterior a un SICA disminuye la mortalidad por cualquier causa a las 6 semanas.Los nitratos, mientras que son seguros y efectivos para aliviar el dolor isquémico, no afectan la mortalidad en los pacientes con un SICA reciente.
Resumen El GISSI-3 fue diseñado para resolver si los IECAs y/o los nitratos disminuyen la mortalidad en pacientes con SICAs.Fueron aleatorizados 19,134 pacientes, con un diseño a sobre abierto factorizado en tabla de 2 x 2 para recibir Lisinopril, Nitroglicerina (IV y posteriormente transdérmica), ambos o ninguno.Lisinopril: A las 6 semanas, los pacientes que recibieron Lisinopril,  Lisinopril + NTG mostraron una disminución significativa en la mortalidad compada con los controles (6.3%, 6.0% y 7.2% respectivamente, p < 0.05 para ambas comparaciones).

Antes del GISSI-3, los IECAs habían demostrado beneficio en un grupo de pacientes con disfunción ventricular izquierda. Los datos en el grupo de pacientes post-IAM eran poco concluyentes. Por lo anterior se diseño el GISSI-3 para aclarar la cuestión a través de un estudio con mayor poder. Los resultados del GISSI-3 sostuvieron la fuerte recomendación por parte de los autores para administrar IECAs lo antes posible en pacientes con SICA sin contraindicaciones.

Nitratos: A pesar de ser una terapia bien establecida en el infarto agudo al miocardio, el uso de los nitratos no habían sido previamente validado en un estudio formal.

En el GISSI-3, el grupo en el que se administró solamente nitratos no mostró beneficio en la mortalidad a 6 semanas comparado con los controles. Sin embargo si mostraron una mejoría importante del dolor isquémico.

Diseño del Estudio
  • Aleatorizado a sobre abierto y controlado, factorizado en tabla 2×2.
  • Se incluyeron 19134 pacientes de 200 unidades coronarias en Italia.
  • Grupo 1: Lisinopril 5 mg VO 2 veces por día, luego 10mg 1 vez por día (n=4,713)
  • Grupo 2: Nitroglicerina IV por 24 hrs y luego parche de 10mg 1 x día (n=4,371)
  • Grupo 3: Lisinopril + Nitratos, (n=4,722
  • Grupo 4: No Lisinopril, no nitroglicerina (n=4,729)
  • Seguimiento a 6 semanas.
Criterios de Inclusión
  • Pacientes admitidos dentro de las primeras 24 hrs con síntomas de SICA definido por al menos dos de las siguientes:
    • Síntomas típicos
    • CK sérica > 2x el limite normal.
    • Cambios EKGs: Ondas q patológicas nuevas, elevaciones o depresiones del ST >1mm en 2 o mas derivaciones de los miembros o >2mm en derivaciones precordiales.
Criterios de exclusión
  • Alto riesgo para deterioro hemodinámico
  • Killip IV
  • Elevación significativa de la creatinina sérica
  • Proteinuria importante
  • Estenosis de la arteria renal bilateral
  • Alergia a cualquiera de las drogas del estudio
  • Enfermedad concomitante severa.
Métodos
  • Los tratamiento administrados en fase aguda incluyeron trombolisis, aspirina y betabloqueadores cuando no existía contraindicación.
  • Lisinopril se administro de la siguiente manera:
  • 5mg al momento de la randomizacion y 24hrs después, posteriormente 10mg diario por 6 semanas.
  • Si la TA sistólica <120mm/Hg en los primeros 3 días se administraban 2.5mm/Hg.
  • Si la TA sistólica <100mm/Hg en cualquier momento la dosis de mantenimiento era 5mg diariamente.
  • Si la TA sistólica <90mm/Hg, el tratamiento podía ser suspendido.
  • La NTG se administro de la siguiente manera:
  • 5mcg/min inicialmente incrementado 5-20mcg cada 20 mins hasta que la TA haya disminuido >10%  vigilando que estuvira >90mm/Hg.
  • Después de 24 hrs se suspendía la infusión y se reemplazaba por parches de 10mg. Cada parche se colocaba en la mañana y se retiraba por la noche dejando un periodo de descanso de 10hrs.
  • Si el parche no se toleraba se administraba mononitrato de isosorbide 50 mg VO diariamente.
  • El estudio permitía utilizar nitratos en el grupo de control si el paciente presentaba angina, falla cardiaca o hipertensión.
  • Se realizo ecocardiografía transtorácica a las 6 semanas en la que se valoró función ventricular izquierda y anormalidades en la movilidad segmentaria.
 

 

Características Basales de los pacientes
Características
Mayores de 70 años

27%

IAM previo

14%

Hipertensión

30%

Diabetes

15%

 

Punto final primario Mortalidad de cualquier causa a las 6 semanas.

  • 7.2% en los controles
  • 6.2% en el grupo de lisinopril, OR 0.88 (IC 0.79-0.99), p=0.03
  • 7.0% en el grupo de nitratos, OR 0.97 (IC 0.83-1.14), p=no declarada
  • 6.0% en el grupo de lisinopril + NTG, OR 0.83 (IC 0.7-0.97), p=no declarada
Puntos finales secundarios
  • Muerte, signos clínicos de falla cardiaca, FEVI <35% o disquinesias:
  • Ø 17.0% en grupo control
  • Ø 16.4% con lisinopril, OR 0.96 (IC 0.86-1.07)
  • Ø 17.0% con nitrato, OR 1.00
  • Ø 14.8% con lisinopril + nitratos, OR 0.85 (IC 0.76-0.94)
Financiamiento El Grupo de Estudio GISSI-3
Referencias Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6 week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. Lancet. 1994 May 7;343(8906):1115-22.
 

 

Realizado por: Mauricio Kuri Ayache. Residende de Cardiología. Instituto Nacional de Cardiología Ignacio Chávez