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Fetal origin of cardiovascular disease.
High blood pressure as a paradigm

Pérez Fernández, Guillermo

Clinic: "José Ramón León Acosta", Santa Clara, Villa Clara, Cuba

SUMMARY
Introduction: Since the final of 80s decade several works started to point out that the origin of cardiovascular disease (CAD) get back to embriogenic period during gestation.
A new theory has pretended to solve this attractive mechanism, the Barker´s hypothesis, also known as the intra-uteri programming effect, which takes the low birth weight (LBW) as the major representant in order to demonstrated the correlation between an adverse intrauterine environment and the future possibility for the beginning of determinant CAD.
Objectives: To expose the preliminary results of the "School screening of high blood pressure (HBP (in the adolescence" (PESESCAD_HTA) investigation project concerning to the interrelation of LBW and arterial hypertension.
Material and Methods: A longitudinal and descriptive study was done to a sample of 644 students aged 12-15 years old, extracted from the total of 1305 participants recorded in the PESESCAD-HTA project. A questionnaire was applied asking for general and epidemiological data and three measurements of blood pressure(BP) were executed to each one.
Results: The LBW(5.12%) was linked to the superior values of BP. There were negative correlations between birth weight and the BP means. A prevalence of established HBP of 2.17% was found, while 9.01% were included inside of "frontier" HBP. Figure 1.

Discussion: An early intrauterine undernourish is an insult in determinant sensitive period when an organism is growing up, programming changes which would be irreversible.
In this way we found an significant inverse association between birth weight and the BP values for the age, in major degree for systolic, as is well illustrated in literature.
Conclusions: The negative influence of LBW over the systolic values of BP in present in the adolescence, and since here, and going ahead could reach a notorious relevance.

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INTRODUCTION
   From the ends of the decade of the eighty, several works began to indicate and demonstrated that the origin of the cardiovascular disease (CAD) is soared to the embriogenic period during the gestation (1-5).

   Currently the investigations about this topic have started, without losing supported advance, to follow a "retrospective" course directed to the roots of this recognized problematic of health, taking as paradigm the high blood pressure (HBP), the most important and common entity affecting all the populations of the world (6,7).

   In this context a new risk factor has emerged in the wide spectrum of those of atheroesclerotic type: the low birth weight (LBW), which evidences the relationship between an adverse intrauterine environment and the genuine possibility of a future vascular disease.

   With the present work we intend to expose some of the partial results about the relationship between LBW and HBP obtained until the moment by the Investigation Project "School Screening of High Blood Pressure in Adolescents (PESESCAD-HBP) underway at present in our province of Villa Clara. In the same way to recapture a topic that in not few occasions is relegated to the forgetfulness: the HBP in the pubescence, a recognized problematic of health today over the world (1,2,8), this time, from one of their multiple origins: the intrauterine life.

METHODS
   It was accomplished a longitudinal study of descriptive type to a representative sample of 644 students, aged between 12 and 15 years, extracted of the total of 1305 registered in the PESESCAD Project, belonging to the secondary schools "El Vaquerito" and "Juan Oscar Alvarado" of this city of Santa Clara, in a period of time that encompassed from 6 of February of the year 2000 until 15 of June of that same year (course 1999-2000).

   The students were extracted approximately 30 minutes after from have begun a shift of classes, previous insurance of the fact that the same elapsed without the stress of some evaluation or other not frequent incidence. Then, previous examination and complete physical examination to each one were practiced 3 measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with an interval of 5 to 7 days according to criteria established for the pediatric age (1,2) in the medical doctor's office.

   To each student was applied a survey where were collected a series of useful epidemiological variables for the present work: age, sex, race, weight in kilos, height in cm, personal pathological precedents (PPP), atheroesclerotic familiar risk precedents (AFRP), birth weight (BW), smoking and practical of physical exercise.

   Criteria and definitions.
Low birth weight (LBW): Pondered valuation at birth inferior to 5.5 pounds (2500 grams), independently they had a complete pregnancy or not.

   High normal blood pressure (HNBP): Subject whose values of BP were above of the 90 percentile and less than 95 in three or more occasions. For the age of: 10-12 years: SBP>=117-125 and DBP>=75-81. And of 13-15 years: SBP>=124-135 and DBP>= 75-85, according to the standards established in the II Task Force for the control of the HBP in children and adolescent. (1)

   Frontier or borderline hipertensives (FH): Individuals who presented values of BP above 95 percentile in one occasions, having otherwise two within a normal range.

   Established high blood pressure (EHBP): Students whose values of BP were above of the percentile 95 in three or more occasions according to the standards established in the II Task Force for the control of the HBP in children and adolescent (1).

   Established high blood pressure to predominance of systolic. Subject who presented two values SBP (of the three taken) considerate of moderate or severe, and the remainders in the range of mild. Established high blood pressure to predominance of diastolic. Subject who presented two values DBP (of the three you taken) considerate of moderate or severe and the remainders in the range of mild.

   The obtained data were seated in a database of Microsoft Access created to the effect. For the final conformation of our results was accomplished a statistics characterization using the following statisticians: mean arithmetic, standard deviation, and test t of student, correlation coefficients and linear regression analysis. It was considered the difference statistics from meaning level of 0.05 of probability of committing the mistake type I, in tests of two tails (p<0.05). The high significance happened for p<0.01 and the very high when p<0.001. To carry out this analysis we supported on the statistic package of Microsoft Excel belonging to the Microsoft Window 2000.

RESULTS
   Of 644 adolescent with a mean age of 12,35 +/- 0,35 years, the greater number was framed in the ages of 12(32,74%) and 13 years (37,26%). Their respective averages of SBP, DBP and mean BP are exposed in the figure 1. It is noted the linear increase of the means of BP with the age that it was highly significative toward 15 years upon the remainders (p<0.001). In our study existed 33 patient with insufficient weights at birth for a 5,12%, table 1 reflects convincingly the general superiority of the mean values of BP of those in this category on the remaining subgroups with signification for the systolic mean (p<0.05), it did not happen equal for the DBP with greater values but not significative (p>0.05).

   There were interrelated, through linear regression analysis, between the variable BW and the means of SBP, DBP and mean BP of the students diagnosed with established HBP to predominance of systolic (figure 2, Panel A) and there was an evident negative significative correlations for the mean of SBP (r = - 0.81; p = 0.02). Similar resulted for those in those which the predominance was of the diastolic (figure 2, panel B), where the correlation resulted negative however not meaningful(r = - 0.45; p>0.05), on the other hand the trend of the DBP is equally not proportional to the pondered valuation at birth.

   Fifty eight patient presented frontier HBP and existed in them in the same way linear correlation, not proportional and highly significative between their respective averages of SBP and the BW (r = - 0.34; p = 0.007), is emphasized the existence of a forecast for this tensional value forward a diminishing trend while increases the weight to the birth (figure 3). Similar results were obtained for the DBP (not showed), which presented a weak relationship, however, negative. (r = - 0.18, p>0.05)

DISCUSSION
   The nutritional prenatal status plays a crucial role in the postnatal growth and development. An early malnutrition constitutes a precocious stimulus or "affront" in a given sensory period of the growth organization process, "programming" of this manner changes that could be practically irreversible.(8-10)

   Before such facts and taking as first point the firm issued annotation for the first time in England done approximately 10 years taken from several multicentric trials that confirmed that the individuals with insufficient weight at birth are at increased risk of CAD in subsequent stages of their life (11 ,12), a succeeded explanation to this phenomenon did not delay in seeing the light.

   In 1995 the notable british researcher David Barker (13) issued an attractive hypothesis that carries his name, on the fetal origin of the CAD, seating that an improper nourishment of the embryo from half until the end of the pregnancy guides to a disproportionate fetal growth which "program" since then the possibility of events of cardiac origin in the adulthood. The previous statement presents interesting two premises, that they should be had in account:

1) In the fetal period, from the ninth week of the conception until the end of the pregnancy, beginning in the fetus the rapid tisular growth phase (TGP), that continuous even postnatal. The fundamental promoter of this growth is the cellular division (CD) and different tissues of the organism have the characteristic of growing in periods called "critical", where the CD is very hurried depending without doubts on demands on nutrients and oxygen, as well as on the adjustment of the fetus to its lack. In nourished fetus, evidently is going to exist a delay CD, and consequently a reduction of the number of cells that experience a TGP, what would constitute a negative " genetic memory report "(GMR).
2) Another injurious GMR that happens until the adult age would be the fact that this improper embryonic nourishment, would cause changes in different cell functions, what is translated in persistent alterations, so much of the hormonal secretion and metabolic activity, as of structure and various corporal organs function that stay latent in corporal memory almost from the installation of the egg, with a high possibility of becoming pathological toward pubertal ages or adult as annotated most recently the same author (14).

   The same Barker (13,17) and others (12,14-18) patenting the bylaws of the programmer theory have offered a supreme independent influence to the variable LBW as risk factor, equal to the one which could have the own HBP, the coronary disease, dislipidemias, obesity and hiperfibrinogenemia. All conclude that the influence of the LBW is not altered even before the most potent risk situation that could coexist with an adverse fetal situation (smoking, overdone alcohol consumption or motherly atheroesclerotic disease).

   The mechanisms by which an insufficient weight at birth increases the values of BP in a given individual if we take into account the theory of Barker and also the Brenen´s issuing (18) referring to the theory of the "nefron", which states that a detained growth during the embryonic phase with cellular hipodevelopment would lead to smaller kidneys and smaller population of nefrons, then the filtration of course would be depressed, with the cumulative effect of the years the volemia would be increased with the consequent increase of the cardiac output and the BP over life. A premature activation of the system renin-angiotensin system produced by an adverse intrauterine environment adverse also has been proposed (11).

   The work of Gardiner and coll (19) gives response to the mechanism that involves to the placental dysfunction inside these complex mechanisms leading to the elevation of the arterial tension later in life. This authoress alludes recapturing the previous explanation as premise that an overcharge of intrauterine volume would increase the resistance of the placenta (organ that intervenes in the development of the cardiovascular fetal system) provoking increase in the vascular resistance especially in the inferior extremities with the evident decrease of the sanguine flow what would carry to alterations in the pulsating capacity on the arterial vessels, beginning structural changes in the falling aorta and the arteries of the inferior members. Finally these structural defects that are established throughout life go to reduce the arterial complianza with the consequent bias to the HBP.

   It is exemplify the coincidence of our results with what is reported in the literature, and that already we comment: the BW is interrelated linear and inversely with the BP in greater degree for the maximum values. Then, we think, that it is well consequent to outline that on the figures of BP of our hipertensives influenced in a linear and negative way the pondered weight at, in spite of the fact that the adolescence constitutes also a critical stage of life where the called " growth spurt" in english, or "growth to jet"(20), that happens in the teenage years responsible for the influence not so energetic of the BW this stage of the life, that for us was evident for the DBP.

   These results sustain yet more, the real probability of the fact that the presentation of the risk characteristic LBW in an already adult subject, of course would show closer associations with figures inside the range on HBP, so much for established or for frontier hipertensives individuals, may be would not be the same of anothers as obesity, smoking or DM, the most influential to these precocious ages, but it would be a new or an added risk for a patient with the characteristic of being independent as the prior for the development of CAD, in the other hand would constitute a succeeded reveille to face from an additional sight this other scourge of our times: the HBP.

CONCLUSIONS
   We assumed that the negative influence of the LBW on the high values of arterial pressure and its close association with the same already exists in the adolescence, and from here, and in forward, would reach a notorious relevancy

REFERENCES

1. Update on the Task Force Report (1987) on high blood pressure in children and adults: a working group report from the national high blood pressure education program. NHI Publication 1996. No. 96-3790:[24 screams], available from: URL: http://www.nh/binih gov/health/prof/heart/hbp-ped.pdf.

2. Strong JP, Malcon GT, McMahan CA, Tracy RE, Newman WP, Herderic KE, et al. Prevalence and extent of atheroesclerosis in adolecents and young adults. J Am Med Assoc 1999; 281: 727-735.

3. McGill Hc. Jr, Michfahan CA, Zierke Ca, Tracy RR, Herdenick RR, Strong JP. Association of coronary heart disease risk factors with microscopic quantities of coronary atheroesclerosis in youth. Circulation 2000 Jul;106(4): 374-379.

4. Fuster V. Gotto Am, Libby P, Loscalzo J, Mcbill HC. Task Force 1. Pathogenesis of coronary disease. The biology role of risk factors. J Am Coll Cardiol 1996 Apr; 27(5): 964-976.

5. Clark PM, Hinelmarsh Pc, Shiell AW, Law CM, Honour JW, Barker DJP. Size and birth and adrenocortical fuction in childhood. Clin Endocrinol 1996; 45: 721-726.

6. Macías Castro I, Cordies Jackson L, Landrove Rodríguez O, Pérez Caballero D, Vázquez Vigoa A, Alfonso Guerra J. et al. Programa nacional para la prevención, diagnóstico, evaluación y control de la hipertensión arterial. Ciudad de la Habana: MINZAP, 1998: 1-58.

7. The VI Report of the Joint National Committe on detection, evaluation and treatment of high blood pressure. Arch Inter Med 1997;157:2413-46.

8. Engelbreght MJT, Howdijk ME, Snijder SC, Vanderwaal HA. The effects of intrauterine growth retardation and posnatal undernutrition on onset of puberty in male and female rats. Pediatr Res 2000; 48: 803-807.

9. Taylor SJC, Whincup PH, Cook DG, Papacosta O, Walker M, Size at birth and blood pressure; cross sectional study in 8-11 years old children. BMJ 1997; 314: 475-480.

10. Fall CHD, Barker DJP, Llals CM, Stirling Y, Meade W. Fetal and infant growth and cardiovascular risk factor in women. BMJ 1995; 310: 428-432.

11. Barker DJP. In utero programming of cardiovascular disease. Theriogenology 2000; 53: 555-574.

12. Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hakinson SE, Colditz GA, et al. Birthweight and cardiovascular disease in a cohort of women followed up since 1976. BMJ 1997; 315: 396-400.

13. Barker DJP. Fetal origins of coronary heart disease. BMJ 1995; 311(15): 171-174.

14. Barker DJP. Early growth and cardiovascular disease. Arch Dis Child 1999 Apr; 80: 305-307.

15. Power C, Li L. Cohort study of birthweight, mortality and disability. BMJ 2000; 320: 840-841.

16. Rabbia F, Veglio F, Nacca R, Martini G, Riva P, di Cella SM, et al. Relationship between birthweight and blood pressure in Adolescence. Prev Med 1999 Dec; 29: 455-459.

17. Walker BR, Noon JP, Walt GCM. Contribution of parental blood pressure to association between low birthweight and adult high blood pressure: across sectional study. BMJ 1998; 316: 834-837.

18. Bernner BM, Chertow GM. Congenital oligonephopathy: an inborn cause of adult hypertension and progessive renal injury?. Curr Opin Nephrol Hypertens 1993; 2: 691-695.

19. Gardiner H, Chaung YF. Reduced arterial distensibility in the fetus may link placental dysfunction in utero and later. BMJ 1999 Dec(letter to the editor): available from: URL: http://www/Biomednet.com/BMJ.

20. Yiu V, Buka S, Zurakowski D, McCormick M, Brenner B, Jabsk K. Relationship between birthweight and blood pressure in childhood. Am J Kidney Dis 1999 Feb;33(2):253-60.

 

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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