Cardiovascular Phenotypes and Functional Parameters in the General Population - Results of the MONICA/KORA Studies

Introduction

Given the increasing prevalence of multiple risk factors in our societies, cardiovascular diseases play a growing sociomedical role. Moreover, based on precise measurement of arterial blood pressure as well as of other traditional risk factors the pathophysiological understanding of coronary heart disease and heart failure is rapidly growing. The sequential MONICA/KORA surveys became focus of these increasing scientific and methodical possibilities. On the one hand, improved echocardiographical evaluations of left ventricular geometry and function allowed a detailed documentation of cardiac function. Additionally, the MONICA/KORA surveys were accompanied by steadily improved genetic technologies. Thereby, correlations between multiple anthropometric factors with pathological changes of heart volume and function as well as the evaluation of genetic polymorphisms or mutations yielded a plethora of novel insights. The present paper sums up the essential results of these works.

Methods

Electro- and echocardiographic examination form the core methods in this part of the MONICA/KORA surveys. About 2,200 standard examinations have been carried out on subjects of a follow-up of the first survey in 1984/85 (S1) in 1994 as well as large parts of the third survey in 1994/95 (S3). The number of participants in these echocardiographic sub-studies was lower than in the overall survey, due to restriction to the Augsburg city recruitement center. The studies made use of data from the first MONICA survey that allowed comparative analyses in terms of blood pressure and ECG data. Technically, the protocols were carried out in a standardized fashion by specially trained personnel. Particularly, great care was used in order to generate high quality echocardiographic readings. For this purpose, two highly experienced investigators underwent specific training to produce consistent results. The same applies for electrocardiographic readings that were digitized for further analyses. Blood was subsequently taken for generation of serum, plasma and DNA samples. Biochemical and molecular genetic methods have been described elsewhere in great detail.

Results

Left ventricular hypertrophy

Renin angiotensin system

Starting point for the epidemiological studies were experimental data of our group that demonstrated the involvement of angiotensin converting enzyme (ACE) in the development of pressure induced left ventricular hypertrophy [1] [2]. Interestingly, data on a polymorphism that results in elevated ACE levels corroborated these findings and demonstrated that this genetically driven induction of the renin angiotensin system elevates the risk of left ventricular hypertrophy [3]. Subsequently, our group demonstrated that an ACE insertion/deletion (I/D) polymorphism specifically elevates ACE activity in the heart [4]. Likewise, other components of the renin angiotensin system were associated with cardiac mass [5] [6]. In conjunction, experimental and epidemiological data further strengthened the pathophysiological role of an activated renin angiotensin system in the development of left ventricular hypertrophy [7]. Not surprisingly, recent clinical studies using blockers of the renin angiotensin system came to the conclusion that inhibition of this system is specifically useful for reversal of these effects [8].

Blood pressure

Pressure overload, i. e. a continuously higher systolic pressure in the heart giving rise to an increased wall tension, is traditionally seen as a major contributor to the development of left ventricular hypertrophy. The same was true in the MONICA/KORA studies, although the intensive cardiovascular phenotyping produced a number of additional modifying factors. One of these was the so-called white coat effect, i. e. the surge of blood pressure upon contact with a physician. This slightly stressful encounter was also observed in some study participants who displayed higher blood pressure readings when measurements were taken by the physician as compared to the technician. Interestingly, the white coat effect was also found to increase the probability of left ventricular hypertrophy [9]. Moreover, obesity and obesity related hypertension were found to come with substantial implications for left ventricular geometry. While hypertension was particularly correlated with a concentric type of hypertrophy, obesity was found to induce an excentric pattern. The combination of both, hypertension and obesity, came with the strongest effects [10] [11] [12] [13] increasing both geometric forms of left ventricular hypertrophy.

Indexation

Detailed measurements of fat and fat-free mass allowed further novel investigations with respect to implications of body composition and left ventricular geometry [14]. First, these studies clearly demonstrated that left ventricular mass is best correlated with fat-free mass, i. e. the type of tissue that deserves most of the blood supply [15]. By contrast, fat mass was associated with the risk of hypertension and, thus, a concentric pattern cardiac hypertrophy. Interestingly, the indexation of left ventricular mass for fat-free mass of a given individual diminished the association between fat mass and left ventricular mass. This surprising effect may be explained by higher fat-free mass as a result of obesity in addition to the expected increase of fat mass. Indexation for this increase of fat-free mass reduces the association of fat mass or obesity with left ventricular mass considerably. Moreover, this type of indexation (LVM divided by fat-free mass) completely abolished the differences in cardiac size traditionally observed between men and women. In fact, indexation of fat-free mass was the first ever observed indexation that produced identical (adjusted) heart sizes for men and women [15].

Hypertension

A number of neurohormones were also associated with blood pressure in the MONICA/KORA samples. In addition to components of the renin angiotensin system [16] dehydroepiandosterone was found to correlate with blood pressure [17]. This effect was particularly interesting, because substitution of this hormone is considered to delay aging in men resulting in enormous over the counter prescriptions in the United States.

Natriuretic peptides

Another class of hormones related to cardiac function are the natriuretic peptides. Measurements of arterial natriuretic peptides (ANP), brain natriuretic peptides (BNP) and their second messengers cGMP were also correlated with left ventricular mass and function as well as renal function in the MONICA/KORA surveys [18] [19] [20]. The data served to create population-based reference levels given that these markers proved to be useful for clinical diagnosis of heart failure, cardiac hypertrophy and aortic stenosis and, finally, may prove useful for making treatment decisions.

Medication

In addition to anthropometric, genetic and biochemical promotors, medication was investigated with respect to its consequences on blood pressure, hypertrophy and neurohormone levels [21] [22] [23] [24] [25] [26]. Interestingly, these studies produced highly differential results with respect to drugs affecting the renin angiotensin system or sympathetic nervous system, respectively. Specifically, diuretics, ACE inhibitors or the combination of both resulted in a stepwise increase of renin levels, whereas beta blockers, either alone or in combination with such drugs, almost abolished this effect. By contrast, beta blockers were related to an increase of ANP, BNP and cyclic GMP levels. These data were of great interest given the pathophysiological implications of an activation of the renin angiotensin system [1] [2] [3] [4] [5] or the diagnostic value of the natriuretic peptides [18].

Genetic factors

In parallel with the evolution of the human genome project, the MONICA/KORA studies produced a large wealth of data on genetic factors with respect to their implications for arterial hypertension and left ventricular hypertrophy [3] [27] [28] [29] [30] [31] [32] [33] [34] [35]. In addition to the ACE I/D polymorphism, other genetic variants of the renin angiotensin system including angiotensinogen, AT1 receptor, aldosterone synthase, PPARα and GNB3 polymorphisms were studied in great detail. In conjunction, these studies document both the profound implication of inherited factors in general [36] and those of the renin angiotensin system in particular.

Cardiac function

The systematic exploration of more than 2,000 inhabitants of the Augsburg region allowed for the first time to produce population-based data on systolic and diastolic function of the heart [37] [38] [39]. In the context of other echocardiographic investigations of MONICA populations including Glasgow and others, these data were important for the definition of screening strategies for these dreadful conditions. In detail, these studies revealed that men are more likely to suffer from both systolic and diastolic dysfunction of the heart. Moreover, blood pressure, obesity and anemia proved to affect cardiac function substantially [37] [38] [39] [40] [41].

Discussion

The close interaction between cardiologists and epidemiologists in the MONICA/KORA surveys proved to be highly fruitful for the elaboration of cardiac geometry and function. Indeed, this interdisciplinary interaction allowed for the first time to generate an extensive German database on cardiac function and geometry as well as their related factors. The wide scope of these investigations and the enormous success in terms of high impact publications certainly enhanced the visibility of the Augsburg MONICA/KORA studies substantially. Indeed, some of the landmark studies on epidemiological aspects of left ventricular hypertrophy, heart failure and contributing factors such as the ACE I/D polymorphism were derived from the MONICA/KORA studies that introduced novel concepts to be reproduced in many other studies [3] [15] [37]. The follow-up of these investigations kicked off numerous successful grant applications including the BMBF Kompetenznetz Herzinsuffizienz and NGFN2.

Future planning

In the currently ongoing study the population-based follow-up of the third survey from 1994/95 (S3) in 2004/05 (F3) allows to investigate for the second time a population-based sample by electro- and echocardiography as well as measurement of body impedance. These consecutive measurements covering a period of 10 years will form a unique database for the investigation of factors affecting the incidence of hypertension, left ventricular hypertrophy and heart failure. Thus, the ongoing evaluations are likely to contribute to these topics under investigations for many years to come.

Acknowledgement

The investigations have been supported by GSF and grants from BMBF - Federal Ministry of Education and Research (KBF 01 GB 9493, 01GI0205, 01GS0499) and DFG - Deutsche Forschungsgemeinschaft (Schu 672/9-1, Schu 672/10-1, Schu 672/12-1).

Fig. 1 Factors studied in the Augsburg MONICA/KORA population affecting left ventricular hypertrophy.

Fig. 2 Factors studied in the Augsburg MONICA/KORA population affecting cardiac function.

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