ARTERIAL STIFFNESS PREDICTS SEVERE PROGRESSION IN SYSTEMIC SCLEROSIS: THE ERAM STUDY

Joël Constans(a), Christine Germain(b), Philippe Gossec(c), Jacques Taillard(a), Kiet Tiev(d), Isabelle Delevaux(e), Luc Mouthon(f), Claude Schmidt(g), Florence Granel(h), Pascale Soria(i), François Lifermann(j), Gabriel Etienne(k), Fabrice Bonnet(l), Karim Zoulim(m), Dominique Farge-Bancel(n), Isabelle Marie(o), Yannick Allanore(p), Jean Cabane(d), Alain Amonchot(q), Isabelle Macquin-Mavier(r),
Marianne Saves(b), Faiez Zannad(s) and Claude Conri(a), the ERAMS investigators.

Objective
The ERAMS study addressed the value of arterial stiffness in predicting the severity of systemic sclerosis.

Methods
ERAMS was a prospective multicentre cohort study including patients with definite systemic sclerosis.
Arterial stiffness was measured by the standardized noninvasive QKd 100-60 method. Clinical evaluation, biological measurements, functional respiratory tests and cardiac Doppler echography were performed at inclusion then each year until 3 years’ follow-up was completed. Progression was defined as mild (articulations, muscle, oesophagus or skin involvement) or severe (lung, heart or kidney involvement) by a critical event committee. The prediction of severe progression was studied for QKd 100-60 as well as clinical and biological data at baseline by univariate and multivariate analysis.

Results
Ninety-nine patients were included (81 women, 18 men, mean age 57 years, standard deviation 12.5). Although their blood pressure profile was normal, half the patients had increased arterial stiffness (QKd 100-60<200 ms). There was a significant relationship between age-adjusted arterial stiffness and decrease in carbon dioxide diffusion (P<0.03) or haemoglobin rate (P<0.01). By univariate analysis, severe progression after 3 years was predicted by age (PU0.04), lung involvement (PU0.04), diffusion of lung carbon oxide (DLCO) (P<0.01), skin score (PU0.02), haemoglobin (P<0.01) and baseline Qkd 100-60 divided into two classes according to the median (P<0.01). By multivariate analysis, only haemoglobin rate [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2–0.9] and QKd 100-60 (OR 19.6, 95% CI 1.2–308.2) predicted severe progression of systemic sclerosis.

Conclusion
The measurement of arterial stiffness by the QKd method is a useful objective method for assessing the
prognosis of systemic sclerosis independently from other data. J Hypertens 25:1900–1906
2007 Lippincott Williams& Wilkins.

Journal of Hypertension 2007, 25:1900–1906

Keywords
arterial stiffness, prognosis factors, systemic sclerosis, vascular disease

(a)Vascular and Internal Medicine Unit, CHU Bordeaux, (b)Clinical Epidemiology Unit, CHU Bordeaux, (c)Cardiology and Hypertension Unit, CHU Bordeaux, (d)Internal Medicine Unit, CHU Saint-Antoine, Paris, (e)Internal Medicine Unit, CHU Clermont-Ferrand, (f)Internal Medicine Unit, CHU Cochin, Paris, (g)Vascular Medicine Unit, CHU Nancy, (h)Dermatology Unit, CHU Nancy, (i)Internal Medicine Unit, CHU Limoges, (j)Internal Medicine Unit, CHG Dax, (k)Internal Medicine and Tropical Diseases Unit, CHU Bordeaux, (l)Internal Medicine and Infectious Diseases Unit, CHU Bordeaux, (m)Internal Medicine Unit, CHU Caen, (n)Internal Medicine Unit, CHU Saint-Louis, Paris, (o)Internal Medicine Unit, CHU Rouen, (p)Rheumatology Unit, CHU Cochin, Paris, (q)Cardiology Unit, CHU Clermont-Ferrand, (r)Clinical Investigation Unit, CHU Henri Mondor, Créteil and (s)Clinical Investigation Unit, CHU Nancy, France

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PROGNOSTIC VALUE OF QKD INTERVAL CORRECTED BY QRS DURATION IN HYPERTENSIVE PATIENTS

P. Gosse(1), R. Lasserre(1), C. Minifie(1), P. Lemetayer(1)

(1) Hopital Saint André, Bordeaux, France

Objectives
The QKD interval is measured between the onset of QRS on the ECG and detection of last Korotkoff sound by a microphone placed on the brachial artery while measuring BP. It is the sum of pre ejection time(PE) and pulse transmission time(PT) and is correlated to PWV. This interval is automatically monitored with BP and HR every 15' during 24h with an ABPM device (Diasys integra, Novacor, France). The 96 measurements obtained allow to automatically calculate the QKD 100-60, QKD value for 100 mmHg SBP and 60 bpm HR. This indices of arterial stiffness has been shown to be linked to future cardiovascular (CV)events, independently of 24h BP. However this interval may be abnormally prolonged in case of left bundle branch blocks (LBBB).

Methods
We tested the effects of simply removing QRS duration from QKD 100-60 value on the prediction of CV events in a population of 412 hypertensives (247 males, age = 53±14 years, office BP = 158±19/97±11 mmHg, 24h BP = 133±17/86±11 mmHg) followed prospectively.

Results
Mean follow up was 65 months, 32 pts were lost, 49 CV events occurred including 11 deaths. Cox model showed that baseline QKD 100-60 (m = 202±19, 142-254 msec) was significantly (p < 0.05) associated to events independently of age, 24h SBP and other traditional risk factors. Removing QRS duration (m = 85±10, 61-158 msec) improves the relation to events (monovariate c 2 = 38 versus 30).

Conclusion
Removing QRS duration from QKD 100-60 improves its predictive value of future CV events and allow to use this method in pts with LBBB.

Abstract: P3.255
Citation: Journal of Hypertension Volume 23, Supplement 2, June 2005, page S347

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Arterial stiffness evaluated by measurement of the QkD interval is an independent predictor of cardiovascular events

Philippe GOSSE, MD; Raphael LASSERRE, MD; Catherine MINIFIE, MD; Philippe LEMETAYER, MD; Jacques CLEMENTY, MD

Background
The QKD interval is the time between the QRS wave on the ECG and detection of the last Korotkoff sound during blood pressure measurement. Measurement of the QKD interval during ambulatory blood pressure monitoring provides an automatic evaluation of arterial stiffness. The objective of this longitudinal study was to examine the relationship between arterial stiffness assessed by this method and the occurrence of cardiovascular complications in a cohort of initially untreated hypertensive patients.

Methods
The initially untreated hypertensive patients were included in the cohort of hypertensives recruited in our center between January 1992 and December 1999. They all benefited from ambulatory measurement of the OKD interval and blood pressure over 24 hours. Most of these patients were given antihypertensive treatment and were followed up by their family physicians unaware of QKD results. Their outcome was evaluated in 2003 by inquiry from the patients themselves or their family physicians.

Results
The initial population comprised 412 patients. At the end point. 33 had been lost to follow up.. We recorded 49 cardiovascular events in this population with an average follow up of 65±36 months. In a Cox model, the arterial stiffness assessed by the QKDIOO-60 as a percentage of the height predicted normal value was significantly associated with the occurrence of cardiovascular complications independently of age and mean 24-hour blood pressure.

Conclusions
This study employing ambulatory measurement of the QKD interval showed that an increase in arterial stiffness was a marker of cardiovascular risk. We show for the first time that its value persists after taking account of the mean systolic pressure over 24 h.

Keywords: Arterial stiffness, QKD interval, ambulatory measurement of blood pressure, cardiovascular complications, hypertension

American Journal of Hypertension, AJH 2005;18:470-476

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Beyond blood pressure measurements: monitoring of the appearance time of Korotkoff sounds

Philippe Gosse, Corinne Braunstein and Jacques Clementy

We have recently proposed a new method to evaluate the physical properties of arteries based on measurement of the QKD interval together with blood pressure arid heart rate with an ambulatory blood pressure monitoring device. This interval is the time
between the onset of the depolarization (ORS) on the electrocardiogram (Q) and detection of the last Korotkoff (K) sound at the level of brachial artery during cuff deflation, corresponding to diastolic blood pressure (D). The QKD interval is the sum of the pre-ejection period and of the pulse transmission time from the aortic valves and the microphone. Thus, it is linked to the pulse wave velocity on an arterial segment which includes the ascending aorta and a portion of the subclavian and brachial arteries. From each 24 h monitoring, the average 24 h OKD, the slope of variation of QKD against blood pressure and a normalized QKD
(QKD 100-60) for systolic blood pressure of 100 mmHg and heart rate of 60 beats/mm are calculated. Stiffer arteries as observed with ageing or hypertension are characterized by the reduction of these three parameters. The reproducibility of this method is good. In a pilot study of elderly hypertensive patients we have shown that QKD1.60 has a strong and independent predictive value for future cardiovascular events. Therefore, this method may add significant information to ambulatory blood pressure monitoring.

Key words: ambulatory blood pressure monitoring, arterial distensibility
Blood pressure monitoring 1, p. 193-195, 1996

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Assessment of Arterial Distensibility by Monitoring the Timing of Korotkoff Sounds

Philippe Gosse, Pascal Guillo, Gilles Ascher, and Jacques Clementy

The timing of Korotkoff sounds, blood pressure, and heart rate can now be monitored in the ambulatory patient the QKD interval is the time between the onset of the depolarization on the electrodiogram (Q) and detection of the last Korotkoff sound (K) at the level of brachial artery during cuff deflation, corresponding to diastolic blood pressure (D). Because this interval is inversely related to pulse wave velocity, this recently developed device enables evaluation of the influence of blood pressure on arterial rigidity, providing valuable information on the properties of the arteries. In this study, we examined the influence of hypertension and age on the above parameters and their correlations to left ventricular mass.

QKD interval, blood pressure, and heart rate were monitored over a period of 24 h (four measurements/hour) in 33 normotensive and 70 untreated essential hypertensive patients. The slopes of the plots of QKD interval versus systolic and pulse pressure during the 24 h were calculated for each patient. The influence of age and hypertension on these slopes was tested by comparison of matched groups and multivariate analysis. Moreover the relationships between these parameters and echocardiographically assessed left ventricular mass were studied in 37 patients. We found a reduction in mean QKD interval with age and hypertension, reflecting the recognized higher pulse wave velocity in these patients. The slopes of the plots of QKD interval versus blood pressure were also lower in these patients, indicating the smaller influence of a change in blood pressure on pulse wave velocity in patients with stiffer arteries. Both average 24-h systolic blood pressure and the slope of QKD interval versus pulse pressure were significantly and independently correlated to left ventricular mass index. The influence of blood pressure on arterial rigidity can be evaluated by this new monitoring device. Our results showed that pulse wave velocity was less affected by a change in blood pressure in the patients with the stiffer arteries.

Key words : Pulse wave velocity, arterial distensibility, hypertension, ambulatory blood pressure monitoring, Korotkoff sounds.

American Journal of Hypertension 7, p.228-233, 1994

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Relationship between arterial distensibility and left ventricular function in the timing of Korotkoff sounds (QkD internal) . An ambulatory pressure monitoring and echocardiographic study

Philippe Abassade, Yves Baudouy. Cardiology.

Timing of Korotkoff sounds (QKd) is the time interval between Q wave ECG and pressure diastolic sound, determined by a routine ambulatory pressure monitoring (AMP) (Diasys Integra, Novacor). It is known to be an arterial distensibility index. However, this interval time includes pre-ejection time (PET) which is related to left ventricular (LV) function.

The aim of the study is to define the relative influences of LV function and arterial distensibility in QKd interval.

Sixty consecutive patients, with or without cardiac disease, out or in-hospital, were included. Patients with left bundle branch block, pace maker, or atrial fibrillation were excluded. The echocardiography-Doppler (ED) study collected LV function index : Shortening Fraction (SF), Ejection Fraction (EF), stroke index (SI), (PET), ejection time (ET). Pulse Wave velocity (PWV) was determined by ED in two points of the descending thoracic aorta. The AMP study collected-usual-pressure data : systolic (Ps), diastolic, mean (Pm), pulse pressure (Pp), simultaneously with PWV and over 24h. An automatic assessment of the QKd interval simultaneously with PWV was performed by the monitoring device. Another arterial distensibility index was calculated from ED and AMP:
Burton index as SI / Pp. Values are mean plusminus SD, relationships between various parameters were fitted by a linear function.

QKd is correlated with PWV (n = 53 , p = 0.007, r = 0.37), with Burton index (n = 50 , p = 0,001,
r = 0.47).

QKd is correlated with CV function index like FE (n = 55, p < 0,001, r = 0,66), Ps/systolic diameter
(n = 54, p < 0.001 , r = 0.75 ), SF/ET (n = 35, p = 0.001, r = 0.55), ET/PET (n = 35, p <0.001, r 0.60).

No correlation was found between QKd and EF when PET are withdrawn from QKd (n = 35, p = 0.21,
r = 0,22).

QKd interval is a composite index which reflects not only arterial distensibility but also LV function.

Key words : Arterial distensibility, left ventricular function, echocardiography.

American Journal of Hypertension 15:4, p.67A, 2002

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PROGNOSTIC VALUE OF AMBULATORY MONITORING OF QKD INTERVAL TO ASSESS ARTERIAL STIFFNESS IN HYPERTENSIVE PATIENT

Philippe Gosse*, Raphael Lasserre*, Catherine Minifié*, Philippe Lemetayer*, Jacques Clementy*
*Hôpital Saint André, Bordeaux, France

Objective
The prognostic value of pulse wave velocity (PWV) was demonstrated in pts with hypertension or renal failure. Another method, the monitoring of QKD interval (inversely correlated to PWV) offer the advantages of being automatic and associated to 24h BP monitoring. Its prognostic value was assessed in hypertensives.

Design and methods
ABPM with a device allowing to monitor the QKD interval allow to assess both 24h BP and the QKD100-60 (value of QKD for 100 mmHg systolic BP and 60 bpm HR). As QKD is linked to the pulse transmission time, QKD100-60 has to be corrected for height and is presented as the percentage of the height predicted value in normal subjects (QKDh). All these parameters are automatically calculated by the software without observer bias. Its prognostic value was assessed in a cohort of previously untreated hypertensives who underwent 24h BP monitoring with QKD interval at inclusion (Diasys from Novacor, Rueil Malmaison, France, 4 measures/h) and were prospectively followed up after antihypertensive treatment was started.

Results
We included 360 pts (222 males,aged=53±14 years, Office BP=158±20/98±11mmHg, 24hBP=133±17/86±11 mmHg, QKD100-60 = 202±19 msec, QKDh=95±9%). During follow up (average=57±31 months) 40 patients were lost (not significantly different from the whole group), 39 cardiovascular events occurred . The population was split into quartiles of baseline QKDh . The outcome was significantly worse (p<0.001) with decreasing QKDh (Fig). Cox model showed a significant relation (p<0.05) between QKDh and events independently of age and 24h average systolic BP. Relative risk for QKDh <95%, adjusted for age and 24hSBP was 4.

Conclusion
Arterial stiffness as assessed from QKD monitoring during 24h is associated with increased cardiovascular risk independently of age and 24h systolic BP.*

Journal of Hypertension, volume 21 (Suppl. 41), June 2003, page S245, abstract P3.67

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Prognostic Value of Ambulatory Measurement of the Timing of Korotkoff Sounds in Elderly Hypertensives, a Pilot Study
 
Philippe Gosse, Philippe Gasparoux, Pascal Ansoborlo, Philippe Lemetayer
and Jacques Clementy

Alteration in the physical properties of the large arteries is probably an important contributory factor in morbidity and mortality in the elderly as well as in patients with hypertension or diabetes. We have developed a simple method based on the ambulatory measurement of the timing of Korotkoff sounds (QKD interval), together with blood pressure, to assess these properties. We report its prognostic value in a retrospective survey of elderly hypertensives. We included in this study 134 hypertensive patients over 45 years of age with no cardiovascular complications, either receiving placebo or prior to treatment with antihypertensive medication and seen between January 1992 and July 1993. In June 1995, a survey was carried out to determine outcome by contacting the patients themselves and their family physicians. Data on outcome were obtained for 111 patients with a mean follow-up period of 30 +/- 8 months. At least one cardiovascular complication was recorded during the follow-up period in 14 patients. From the Cox model, data obtained from QKD monitoring, namely the QKD 100-60, was the best predictor of complications and remained significant (P<.01) even after introduction of age, mean 24h SBP, gender, and smoking into the model. A QKD 100-60 below 187 msec was accompanied by a relative hazard of cardiovascular complications adjusted for age and mean 24 h BP of 7.3 (95% confidence interval : 2.9 to 11.7). The indices provided by the ambulatory measurement of QKD interval are significant predictors of cardiovascular complications independently of age and BP. This new method seems to add useful information to classic ambulatory blood pressure monitoring. However this will require confirmation in a large prospective study.
Am J. Hypertens 1997; 10:552-557
Copyrights 1997 American Journal of Hypertension, Ltd.
Keywords : Korotkoff sounds, arterial distensibility, ambulatory blood pressure monitoring, QKD interval, hypertension, prognostic tests.

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