Non-invasive assessment of anti-hypertensive treatment effectiveness

Hypertension 1996 : One Medicine, Two Cultures

F. Fedele, P. Trambaiolo, L. Caciotti, E. Pensalfine
III Cardiology Chair, Department of Cardiovascular and Respiratory Sciences
“La Sapienza” University - Rome

Epidemiological studies highlighted a direct relationship between systolic/diastolic arterial pressure (AP) and organic damage, particularly at a cardiovascular level. Controlled clinical trials demonstrated the benefit of anti-hypertensive treatment with respect to morbidity and mortality (1-2). Thus the effect of anti-hypertensive treatment should be assessed not only in terms of absolute effect on AP reduction, but also in terms of on-going monitoring related both to circadian changes and to administration intervals.
As far as organic damage is concerned, a clear focus of interest is represented by the assessment of left ventricular hypertrophy and by the study of the vessels' atherosclerotic process.
Useful and, probably, nowadays necessary non-invasive techniques for the assessment of the actual effect of anti-hypertensive treatment, also in terms of organic protection, include traditional ones (e.g. ECG and fundus oculi) as well as dynamic arterial pressure monitoring and cardiovascular ultrasound scanning. Our School has been involved with this technique ever since the 1970's.

Arterial pressure measurement

"The while coat"

There are well known limits to the traditional cuff, or so-called "random" measurement of arterial pressure by physicians or other health-care providers, corresponding to the alarmed reaction combined with a subsequent pressure increase associated to medical examination3, as well as to the limited number of possible measurements in 24 hours. However, random data are known to be epidemiological correlated to increased cardiovascular morbidity and mortality, as insurance companies have been aware of for a long time.

"Home self-measurement"

Several studies demonstrated that home pressure self-measurement invariably yields lower AP values compared to those obtained both by physicians and by nurses in the same patient47. The introduction of automatic, cost-effective, reliable, and easy-to-use electronic devices has revitalized this approach, so much so that groups of international experts have established specific procedures both for the technical validation of these devices and for the correct self-measurement of pressure values (8-9-10). As mentioned, technical benefits are represented by a higher number of measurements and by the absence of the alarmed reaction to the physician's presence (5). On the other hand, this method involves some technical limits as well, such as the limited reliability of these measurements and a possibly increased variability when few isolated measurements are performed. Some authors demonstrated that systolic AP values surveyed by home self-measurement in the morning are lower than during night hours, and that both values are lower than in the afternoon (11 14).
Information on the actual prognostic significance of self-measured AP values is still scanty: such values seem to be more closely related to the incidence of left ventricular hypertrophy compared to random AP measurement (4-15). In spite of the importance attached by recent studies to the possible benefits of self-measurement, also in view of an anti-hypertensive treatment, we think that this practice is affected by a lack of the necessary objectiveness.

"Dynamic monitoring"

The description of the first AP dynamic monitoring (APDM) technique, both through continuous and intermittent non-invasive intra-arterial recording, dates back to the 1960's.
We refer here to the intra-arterial technique developed by Bevan et al. (16) in Oxford: a small catheter is introduced into a peripheral (radial or brachial) artery and connected with a transducer unit-perfusion system applied to the patient's chest in the heart region. Even though such method allowed to quantify AP value variability during the night and the day (17), thus providing a careful record of AP's profile in 24 hours beat after beat, its invasive nature has confined its use to research purposes or to very well-defined clinical conditions. At the same time, the so-called non-invasive Remler method (18) was set up: a monitor for the cuff's manual inflation and automatic deflation measures AP values intermittently by means of a microphone, which allows to record both the cuff's pressure and Korotkoff's sounds on a tape for later manual reading. Since then, technological development has allowed to introduce new hand-held devices able to dynamically record arterial pressure values by means of non-invasive measurements performed by automatic cuff inflation and deflation at pre-established intervals. Such devices are based on the microphone or the oscillometric (19) method or on both, and during the years they have been improved to smaller, lighter and easier to handle objects.
The first benefit of monitoring is obviously the possibility to effect a high number of measurements (from 50 to over 100) in 24 hours, while the patient is involved in his/her normal daily activity (20). The comparison between the mean AP values in 24 hours obtained by means of different sampling frequencies highlighted no significant differences compared to the mean AP values in 24 hours calculated non-invasively at intervals between pressure measurements ranging from 5 to 30 minutes (21). Another benefit provided by APDM is that, in spite of the repeated cuff inflation during the night, hardly any change takes place in the trend of heart rate and arterial pressure (22-23). A third benefit of this method consists in an increased reproducibility of daily mean values and values in 24 hours compared to that provided by random measurement: in addition, AP value recording in 24 hours is not influenced by the well-known placebo effect which, even when present, may only be observed in the first 6 to 8 recording hours. These last two properties -reproducibility and no placebo effect are particularly useful in clinical studies on the effect of anti-hypertensive drugs. Indeed they may allow a reduction in the patient sample required to assess the effect of a drug through a simplified experimental design of the study a greater statistical significance and a higher precision in the assessment of the actual direct anti-hypertensive action of the substance under study (24).
A practical consequence is the study of the down/peak ratio of a drug (25), an expression defining the quantitative ratio between the residual anti-hypertensive effect of a drug or a drug group at the end of the administration interval (down) and its maximum effect recorded during the administration interval (peak) (26). This ratio, if assessed in responsive patients based on an appropriately designed experiment - also considering the technique used for atrial pressure value measurement - is a reliable index of the duration and effect of anti-hypertensive treatment. As such, it is a safety parameter provided for by the FDA in order to prevent administering short-term action drugs at excessive doses in view of extending their effect. In addition a favourable down/peak ratio, i.e. >0.50 and possibly close to 1.0, points out to a homogeneous AP value control within a particular administration interval. A drug treatment having such an anti-hypertensive effect may better prevent and cause subsidence of organic damage while improving the patient's compliance with the anti-hypertensive treatment (25).
From the clinical standpoint, it is clearly interesting to define to what extent APDM may improve diagnostic and prognostic hypertensive patient assessment compared to the random method, since the arterial hypertension-related organic damage has been shown to be more closely related with the mean 24 hour arterial pressure value (particularly during the day) than with random measurements (27-29). In particular, the extent of pressure increase in the morning has shown a direct correlation with the incidence of coronary ischaemia, of acute heart infarct, of sudden heart death, and of brain ischaemia (30), while the extent of night tensive values seems to highlight a reverse correlation with the left ventricular mass (31), with the degree of microalbuminuria (32), and with the incidence of silent brain ischaemia (33). In spite of the reported positive effects, however, the benefits ensured by such method in terms of clinical relapse are still partly controversial.

Organic damage: left ventricular hypertrophy

Arterial hypertension causes changes in the heart and large arterial vessels: the heart, the brain, the kidneys, and the retina are mostly involved from the anatomical and clinical viewpoint. Thanks to the considerable technological development that took place in the last few years, the presence of structural cardiovascular changes may now be assessed even at an early stage of the disease's progress, while following up their natural development and changes in time due to anti-hypertensive treatment.
The possibility to assess the size and performance of the left ventricle in systemic arterial hypertensive patients is particularly interesting from the practical clinical and scientific standpoint. The cardiovascular system should not be considered as being only secondarily involved in functional and structural changes following up hypertension, but also as a system actively participating to the onset and self-maintenance of hypertension itself; thus such changes may interact with the different mechanisms that physiologically regulate pressure homeostasis, since they may represent factors for the onset, the maintenance or the progression of the hypertensive condition. Irrespective of its origin, the importance of left ventricular hypertrophy in systemic arterial hypertension as well as in understanding its influence on the left ventricular performance may be great for diagnostic as well as for prognostic and therapeutic purposes. Electrocardiography has been a reference method for the diagnosis of heart hypertrophy for many years, but unfortunately the criteria suggested, although highly specific (90%), are affected by low sensitivity (6%-53%) (34-35). Echocardiography as repeatedly stated by our School, is the only non-invasive method allowing to perform a sort of anatomical in-vivo study of the heart's walls and cavities and is therefore useful to study morphological and functional changes in the left ventricle in case of different physiological and/or pathological conditions characterized by primary and secondary' heart hypertrophy, in order to appreciate their physiopathological and clinical-prognostic significance.
Echocardiography is probably the only method that allows recognising so-called "physiological" hypertrophy forms from pathological signs. In fact, apart from well-know opportunities to study the heart's morphology (particularly ventricle thickness and diameters) and systolic/diastolic functions, the importance of the parameter constituted by the Mass/Volume ratio should be stressed. This index, which remains unchanged in physiological conditions and does not vary according to age or sex, is not altered in case of "physiological" hypertrophy in athletes, while it shows clear changes in all forms of primary' and/or secondary pathological hypertrophy.
Ultrasound left ventricular hypertrophy indexes highlight 57% sensitivity in mild forms and 98% sensitivity in severe forms, as shown by the results of comparative studies on anatomical data as well (36).
The data provided by our first studies (37) carried out in the late 1970's by means of the M-mode technique, showed a district increase in the thickness of left ventricular walls in both borderline and steady hypertension, but more frequently in the former, in compliance with data in literature. As far as the trend of left ventricular function indexes is concerned, even considering all the limits given by their actual value, we observed the following: 1) with respect to Vcf. a reduction compared to normal individuals, non-significant in borderline hypertensive patients and significant in steady ones; 2) a progressive significant increase, compared to normal individuals, both in borderline and in steady hypertensive patients, of the isovolumetric release time, a direct index of left ventricular compliance.
Normalized pressure values and ventricular mass reduction constitute the two main goals of anti-hypertensive treatments. Also in this field we were among the first to demonstrate the value of echocardiography for the assessment of hypertrophy following up anti-hypertensive treatment. In a recent metanalysis (38) of 109 studies on anti-hypertensive treatment (2357 patients), an 11.9% regression of the heart mass was highlighted vis-à-vis a 14.9% mean reduction of arterial pressure values. In particular, a 15% mass reduction was observed for ACE-inhibitors, along with an 8.5% reduction for calcium-antagonists, an 8% reduction for Beta-blockers and an 11.3% reduction for diuretics. The absolute value of this reduction amounted to 44.7 gr. for ACE-inhibitors, to 22.8 gr. for Beta-blockers, to 26.9 gr. for calcium-antagonists, and to 21.4 gr. for diuretics. All therapies are supposed to affect thickness, with the exception of diuretics, which would mostly reduce the ventricle's diameter. As to the subsidence of left ventricular hypertrophy, the importance of a study not limited to anatomy but also involving functions should be stressed: indeed, in case of normal wall thickness, parallel improvements in release and ventricular compliance are not always observed. In this respect it is worth mentioning our School's contribution in terms of studies on diastolic functions: by means of computerized and subsequently digitalized M-mode echocardiography, we could study diastolic functions before and after an anti-hypertensive treatment, thus obtaining curves of the change in heart diameters from which the duration of the different diastolic phases could be obtained (39). Before treatment, patient comparison with normal individuals highlighted 1) an extended isovolumetric release time along with increased changes in ventricular telediastolic diameters; 2) a reduced change in ventricular telediastolic diameter and in the relevant peak speed during quick filling; and 3) a sharp compensation increase of these parameters during atrial systole. A partially normalized diastolic function could be observed after treatment along with the correct redistribution of diastolic filling. These data published by our School almost 10 years ago were considerably advanced since they provided information that may be obtained today by means of transmitral Doppler flowmetric analysis. The most frequently highlighted diastolic pattern in hypertensive patients, even before hypertrophy is highlighted is due to “altered release” (E<A with an increased E wave deceleration time and an increased isovolumetric release time). At later stages, in case an unproportional increase in the left ventricle's stiffness occurs a “restrictive” condition may be found (E>>A with a much reduced E-wave deceleration time and a reduced isovolumetric release time). As a conclusion to this brief overview of the possible subsidence of left ventricular hypertrophy. we would like to mention the “J-shaped curves” considered in the study by Cruickshank (41), who observed a higher incidence of coronary events vis-à-vis an excessive fall in diastolic pressure values due to diuretics or Beta-blockers (41-43). From the physio-pathological standpoint, such data may probably be accounted for by a possible lack of proportion between reduced AP values and left ventricular mass reduction, with subsequent negative effects on coronary flow and on the systolic phase. These may include an increased heart consumption of oxygen following up an increased wall stress and a reduced sub-endocardiac flow reserve: the former occurs whenever the mass decreases while pressure values are still high, whereas the latter occurs if the reduced pressure is not associated with a proportional mass decrease. With respect to relations between coronary disease and hypertension, we remind that an ECG under stress sometimes does not succeed in recognizing both diseases due to a clear baseline repolarization damage; in this case the superiority of echocardiography under stress clearly stands out.
The different studies (44-48) carried out in these years in order to investigate vascular damage combined with arterial hypertension highlighted a marked change in the arterial compliance of large vessels under this condition. The use of ultrasound for the assessment of vascular compliance underwent considerable development, both due to the non-invasive character of the methods available and to the accuracy and reproducibility of results. Echo-colour Doppler scanners are particularly useful in this field, since they allow a morphological and functional assessment of the vascular wall and of the damage occurring in hypertensive patients at a very early stage, and may at the same time highlight the presence and morphology of atheromatous plaques by means of a sort of “ultrasound biopsy”. In this respect, some data obtained by our School (49) show a significant correlation between the wall thickness of carotid arteries, the indexed ventricular mass, and the tortuosity of coronary arteries, thus highlighting the general involvement of the cardiovascular system in hypertensive patients. In addition, the increased myo-intimal thickness would appear as an earlier marker of cardiovascular damage compared to the onset of a clear left ventricular hypertrophy. Still with respect to the assessment of ventricular compliance, we would like to remind of the possible use of Magnetic Resonance Imaging (50-51) which, due to its multi-plane character and reproducibility, may be employed both for an accurate morphological study and for an investigation of the treatment's effects.

Conclusions

Clinical cardiologists of the year 2000 may not disregard currently available technologies for the assessment of hypertensive patients and of their treatment. In the light of current knowledge, anti-hypertensive treatment may not be exclusively assessed by means of occasional AP value measurements and electrocardiographic recordings at rest; provided that the clinical examination and the study of the fundus oculi may not be substituted, an ultrasound investigation, also spreading to epaortic vascular districts, and one or more on-going AP value recordings in 24 hours. constitute crucial steps for the assessment of hypertensive patients.

References

Hebert PL: Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch hit Med. 1993; 153: 578-81.
Collins R. MacMahon S: Blood pressure. An hypertensive drug treatment and the risks of stroke and of coronary artery disease. Dr Med. Bul 1994; 50: 272-98.
Mancia G. Parati G., Pomidossi G et al: Alerting reaction and rise in blood pressure during measurement by physician and a nurse. Hypertension 1987; 9: 209-215.
Kleinert HD, Hartshfield GA, Pickering TG et al: What is the value of home blood pressure measurements in patients with mild hypertension? Hypertension 1984; 6: 574-578.
James GD Pickering TG, Yee LS et al: The reproducibility of average ambulatory, home, and clinic pressure. Hypertension 1988; 11: 545-549.
Julius S. Ellis CN. Pascual AV et al: Home blood pressure determination. Value in borderline (“labile”) hypertension. IAMA 1974: 229: 663-666.
Battig B. Steiner A. Jeck T: Blood pressure self-monitoring in normotensive and hypertensive patients. J hypertens 1989: 7: (suppl 3): 859-863.
O’Brien E. Petrie J. Littler W. et al: The British Hypertension Society Protocol for the evaluation of automated or semiautomated blood pressure measuring devices with special references to ambulatory system. J Hypertens 1990: - 607-620.
O’Brien E. Petrie J. Littler W. et al: The British Hypertension Society Protocol for the evaluation of automated or semiautomated blood pressure measuring devices. J Hypertens,1993; 11: 677-679.
Mallion JM. Asmar R. Poggi L. et al: Arterial pressure, self-measurements recommendations. France Society for Arterial hypertension. The Measurement Group. Arch Mal Coeur Vais 1989,. 82:1001-1005.
Welin L Swardsudd K. Tibblin G.: Home blood pressure measurements: Feasibility and results compared to office measurements. Acta Med. Scan 1982; 2l1: 275-279
Beckman M. Panfilov V, Sivertsson R et al: Blood pressure and heart rate recordings at home and at the clinic. Acta Med. Scan 1981.210:97-102
Laughlin KD., Fisher L. Sherrard DH: Blood pressure reduction during self recording home blood pressure. Arn Heart J 1979; 98: 629-624
Verdecchia P, Gatteschi DC, Benemio G. et al: Home ambulatory blood pressure readings do not differ from clinic readings taken at the same time of day. J Hum Hypertens 1988; 2: 235-240
Verdecchia P, Bentivoglio NL Provvidenza M. et al: Reliability of self recorded arterial pressure in essential hypertension in relation to the stage of the disease. In: Geramanò G. (ed.): Blood pressure recording in clinical management of hypertension Luigi Pozzi Roma 1985.
Bevan AT, Honour AJ, Stott FH et al Direct arterial pressure recording in unrestricted man. Clin Sci 1969; 36: 329-344
Mancia G., Ferrari A, Gregorini L et al: Blood pressure and Heart rate variability in normotensive and hypertensive human beings. Circ Res 1983: 53: 96-104
Hinman AT, Angel BT, Bickford AF: Portable blood pressure record: accuracy and preliminary use in evaluating intra-daily variations in blood pressure. Am Heart J 1962; 63: 663-668
Pickering TG: Ambulatory monitoring and blood pressure variability Science Press, London 199 2.1; 2.15
Parati 6 Mutti E, Ravogli A. et. al: Advantages and Disadvantages of non-invasive ambulatory blood pressure monitoring. J hypertens 1990; 8 (suppl 6): 533-538
Di Riennzo M' Grassi 6, Pedotti A et al: Continuous vs intermittent blood pressure measurements in estimating 24 hours average blood pressure. Hypertension 1983; 5: 264-269
Parati G.. Pomidossi G., Casadei R at al: Ambulatory blood pressure monitoring does not interfere with emodynamic effects of sleep. J Hypertensive 1985; 3(suppl 2): S107-S 109
Villani A, Parati 6, Groppelli A et al: Non invasive automatic blood pressure monitoring does not attenuate night time hypotension evidence from 24-h intra-arterial blood pressure monitoring. Am J Hypertens 1992; 5: 744-747
Conway J, Coats A Value of ambulatory blood pressure monitoring in clinical pharmacology. J Hypertens 1989; 7(suppl 3): S29-S32
Salvetti A. Virdis A.: Il rapporto valle/picco. Am Ital Med hit 1995: 10(suppl): 91S-95S
Mancia 6, Salvetti A: II rapporto valle/picco nella valutazione di un farmaco anti-ipertensivo. 6 Ital Cardiol 1994; 24:1043-8
Mancia G.: Ambulatory blood pressure monitoring research and clinical applications. J Hypertens,1990; 8: (suppl 7): S1-S13
Prisant LM, Carr AA: Ambulatory blood pressure monitoring and echocardiographic left ventricular wall thickness and mass. Am J Hypertens 1990; 2: 81-89
Parati 6, Pomidossi 6, Albini F et al: Relationship of 24 H blood pressure mean and variability to severity of target organ damage in hypertension. Hypertension 1987: 5: 93.98
Rocco MB, Nadel EG, Selwyn AP: Circadian rhythm and coronary artery disease. Am J Cardiol l987: 59: 13C-17C
Verdecchia P. Schillaci 6. Guerrieri M et al: Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990: 81: 528-536
Giaconi. S. Levanti C Fommei F et al; Mucroalbuminuria and casual and ambulatory blood pressure monitoring in normotensives and in patients with borderline and mild essential hypertension. .Am J hypertens 1089: 2, 259-261
Shimada K. Kawamoto A. Marsubaiashy K et al: Diurnal blood pressure variation and silent cerebrovascular damage in elderly patients with hypertension. J Hypertens 1992: 10: 875-878
Casale PN. Devereux RB, Kligfield P et al. Electrocardiographic detection of left ventricular hypertrophy: development and prospective validation of improved criteria. JACC 1985 6 572
Devereux RB, Reichek N.: Echocardiographic determination of left ventricular mass in man. Ciculation 1977: 55:6l3
Devereux RB. Alonso DR. Lutas EM et al: Echocardiographic assessment of left ventricular hypertrophy: comparison to necroscopv findings. Am J Cardiol 1986; 57:540.
Fedele F. Agati L, Penco M et al: L’importanza dello studio ecocardiografico nella valutazione della cardiopatia ipertensiva Rassegna geriatrica
Dahlof B, Pennert K. Hansson L.: Reversal of left ventricular hypertrophy in hypertensive patients: A meta-analysis of 109 treatment studies. Am J Hypertension 1992; 5: 95-110
Agati t, Fedele F. Penco M et al: Left ventricular filling pattern in hypertensive patients after reversal of myocardial hypertrophy. hit J Cardiol 1987; 17:177-186
Cruickshank JM: Coronary flow reserve and the J curve relation between diastolic blood pressure and myocardial infarction. Br Med. J 1988; 297:1227
Cruickshank JM. Thorp JM, Zacharias FJ: Benefits and potential harm of lowering blood pressure. Lancet 1987; 1:581-584.
Aldennan MH. Ooi WL, Madharsn S: Treatment induced blood pressure reduction and the risk of miocardial infarction. JAMA 1989; 262: 920-924
Farnett L. Mulrow CD, Linn WD et al: The J-curve phenomenon and the treatment of hypertension. IAMA 1991; 265: 489-495
Guilace G, Ruffa F: Aorta addominale e carotide destra: interrelazione dei parametri di elasticità e stiffness negli ipertesi SIEC 1995; Atti: 440-441
Giannattasio C, Mangoni A. Grassi G et al: Valutazione della compliance arteriosa nell'uomo Cardiologia 1992: 37(suppl 1- 12): 399-404.
Ventura H., Messerli FH, Oigman W et al: Impaired systemic arterial compliance in borderline hypertension. Am Heart J 1984; 108:132
Bouthier JD, De Luca N, Safar ME et al: Cardiac hypertrophy and arterial distensibilitv in essential hypertension. Am Heart J 1985; 109:1345.
Pearson TA' Heiss GM: Atherosclerosis: Quantitative Imaging, Risk Factors, Prevalence, and Change. Circulation 1993 Supplement II Vol. 87, No 3.
Ciciarello FL, Dragagna G, Saponarro A. Dagianti A: Correlation between cardiac and vascular hypertrophy in hypertensive patients without CAD. 8th International Congress on Echocardiography 1993:110
Higgins CB, Kaufman Crooks LE et al: magnetic Resonance Imaging of the cardiovascular system Am Heart J 1985; 109:136.
Di Renzi P, De Santis M. Fedele F et al: Valutazione della distensibiilità aortica con cine-RM prima e dopo trattamento antipertensivo con calcioantagonisti ad ACE-inibitori Cardiologia, 1993; 38(12): 779-784.

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