Pharmacometabonomics, pharmacogenomics and personalized medicine.

The development of genomics in the last decade opened new perspectives to fulfill the permanent ideal of therapy, namely personalization of therapy (of medicine) by using of adage: "the right drug to the right patient". The pharmacogenomics, developed in these 10 years, already permitted the identification of the patients with side drug effects risk by detection of the presence of single nucleotide polymorphisms (SNPs) from enzymatic systems implied in drugs metabolism such as CYP450. More recently, the emergence of pharmacometabonomics permitted the appreciation of the influence of the metabolic factors (and of the environment) on the genes expression. The combination of these sciences can permit a better individualization of drug therapy concerning both the genetic background of individual and exterior interventions. Actual studies seem to confirm this supposition.

Feasibility study of substitution hormonal therapy on cardiovascular diseases in post-menopausal women (part II).

BACKGROUND: In a finished feasibility study concerning the effects of substitution hormonal therapy (SHT) on the cardiovascular status in the post-menopausal women (pmw) we analysed the rate of participation of the Romanian women, the reasons for abandon to participation, etc. in a multicentric international study. OBJECTIVES: This study had intention to analyse the cardiovascular status of the pmw proposed for STH. MATERIAL AND METHODS: Only 121 women, who accepted all conditions for participation to study, were included. Mean age was 55 +/- 5 years (45-64 years), 93 women were in natural, and 28 in surgical menopause. The study protocol included analysis of: 1) the coronary risk factors (arterial hypertension, diabetes, smoking, serum lipids level, etc.), 2) inflammatory syndrome (serum fibrinogen, C reactive protein), 3) cardiovascular status (clinical data, ECG). RESULTS: 1) Incidence of essential hypertension was 23%; type II diabetes 17%; smoking 15%; serum high cholesterol was presented in 82%; high lipids level in 56%; high serum triglycerides in 35%; HDL was reduced in 56%. 2) Serum high fibrinogen was detected in 20% and CPR presence in 20%; 3) ECG was altered in 30% (HVS, ST-T modifications). Only 20% from pmw with alterations of ECG have not presented coronary risk factors or inflammatory syndrome. DISCUSSION: It is a feasibility study in a domain very extended actually by many multicentric clinical trials. The problem of the effects of SHT on cardiovascular system is still in dispute, and our study estimates the preliminary data at the beginning of a trial. These data show a high percent of pmw, which have already alterations of ECG and a concurrency of coronary risk factors and inflammatory indices. The effects of SHT in these women necessitate still a study on long time interval. For Romanian pmw, these data indicate the importance of the precocious investigations and detection of all coronary risk factors concerning the correct indications of SHT and its effects.

Diagonal earlobe crease: a coronary risk factor, a genetic marker of coronary heart disease, or a mere wrinkle. Ancient Greco-Roman evidence.

In a new study on the relationship between the diagonal earlobe crease (DELC), first described by Frank in 1973, and the presence of chronic ischemic heart disease, four main hypotheses are presented. Hypothesis 1: DELC is a coronary risk factor or a marker of coronary risk factor. Hypothesis 2: DELC is a genetic marker of atherosclerotic coronary disease. Hypothesis 3: DELC is, in fact, the result of aging and the relationship with atherosclerotic coronary disease is mere coincidence. Hypothesis 4: DELC is an anatomic peculiarity of the ear lobe, perhaps the result of a particular way of sleeping. These hypotheses are discussed in the light of the most important results obtained so far, in the literature and in the author's personal studies. Moreover, the data reported by Petrakis, who was the first to mention in 1980 the presence of this sign in some of the Greco-Roman sculptures in the museums of Rome, are corroborated by the observations of one of the authors, made in the Louvre Museum in Paris.

Ventricular late potentials. Part II. Clinical importance and interpretation.

This second part of a review on the ventricular late potentials (VLP) includes most of the latest data on their clinical interpretation. A description of VLP characteristics in normal subjects is followed by an analysis of their significance in several cardiovascular diseases in which VLP presence has been almost currently investigated, i.e., acute myocardial infarction, postinfarction states, unexplained syncopes, cardiomyopathies and post-heart surgery states. Particular situations such as the congenital or acquired syndrome of long QT and VLP incidence, bundle branch blocks and VLP presence, the effect on the VLP of some anti-arrhythmogenic blockers of sodium channels are further discussed. Up to date information on the VLP significance in cardiovascular pathology and the author's personal experience on the VLP significance in patients with ischemic heart disease, syncopes, dilating cardiomyopathies or long QT interval are presented.

Ventricular late potentials. Part I. Techniques, detection, interpretation.

The first part of this review on the ventricular late potentials (VLP) presents the actual methods of diagnosis by: 1. Analysis in the time domain (ATD), currently used in most of the studies on the VLP. 2. Analysis in the frequency domain (AFD), in course of study, in which the author has a personal experience and has drawn criteria for the VLP diagnosis. 3. Beat-by-beat analysis, also in a stage of study. Irrespective of the analysis type, the criteria of positivity for VLP presence and the techniques of recording are analysed and commented according to the author's own experience. The interpretation of these techniques and their application in clinical practice shall make the object of the second part of this review.

Contribution of the high amplitude electrocardiography to the detection of ventricular late potentials in several cardiovascular diseases.

The criteria for detection of ventricular late potentials (VLP) by high amplitude electrocardiography (ECG) in the frequency domain were evaluated in 75 patients with cardiovascular diseases, mostly men (85%), with a mean age of 57 years, distributed by disease type into three subgroups: (1) with a history of myocardial infarction (MI)--53 cases; (2) with syncopes, episodes of prolonged ventricular arrhythmias--18 cases; (3) with unobstructive, primary cardiomyopathies--4 cases. Complete clinical examination, standard ECG, continuous 24 hr Holter ECG, high amplitude ECG (Corazonix system) for detection of VLP by analyses in the time domain (TD) and in the frequency one (FD) were performed in all the cases. The VLP incidence was evidently high in all the cases. By association of the analyses in TD and FD, the accuracy of VLP detection increased by 17.3% in the whole group (from 64% to 81.3%). The incidence of severe ventricular arrhythmias (class 4-5 Lown, i.e., doubled and/or trebled ventricular extrasystoles, salvos of unsustained ventricular tachycardia) was evidently higher in the patients with VLP (88% compared with 77% in the absence of VLP), thus demonstrating the presence, in most of the patients studied, of an arrhythmogenic mechanism by ventricular reentry.

Evaluation of the electrocardiographic signs of left ventricular hypertrophy, using the echocardiography in patients with hypertensive cardiopathy.

The electrocardiography (ECG) contribution in the diagnosis of left ventricular hypertrophy (LVH) associated to arterial hypertension was evaluated in 54 hypertensive patients, 39 men and 15 women, with a mean age of 51.6 years, mean systolic and diastolic pressure 186 +/- 46 and 111 +/- 46 mmHg, respectively. The investigations included routine clinical and biologic tests as well as standard ECG in 12 derivations, Frank vectorial ECG and mono and bidimensional echocardiography (ECOCG). A correlative study of the ECG parameters demonstrated that the left ventricular mass index evaluated by ECOCG correlates best with Romhilt ECG index and with an LVH index elaborated by the authors of the present study, based on the Frank vectorial recordings (R wave amplitude in X and Z derivations; QRS duration in Z). These data were used in drawing linear regression equations for evaluation of the left ventricular mass, starting from the above-mentioned parameters. The results are discussed in comparison with those of other authors and their practical value is demonstrated.

Early re-extension of necrosis in myocardial infarction. Favouring factors and prognosis in the first months of evolution.

To determine the risk of myocardial necrosis re-extension (RN) appearance in the first month of evolution of myocardial infarction (MI) confirmed clinically, by ECG, and enzymatically, 262 patients (mean age 64.5 years, 64.6% males) were studied. The incidence of RN was found present in 67 patients (25.6%). A complex statistical analysis (stepwise regression analysis) of the variables presented by the patients (clinical, ECG and laboratory) showed that only 5 variables are important in the determination of the risk of RN namely: nontransmural localization of initial necrosis, atrial fibrillation, past history of angor pectoris, prolonged pain at onset and presence of idioventricular rhythm. The introduction of these 5 variables in a multiple regression equation will allow the distribution of patients, already at entry, in subgroups of risk of re-extension necrosis within the first month of MI evolution thus allowing a more careful management of disease.

Relation between diagonal ear lobe crease and ischemic chronic heart disease and the factors of coronary risk.

The presence of a diagonal ear lobe crease (DELC) was studied in 350 non-selected patients admitted to the Clinic. The overall incidence of DELC was 45%, with a significant increase after the age of 50 years (24.8% before and 59.5% after fifty, p less than 0.001). The relationship between DELC and ischemic chronic heart disease (65% as against 23% in the patients without DELC, p less than 0.001) and with some coronary risk factors: arterial hypertension (40% in patients with DELC, 29% in those without, p less than 0.01), smoking (43%) as against 35% in those without DELC. The relationship with diabetes mellitus and obesity was not significant. A higher incidence of DELC was observed in males (66%) than in females (34%) (p less than 0.02). The lipid profile of patients with DELC presents significant cholesterolemia changes (251 +/- 71 mg as against 232 +/- 70 mg in those without DELC) and a less marked increase in lipemia and beta-lipoproteins. All risk factors presented a net increase in the subjects with bilateral DELC. It is concluded that DELC can be used for selecting asymptomatic subjects in the screening of a possible coronary heart disease.

Psychologic investigation in the estimation of the effects of hypotensive therapy in hypertensive patients working in the railway and highway traffic security.

Sixty four hypertensive patients working in railway and highway traffic security (engine operators, drivers, switchmen, etc.) were studied clinically and paraclinically and were also submitted to psychologic tests since the characteristics of their work requires a normal psychophysical state. The patients investigated, mostly males (93%), mean age 45.2 years, had essential arterial hypertension (AH) stages I (36 patients) and II (28 patients). After 3-4 days of low salt diet, therapy with propranolol (8 to 360 mg/day) and diuretics was started in most of the patients. In 8 patients with AH stage II, hydralazine (50-100 mg/days) was added to the treatment. The psychologic tests used were: the pencil-paper test "Labyrinth", "Barrage" and "A.D. Praga" and a motor test "Piorkowsky" used 2 times, i.e., before and after treatment. After 15 days of treatment the blood pressure values decreased: systolic from a mean value of 155 +/- 25 mmHg to 136 +/- 81 mmHg; diastolic from 102 + 18 mmHg to 84 +/- 11 mmHg. The marks for the psychologic test were: very poor, poor, medium, good, very good. The post-therapeutic changes obtained were noted in percentages. Improvements obtained: for the "Praga" test in 54% of the patients, for the "Barrage" in 44% of the patients and for the "Labyrinth" in 66% of the patients. Improvements for the first "Piorkowsky" test (slow rate stimuli) were obtained in 54% of the patients and for the second (faster rate stimuli) in 69%. No decrease of psychologic performance was observed in any of the patients. Therefore the psychologic tests used may contribute to the follow-up of the effectiveness and of the side effects of modern hypotensive therapy especially in patients working in traffic security in whom the psychophysical state should be at its best.

Prognosis of acute myocardial infarction using systolic time intervals recorded on the carotidogram.

The prognostic value of systolic time intervals and of other clinical and laboratory parameters was investigated in 68 patients with acute myocardial infarction (AMI) (55 males and 13 females; mean age 61 years) over a period of one month after onset of the disease. The statistical analysis of data was made by the STR stepwise regression method, using an IBM-360 computer. Finally the study resulted in a stepwise multiple regression equation with 4 factors of maximum statistical significance in the prognosis of AMI: peak SGOT level, age of patients, uncorrected left ventricular ejection time and index of preejection period. This new prognostic index allows a classification of patients with acute myocardial infarction (starting with the second day after onset) into groups of various severity, thus helping the practitioners in the choice of therapy.

Study of the immune state in patients with a history of subacute bacterial endocarditis and in their direct relatives. Pathogenic implications.

Immunologic investigations were performed in 18 patients at a mean interval of 1.8 years after cure of subacute bacterial endocarditis (SBE) and in 17 of their direct relatives. The results were compared with those obtained in a control group of 52 healthy subjects. Assay of serum immunoglobulins revealed deviations from the normal (mean +/- 2 SD) in 65% of the post-SBE patients and in 77% of their relatives. Tests for the presence of nuclear, smooth muscle, mitochondrial, cytoplasmatic, albumin and interstitial antibodies showed the presence of such autoantibodies, either single or associated, in 55% of the post-SBE patients and in 58% of their relatives. The serum complement titer was low in 54% of the former SBE patients and in 66% of their relatives. A series of antimicrobial skin tests or intradermal reaction to dinitrochlorobenzene showed hypergy or anergy in 54% o the post-SBE patients investigated. These results, alongside with the data in the literature, support the hypothesis of the preexistence of the immune deficit (probably inherited) in the cardiac patients who develop SBE.

Prognosis of acute myocardial infarction using systolic time intervals recorded on the carotidogram.

The prognostic value of systolic time intervals and of other clinical and laboratory parameters was investigated in 68 patients with acute myocardial infarction (AMI) (55 males and 13 females; mean age 61 years) over a period of one month after onset of the disease. The statistical analysis of data was made by the STR stepwise regression method, using an IBM--360 computer. Finally the study resulted in a stepwise multiple regression equation with 4 factors of maximum statistical significance in the prognosis of AMI: peak SGOT level, age of patients, uncorrected left ventricular ejection time and index of preejection period. This new prognostic index allows a classification of patients with acute myocardial infarction (starting with the second day after onset) into groups of various severity, thus helping the practitioners in the choice of therapy.

Value of systolic time intervals in the estimation of heart failure secondary to acute myocardial infarction.

Serial measurements of left ventricular systolic time intervals (STI) were carried out in 44 patients with acute myocardial infarction (AMI) in the first 5 days after onset, by indirect methods. The patients with heart failure showed significant decreases of ejection time (ET) (p less than 0.001) and of the ejection time index (p less than 0.005) and increases of Wiessler's ratio (PEP/ET) (p less than 0.001). The pre-ejection period (PEP), the isovolumetric contraction time and the total electromechanical systole were unsignificantly changed. Ejection time was shorter than 250 msec in the patients with acute pulmonary edema or congestive heart failure, in most of the patients with flutter or atrial fibrillation and in 16 of the 17 patients who died. Ejection time may have a prognostic significance and may be useful in the early detection of heart failure in AMI. The changes of STI after administration of lanatosid C show the positive inotropic effect of this drug in patients with AMI.

Electrocardiographic diagnosis of myocardial infarction in patients with pacemakers.

The ECG changes of myocardial infarction during permanent or transient right ventricular pacing were studied in 32 patients with transvenous pacemakers who developed myocardial infarction. During right ventricular pacing the electrocardiogram resembled left bundle branch block in 29 patients, right bundle branch block in two, and in one patient the pattern could not be determined. Myocardial infarction induced new ECG changes during pacemaker rhythm in 20 of the 32 patients. There were only QS complexes in 5 cases, ST segment abnormalities in 4 and T wave inversions in 4, negative Q and T waves were simultaneously observed in one patient, Q wave and S-T segment changes in 3 and S-T segment change and T wave inversion in 3 patients. It is concluded that knowledge of the ECG changes induced by myocardial infarction in most patients under artificial pacing can be useful for diagnosis.