Clinical and Genetic Determinants of Carbohydrate Metabolism Disorders and Cardiovascular Complications in Patients with Arterial Hypertension. Organ-Protective Effects of Antihypertensive Drugs

The dissertation is devoted to the study of clinical and genetic determinants of carbohydrate metabolism disorders and cardiovascular complications in patients with arterial hypertension and overweight, as well as to the assessment of the organ-protective effects of antihypertensive drugs. The work characterizes the frequency and variants of carbohydrate metabolism disorders, examines the associations of polymorphisms of the PPARa, PPARy, IRS-1 and IRS-2 genes with insulin resistance, and investigates the peculiarities of remodeling of the microcirculatory bed and arterial elastic properties, including by means of the cardio-ankle vascular index. Special attention is given to the syndrome of disproportionately high left ventricular myocardial mass and its relationship with risk factors. The clinical-pharmacological part analyzes the influence of eprosartan, metformin, moxonidine, bisoprolol and aliskiren on microcirculation, carbohydrate metabolism and blood pressure control, and studies pharmacogenetic predictors of response to therapy and genetic determinants of cardiovascular complications in hypertensive patients with type 2 diabetes mellitus.

Topicality of the study. Arterial hypertension (AH) continues to be one of the leading problems of modern medicine owing to its prevalence and decisive contribution to cardiovascular morbidity and mortality (Wachteil K. 2005, Zeller M. 2005, Kearney P. 2005). In view of the proven strong association with the development of cardiovascular events, the problem of AH combined with carbohydrate metabolism disorders and overweight attracts close attention. Despite the undoubted benefit of lowering elevated blood pressure, a number of issues remain to be discussed, including the significance of hard endpoints in patients with low/moderate cardiovascular risk. In these patient groups, the use of validated endpoints to assess the efficacy of antihypertensive drugs appears appropriate.

It is assumed that insulin resistance is the unifying pathophysiological factor in the majority of cases of AH and carbohydrate metabolism disorders. The significance of insulin resistance as a surrogate endpoint has been demonstrated (Erik H. 2007). Insulin resistance may develop as a consequence of long-standing AH, which leads to a decrease in peripheral blood flow and capillary rarefaction (Forder J. 2005). Conversely, insulin resistance, by causing capillary dysfunction and an increase in total peripheral resistance, promotes the development of AH (Mitchell G. 2005, Yki-Jarvinen H. 2006, Erik H. 2007). Thus, the microcirculatory compartment of the vascular bed may represent a potential therapeutic target (Makolkin V.I. 2006, Franc F. 2006). The contribution of polymorphisms of the peroxisome proliferator-activated receptor (PPAR) genes and of the insulin receptor substrate genes of types 1 and 2 (IRS-1, IRS-2) to the development of insulin resistance and carbohydrate metabolism disorders is being actively studied (Hegele R. 2006, Bosse Y. 2006). However, the role of the C/G polymorphism of PPARa, the Pro12Ala polymorphism of PPARy, the Ala512Pro polymorphism of IRS-1, and the Gly1057Asp polymorphism of IRS-2 in the development of carbohydrate metabolism disorders and insulin resistance in AH patients with overweight has not been clearly defined.

In the modern concept of AH pathogenesis, growing interest has been observed in the study of arterial elastic properties. Numerous prospective studies in various populations, including individuals with normal blood pressure, have demonstrated the significance of aortic wall stiffness as an independent risk factor of cardiovascular complications (Van Bortel L. 2002, Abassade P. 2002, Dernellis J., Panaretou M. 2005). In AH patients with clinically manifested type 2 diabetes mellitus, an early increase in aortic wall stiffness and its rapid progression are observed (Kullo I. 2006, Tomiyama H., Hashimoto H. 2006). However, the influence of other variants of carbohydrate metabolism disorders (impaired glucose tolerance, fasting hyperglycemia) on the elastic properties of the aorta and arteries remains insufficiently studied.

In recent years, the problems of left ventricular hypertrophy resistant to antihypertensive therapy have become evident (Moiseev V.S., Kobalava Zh.D. 2001). Numerous attempts to use antihypertensive agents in AH patients to achieve regression of left ventricular hypertrophy have been successful only in a certain proportion of patients. Therefore, the study of the proportionality of the increase in left ventricular myocardial mass and of its blood-pressure-independent determinants, the impact on which may potentially contribute to a more substantial regression of myocardial hypertrophy, remains relevant.

Despite the fact that much is presently known about the mechanisms of AH and its complications, no precise prognostic criteria are available to determine the course of the disease. The identification of genetic markers for detecting patients with an increased risk of carbohydrate metabolism disorders and cardiovascular complications remains a pressing issue. Considerable hopes are associated with the study of pharmacogenetic approaches to implementing more aggressive measures for the treatment and prevention of AH complications and to predicting the efficacy of various classes of antihypertensive and antidiabetic drugs (Ellmerer M. 2006, Ross R. 2007).

The results of controlled clinical trials have demonstrated the validity of the strategy of maximal reduction of cardiovascular morbidity and mortality risk, based on the individual selection of drugs in accordance with the individual spectrum of risk factors (Kobalava Zh.D. 2006, Barbato J. 2005). Despite the wide choice of antihypertensive drugs, target blood pressure levels are not achieved in at least two-thirds of AH patients (Wolf-Maier K. 2006). In high/very high risk groups, the need remains to select an effective and proven combined drug regimen. Given the key role of the renin-angiotensin-aldosterone system in the development of AH and the progression of cardiovascular complications, it may be assumed that blockade of this system at different levels will exert an additional organ-protective effect in these patients (Chrysant S. 2004, Waeber B. 2006). Data are available on the organ-protective effects and the prevention of type 2 diabetes mellitus by angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. In 2007, the FDA approved the first oral renin inhibitor, aliskiren. A long-term program was launched to evaluate the efficacy of this drug in improving outcomes in patients with various forms of carbohydrate and lipid metabolism disorders, target organ damage, and associated clinical conditions (Villamil A., Chrysant S. 2007).

Thus, the study of clinical and genetic determinants of carbohydrate metabolism disorders and insulin resistance in AH patients remains relevant. Investigation of the contribution of carbohydrate metabolism disorders to the remodeling of different compartments of the cardiovascular system may potentially optimize the ways of pharmacological correction. The study of the pharmacogenetic aspects of therapy potentially affecting insulin resistance and carbohydrate metabolism disorders is also relevant.

Aim of the study.

In AH patients with overweight, to study the clinical and genetic associations of carbohydrate metabolism disorders and insulin resistance, their contribution to the remodeling of the cardiovascular bed and the possibilities of optimizing drug correction, and to identify genetic predictors of cardiovascular complications in patients with type 2 diabetes mellitus.

Tasks of the study:

1. In AH patients with overweight, to study the variants and clinical-genetic determinants of carbohydrate metabolism disorders and their relationship with insulin resistance.

2. To study the peculiarities and determinants of the remodeling of the microcirculatory bed and of arterial elastic properties in AH patients with different variants of carbohydrate metabolism disorders.

3. To assess the contribution of different carbohydrate metabolism disorders to the presence of disproportionately high left ventricular myocardial mass in AH patients.

4. To study the possibilities of correcting specific changes of the microcirculatory bed in AH patients with disorders of carbohydrate regulation and type 2 diabetes mellitus using monotherapy with the AT1 angiotensin II receptor antagonist eprosartan, the biguanide metformin, the selective beta-1-adrenoblocker bisoprolol, and the agonist of central I1 imidazoline receptors moxonidine.

5. To establish clinical and genetic predictors of the pharmacodynamic effects of moxonidine and metformin in AH patients with overweight, carbohydrate metabolism disorders and insulin resistance.

6. In a case-control study, to investigate the genetic determinants of fatal and nonfatal cardiovascular complications in AH patients with type 2 diabetes mellitus.

7. To study the efficacy and safety of the first oral renin inhibitor, aliskiren, in monotherapy and in combination with hydrochlorothiazide, depending on the renin profile, in AH patients with overweight, using twenty-four-hour blood pressure monitoring.

Scientific novelty.

In AH patients with overweight without clinical and laboratory manifestations of type 2 diabetes mellitus, the frequency of carbohydrate metabolism disorders revealed by the oral glucose tolerance test is 69%: impaired fasting glycemia is detected in 28.6%, impaired glucose tolerance in 23.5%, and diabetes mellitus in 16.9%. Insulin resistance is detected in 93% of patients with carbohydrate metabolism disorders and in 54% of those without such disorders.

The genetic determinants of insulin resistance have been studied. The C allele and CC genotype of the Pro12Ala polymorphism of the PPARy gene are associated with insulin resistance, while the C allele and CC genotype of the C/G polymorphism of the PPARa gene are associated with the development of carbohydrate metabolism disorders. It has been demonstrated that the pharmacodynamic effects of moxonidine and metformin are associated with the A allele of the Pro12Ala polymorphic marker of the PPARy gene and with the C allele of the C/G polymorphic marker of the PPARa gene.

It has been shown that the specific features of microcirculatory bed remodeling in carbohydrate metabolism disorders include the hyperemic hemodynamic type of microcirculation. In patients with type 2 diabetes mellitus, microcirculatory changes are of a more complex character owing to the aggravation of disturbances in autoregulation mechanisms. It has been established that monotherapy with eprosartan and metformin reduces the severity of specific microcirculatory disorders in patients with disturbances of carbohydrate regulation. Monotherapy with bisoprolol and moxonidine allows correction of specific microcirculatory disorders in patients with clinically manifested type 2 diabetes mellitus.

For the first time, it has been shown that the cardio-ankle vascular index, whose calculation algorithm takes into account pulse wave velocity in the aorta and minimizes the influence of systolic blood pressure level, makes it possible to detect differences in aortic elastic properties in AH patients with different variants of carbohydrate metabolism disorders without clinically manifested diabetes mellitus.

The syndrome of disproportionately high left ventricular myocardial mass has been described, being detected in 83% of AH patients with carbohydrate metabolism disorders. An association has been established between the degree of disproportion of left ventricular myocardial mass and the increase in the number of cardiovascular risk factors.

For the first time, it has been demonstrated that the renin inhibitor aliskiren is effective and safe for the treatment of AH as monotherapy and in combination with hydrochlorothiazide. The antihypertensive efficacy of the drug does not depend on the initial renin profile of the patients, and satisfactory blood pressure control is maintained 14 days after drug withdrawal according to clinical measurement and twenty-four-hour blood pressure monitoring.

The case-control study established associations of polymorphisms of the ACE gene, the vascular AT1 angiotensin II receptor gene, the angiotensinogen gene, the endothelial NO synthase gene, the catalase gene, and the glutathione peroxidase gene with the risk of fatal and nonfatal myocardial infarction, stroke, chronic renal failure, and diabetic foot syndrome.

Practical significance.

For a more accurate characterization of the morphofunctional state of the myocardium in AH patients with carbohydrate metabolism disorders, it is advisable to determine the disproportion coefficient of left ventricular myocardial mass.

To assess aortic elastic properties in AH patients with carbohydrate metabolism disorders without clinical manifestations of diabetes mellitus, the investigation of the cardio-ankle vascular index is recommended.

Detection of the hyperemic hemodynamic type of microcirculation in AH patients is associated with carbohydrate metabolism disorders. Administration of eprosartan, metformin, moxonidine, and bisoprolol corrects these disturbances of the microcirculatory bed.

Determination of the genetic markers PPARa and PPARy allows prediction of the pharmacodynamic effects of metformin and moxonidine on carbohydrate metabolism in AH patients with overweight.

Determination of the polymorphic markers I/D of the ACE gene, T174M of the angiotensinogen gene, A1166C of the angiotensin II type 1 receptor gene, the minisatellite eNOS4a/4b of the NO synthase gene, C1167T of the catalase gene, and P197L of the glutathione peroxidase gene makes it possible to identify patients with an increased risk of fatal myocardial infarction, stroke, end-stage chronic renal failure, and diabetic foot syndrome among AH patients with type 2 diabetes mellitus.

Statements for defense.

1. The frequency of carbohydrate metabolism disorders according to the oral glucose tolerance test in AH patients with overweight is 69%; in a proportion of patients, carbohydrate metabolism disorders are not accompanied by insulin resistance. The polymorphic markers Pro12Ala of the PPARy gene and C/G of the PPARa gene are associated with insulin resistance and carbohydrate metabolism disorders.

2. The specific features of the microcirculatory bed in carbohydrate metabolism disorders include the hyperemic hemodynamic type of microcirculation, which can be corrected by monotherapy with eprosartan or metformin in AH patients with carbohydrate metabolism disorders, and by multilevel sympathetic nervous system blockade with moxonidine or bisoprolol in AH patients with type 2 diabetes mellitus.

3. The cardio-ankle vascular index makes it possible to detect a decrease in arterial elastic properties in AH patients without clinically manifested diabetes mellitus.

4. In AH patients with overweight, the syndrome of disproportionately high left ventricular myocardial mass is encountered in 83% of cases. The degree of disproportion of left ventricular myocardial mass is associated with an increase in the number of cardiovascular risk factors.

5. In patients with grade I AH, overweight and carbohydrate metabolism disorders, the pharmacodynamic effects of moxonidine and metformin are associated with the C/G polymorphism of PPARa and PPARy.

6. Polymorphic markers of the ACE gene, the vascular AT1 angiotensin II receptor gene, the angiotensinogen gene, the endothelial NO synthase gene, the catalase gene, and the glutathione peroxidase gene are associated with the risk of fatal and nonfatal myocardial infarction, stroke, chronic renal failure, and diabetic foot syndrome.

7. The renin inhibitor aliskiren is effective and safe for the treatment of AH patients as monotherapy and in combination with hydrochlorothiazide. The antihypertensive efficacy of the drug does not affect carbohydrate and electrolyte metabolism, does not depend on the initial renin profile of the patients, and is maintained for 14 days after drug withdrawal.