Arterial Stiffness (From Monitoring of QKD Interval) Predict the Occurrence of Cardiovascular Events and Total Mortality

doi:10.21203/rs.3.rs-2072189/v1

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Arterial Stiffness (From Monitoring of QKD Interval) Predict the Occurrence of Cardiovascular Events and Total Mortality

https://doi.org/10.21203/rs.3.rs-2072189/v1

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published 29 Dec, 2022

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Arterial stiffness, most often assessed with carotido-femoral pulse wave velocity predicts cardiovascular events but its use in clinical practice remains limited. The 24h ambulatory monitoring of Blood pressure and timing of Korotkoff sounds (QKD interval) allows an automatic assessment of arterial stiffness and is an independent predictor of cardiovascular events in hypertensive patients. The long term follow up of our cohort of hypertensive patients gave us the opportunity to test the consequences of increased arterial stiffness on the incidence of all causes deaths and to define the populations who could benefit of this measurement beyond risk scores. The sample includes 930 patients (502 males, age 53 ± 13 years, baseline risk SCORE2-OP = 6.70 ± 4.97%) with an average follow up of 12.11 ± 7.4 years (0.3–30). In this population 169 cardiovascular events and 155 deaths were recorded. SCORE2-OP, 24h Systolic Blood Pressure and arterial stiffness (QKDh) as a continuous or discontinuous variable (normal or reduced) were significantly and independently linked to the occurrence of cardiovascular events or all cause deaths in multivariate Cox model. ROC curves analysis show that measuring arterial stiffness with QKD method offers the best predictive value in patients with low or very low risk scores.

arterial stiffness

ambulatory BP monitoring

QKD

mortality

cardiovascular events

What is known?

Markers of subclinical target organ damage increase cardiovascular risk prediction beyond traditional risk factors
Arterial stiffness is one of these markers and observational studies have demonstrated its predictive value for future cardiovascular events independently of traditional risk factors.
QKD method allow to assess arterial stiffness and predict cardiovascular events in hypertensive patients independently of traditional risk factors including 24h BP and left ventricular hypertrophy

What this study adds?

QKD method predicts cardiovascular events independently and total mortality independently of SCORE2 and SCORE OP
The potential add of QKD method seems to be even more important in a very low risk population

Markers of subclinical target organ damage increase cardiovascular risk prediction beyond traditional risk factors. Arterial stiffness (AS) is one of these markers¹. Observational studies have demonstrated the predictive value for future cardiovascular events (CVE) of both the carotido-femoral pulse wave velocity (PWV) (for patients with renal failure², hypertension (HTN) ³ and in general population⁴) and the QKD interval (QKDh, for hypertensive patients⁵) independently of traditional risk factors: sex, age, diabetes, smoking, cholesterol and blood pressure( BP), and left ventricular hypertrophy⁵. Therefore AS is a powerful marker of cardiovascular risk and is helpful to reclassify patients at intermediate risk. The aims of this study are to test the consequences of reduced QKDh on the incidence of all causes deaths and to define the populations for which this measurement could improve the risk prediction beyond traditional risk factors.

Population and inclusion criteria

The patients included in this study belong to the Bordeaux cohort of hypertensive subjects.

Briefly, this registry was started in 1984 and includes all patients consecutively referred to our center before administration of antihypertensive treatment and fulfilling the following criteria:

Confirmed HTN with Office BP > 140/90 mmHg on at least two occasions without secondary cause of HTN; Previous CVE, pathologies likely to affect the prognosis, and type 1 diabetes were exclusion criteria. For the validity of the ambulatory measurement of AS through QKD measurement, two other selection criteria were employed: absence of bundle branch block on ECG (QRS duration < 120 msec), and absence of known thyroid pathology.

We included in this study patients who benefited from an ambulatory measurement of BP and QKD either on inclusion in the cohort prior to treatment, or during the follow-up under treatment. Therefore baseline for this study was defined as the time of the first QKD monitoring available for each patient.

All the patients gave their consent to participate in this registry, which was approved by our local committee of ethics and protection of the individual (Committee for Protection of Persons in the South-West and Overseas III, February 28^th 2007)

Ambulatory measurement of BP and QKD interval

All the patients benefited from an ambulatory measurement of BP coupled with the measurement of QKD interval ⁶. The equipment (Diasys 200RK then Diasys integra and from 2020 Diasys 3 plus, Novacor, France) is a device based on the auscultatory measurement of BP, which also determined for each measurement the duration of the QKD interval as the time between the QRS wave on the ECG and the detection of the last Korotkoff sound on deflation of the cuff. This time is the sum of the pre-ejection time and time of transmission of the pulse wave between the aortic valves and the microphone placed on the brachial artery. This interval is measured every 15 min along with BP and heart rate over 24h. From all the measurements obtained, the software automatically determines the value of the QKD_100-60⁷ which is the theoretical value of the QKD for a 100 mmHg SBP and a 60 bpm heart rate based on the bivariate linear regression linking QKD to these two variables. This index reduces the influence of the pre-ejection time and enables comparison of patients at equal systolic BP. The value obtained is expressed as a percentage of a theoretical normal value based on the height predicted value of a population of normal young subjects⁸ : QKDh. The lower this value, the higher the AS. A low QKDh was defined as < 100% of the normal height predicted value.

The ABPM with QKD device was set up with a suitable size of cuff by a dedicated nurse on the left arm. Good quality criteria were required to take into account the ABPM. Recordings with 70 measurements or more were considered of good quality.

Results of 24h BP recordings were sent to GP but the results of QKD were not as there was so far no evidence that this result should influence the treatment of these patients.

Estimation of risk SCORE

An estimation of 10 year risk of fatal and non-fatal cardiovascular disease was calculated from the SCORE2-OP (SCORE2 for patient<70 years, OP for patients>70 years) ^{9, 10} charts for low risk populations using gender, office systolic BP, smoking status and cholesterol levels. As this SCORE is not validated in patients with diabetes, these patients were excluded from this study.

Follow up

After the initial evaluation, the patients were given antihypertensive treatment and followed up by their family physicians who were not informed of arterial stiffness results. These patients were not systematically convened, but could be sent again by their doctors during the follow-up period. However, information from these patients was obtained regularly (every two years on average) either directly from the patients or from their physicians. A detailed report was requested in the event of CVE. Events retained for analysis were: myocardial infarction, coronary revascularization, stroke documented by CT scan or MRI, sudden death, arteriopathy of the lower limbs requiring revascularization, aneurism of the abdominal aorta operated or ruptured, carotid stenosis requiring angioplasty, aortic dissection. In 2021, we made a systematic search of all cause deaths for all the patients in the registry from INSEE (Institut National de la Statistique et des Etudes Economiques). However, we were not able to obtain the cause of death for all patients.

Statistics

The data were analysed with SPSS 26 IBM software. The relationship between QKDh and the variables used to calculate the SCORE2-OP was analysed by multivariate regression analysis and the linear regression between QKDh and SCORE2-OP was also tested.The associations between QKDh and First we tested the independence of the QKDh to predict events with a Cox proportional model with forward stepwise conditional method and likelihood ratio. The analysis were carried out separately for 1) the first outcome (CVE or death), 2) CVE and 3) all cause deaths. QKDh was tested as a continuous or a discontinuous variable (normal or low). The other variables included for analyses were: risk SCORE2-OP and 24h average SBP.

Then we tested the factors that may influence the predictive value of QKDh. We analysed the link between basal data and events with ROC curves analysis for QKDh (a low value is linked to the event), age, 24h SBP, SCORE2-OP (a high value is linked to the event) in the whole population then in subgroups (SCORE2-OP <=5%, <=10% , males or females, treated or untreated patients). Differences in AUC were tested with paired tests (paired sample design)

In end 2021, 1105 patients with 24h monitoring of QKD were included in the registry. For this study, 96 patients with diabetes, 35 patients with QRS duration exceeding 119 ms and 44 patients with thyroid diseases were excluded so the sample for the present analysis included 930 patients whose main characteristics are summarized in table 1. The average follow-up duration for this sample was 12.11±7.4 years (0.3-33). In this population 169 CVE were recorded (table 2), and 155 deaths (37 of proven cardiovascular origin, 50 of proven non cardiovascular origin and 68 of undetermined cause). Cardiovascular event or death as the first outcome was recorded in 254 patients. All events were significantly more frequent in patients with reduced QKDh at baseline (table 2). QKD as a marker of arterial stiffness was correlated to age (r=-0.32, p<0.001), 24h SBP (r=-0.196, p<0.001) and to cholesterol( r=-0.124, p=0.001) but in multivariate regression analysis these 3 variables explain only 15% of its variance. SCORE2-OP alone is correlated to QKDh (r=-0.346, p<0.001) and explain only 12% of its variance. In this population (table 3), SCORE2-OP, 24h SBP and QKDh as a continuous or discontinuous variable were significantly and independently linked to the occurrence of first outcome (CVE or death), CVE and all cause deaths in multivariate Cox models. As a sensitivity analysis, the same analysis was performed in the whole cohort (n=1105, 192 deaths) with similar results (results not shown).

ROC curve analysis shows that baseline SCORE2-OP, age, 24h SBP and QKDh are significantly linked to future cardiovascular events and all cause deaths. In the population with very low (<=5%) baseline risk, there is a trend to a greater AUC observed with QKDh as compared to SCORE2-OP (p=0.155) for the prediction of CVE. A value of 95% offer the best compromise between sensitivity and specificity (Youden indice = 1.38) with 63% sensitivity and 67% specificity. The same analysis performed separately in males and females showed no significant difference with the limitation of the much smaller number of events in females (supplementary table 1).When taking into account the presence or absence of anti-hypertensive treatment at baseline (supplementary Table 2), the AUC for all predictors were higher in untreated patients. But the lower AUC in treated patients was observed as well for variables dependent of treatment (24h SBP and QKD) or not dependent (age and SCORE).

This study confirms that AS evaluated from 24h ambulatory monitoring of BP and QKD is an independent predictor of CVE and mortality.

The ambulatory measurement of QKD interval enables determination of an index of arterial stiffness coupled with measurements of BP. This time delay is related to the velocity of the pulse wave (PWV) and the length of the arterial route. The QKD_100-60 provides an isobaric index of arterial stiffness, making it possible to compare patients at equal BP. We have also shown with an invasive study¹¹ that the QKD interval was significantly correlated to aortic systolic BP and could be used for an assessment of central BP by a non-invasive method¹². We have already shown in our cohort^{5, 13, 14} that QKDh is significantly related to the occurrence of the CVE independently of age, mean 24h BP and other traditional risk factors including left ventricular hypertrophy. This new analysis of our cohort is based on a larger number of CVE and deaths with a systematic search of deaths from INSEE registry performed in 2021. It confirms our previous results showing a relation between QKDh and CVE or all cause deaths independently of risk SCORE2-OP and 24h SBP demonstrating clearly that QKDh add predictive information to the European SCORE as other measurements of PWV¹⁵. The sensitivity analysis based on the whole registry confirms the robustness of the analysis but as duration of QRS and thyroid diseases strongly influence the QKD via the pre-ejection time, monitoring of QKD cannot be considered as reliable in patients with large QRS, thyroid disease but also cardiac failure.

The present analysis affords new data. The added predictive value of arterial stiffness as compared to SCORE2-OP is greater in patients with low or very low risk. Previous studies on the link between PWV and cardiovascular or total mortality were often performed in populations with higher baseline risk than ours (average age >60 years, renal failure, diabetes, previous cardiovascular events)¹⁶. But AS measurement is probably even more informative in low risk patients and could contribute to an earlier and more efficient control of all risk factors. However the difference between the AUC of SCORE2-OP and QKD did not reach statistical significance in our study and these results deserve confirmation with a greater sample or more events.

Some important limitations stem from the structure of this study. It is a prospective registry. Initially the antihypertensive treatments were proposed by our team, but later choices and modifications were often carried out by the family doctors and were based mostly on the office BP. It was impossible to study the influence of the different classes of anti-hypertensive agent in this cohort. As follow up 24h monitoring of BP and QKD were not systematically performed in this cohort, we have so far not enough data to evaluate the evolution of these parameters with time and treatments but the survey of these patients will continue with more systematic evaluation of BP and QKD with 24h monitoring.

In conclusion arterial stiffness evaluated by the ambulatory measurement of QKD interval has an independent prognostic value in the hypertensive, independent of 24h SBP measured simultaneously and add significant predictive information to the risk SCORE2-OP. The potential add of AS evaluation seems to be even more important in a very low risk population.

SOURCE OF FUNDING: None

CONFLICT OF INTEREST: The university hospital of Bordeaux has received free Diasys 3 plus from Novacor .

ACKNOWLEDGEMENTS: We thank Stephane Laurent for his very useful comments on this study.

Vlachopoulos C, Aznaouridis K and Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318-27.
Blacher J, Safar ME, Pannier B, Guerin AP, Marchais SJ and London GM. Prognostic significance of arterial stiffness measurements in end-stage renal disease patients. Curr Opin Nephrol Hypertens. 2002;11:629-34.
Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P and Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001;37:1236-41.
Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D and Benjamin EJ. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121:505-11.
Gosse P, Cremer A, Papaioannou G and Yeim S. Arterial stiffness from monitoring of timing of korotkoff sounds predicts the occurrence of cardiovascular events independently of left ventricular mass in hypertensive patients. Hypertension. 2013;62:161-7.
Gosse P, Guillo P, Ascher G and Clementy J. Assessment of arterial distensibility by monitoring the timing of Korotkoff sounds. Am J Hypertens. 1994;7:228-33.
Gosse P, Bemurat L, Mas D, Lemetayer P and Clementy J. Ambulatory measurement of the QKD interval normalized to heart rate and systolic blood pressure to assess arterial distensibility - value of QKD100-60. Blood Press Monit. 2001;6:85-9.
Gosse P, Jullien V, Lemetayer P, Jarnier P and Clementy J. Ambulatory measurement of the timing of Korotkoff sounds in a group of normal subjects: influence of age and height. Am J Hypertens. 1999;12:231-5.
group SOw and collaboration ESCCr. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions. Eur Heart J. 2021;42:2455-2467.
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B, Group ESCSD and Societies ESCNC. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42:3227-3337.
Cremer A, Butlin M, Codjo L, Coulon P, Ranouil X, Joret C, Coste P, Asmar R, Avolio A and Gosse P. Determination of central blood pressure by a noninvasive method (brachial BP and QKD interval). J Hypertens. 2012;30:1533-9.
Cremer A, Codjo L, Butlin M, Papaioannou G, Yeim S, Jan E, Kiat H, Avolio A and Gosse P. Determination of central blood pressure by a noninvasive method (brachial blood pressure and QKD interval): a noninvasive validation. J Hypertens. 2013;31:1847-52.
Gosse P, Lasserre R, Minifie C, Lemetayer P and Clementy J. Arterial stiffness evaluated by measurement of the QKD interval is an independent predictor of cardiovascular events. Am J Hypertens. 2005;18:470-476.
Gosse P, Papaioanou G, Coulon P, Reuter S, Lemetayer P and Safar M. Can ambulatory blood-pressure monitoring provide reliable indices of arterial stiffness? Am J Hypertens. 2007;20:831-8.
Laurent S, Mousseaux E and Boutouyrie P. Arterial stiffness as an imaging biomarker: are all pathways equal? Hypertension. 2013;62:10-2.
Sequi-Dominguez I, Cavero-Redondo I, Alvarez-Bueno C, Pozuelo-Carrascosa DP, Nunez de Arenas-Arroyo S and Martinez-Vizcaino V. Accuracy of Pulse Wave Velocity Predicting Cardiovascular and All-Cause Mortality. A Systematic Review and Meta-Analysis. J Clin Med. 2020;9.

Table 1: main characteristics of population studied

	N	Min	Max	Mean	SD
Males/Females	502/428
Smokers (Y/N)	181/749
Hypercholesterolemia (Y/N)	182/748
Untreated at baseline	580/350
Age (years)		18	92	53.15	13.81
BMI (kg/m2)		17.04	41.02	25.67	4.04
Office SBP (mmHg)		106	230	151.67	16.56
Office DBP(mmHg)		60	150	91.93	10.98
24h SBP(mmHg)		95	198	129.44	15.06
24h DBP(mmHg)		54	135	84.63	11.00
24h heart rate (bpm)		41	105	74.40	10.30
QKD_100-60 (ms)		142	259	208.99	18.20
QKDh (%)		66	132	97.90	8.35
Plasma fasting blood glucose (mmoles/l)		3.40	7.15	5.33	0.70
Plasma creatinin(micromoles/l)		35	274	82.76	22.15
Total cholestérol (mmoles/l)		1.36	10.00	5.62	1.12
SCORE2-OP		1	31	6.66	4.97

BMI: body mass index, BP: blood pressure, D: diastolic, S: systolic, M: mean, QKDh: measured QKD_100-60/height predicted value in normal subjects,
Table 2 : Cardiovascular events and deaths observed as a function of normal or reduced QKDh at baseline

	Normal QKDh >=100%, N=386	Reduced QKDh <100%, N=544	p
All CV events	37	132	<0.001
Coronary events	18	63	<0.001
Stroke	17	44	0.025
Other	2	25	0.02
Deaths	34	121	<0.001
CV deaths	8	29	0.006
Non CV deaths	12	38	0.003
Deaths undetermined	14	54	<0.001
Death or CV event (first outcome)	63	191	<0.001

Table 3: Main results of multivariate Cox analysis in the whole population

	First Outcome(CVE or death) N=254			CVE N=169				All cause Deaths N=155
	HR	CI	P	HR	CI	p	HR	CI	p
SCORE2-OP (1%)	1.099	1.078-1.121	<0.001	1.081	1.055-1.109	<0.001	1.130	1.104-1.157	<0.001
24hSBP (1mmHg)	1.08	0.999-1.016	0.07	1.015	1.005-1.025	0.002	1.009	0.998-1.019	0.106
QKDh (1%)	0.977	0.960-0.993	0.005	0.956	0.937-0.975	<0.001	0.965	0.945-0.985	<0.001

QKDh<100% (Y/N)	1.466	1.08-1.98	0.013	1.917	1.311-2.804	<0.001	1.567	1.049-2.342	0.028

HR: Hazard Ratio, CI: 95% confidence interval

Table 4: ROC curves analysis for first outcome (CVE or death)

Whole population 254 events
Variable	AUC	SD	P	95%CI
SCORE2-OP(%)	0.727	0.018	<0.0001	0.692-0.763
Age (years)	0.690	0.019	<0.0001	0.654-0.727
24h SBP (mmHg)	0.627	0.020	<0.0001	0.585-0.669
QKDh (%)	0.675	0.021	<0.0001	0.635-0.715
SCORE2-OP<=5% 74 events
SCORE2-OP(%)	0.664	0.032	<0.0001	0.602-0.725
Age (years)	0.608	0.031	<0.0001	0.547-0.669
24h SBP (mmHg)	0.613	0.035	0.001	0.544-0.683
QKDh (%)	0.663	0.034	<0.0001	0.596-0.730
SCORE2-OP<=10% 163 events
SCORE2-OP(%)	0.678	0.022	<0.0001	0.634-0.721
Age (years)	0.634	0.023	<0.0001	0.590-0.678
24h SBP (mmHg)	0.580	0.027	0.002	0.527-0.632
QKDh (%)	0.635	0.026	<0.0001	0.529-0.631

Table 5: ROC curves analysis for CVE

Whole population 169 events
Variable	AUC	SD	P	95%CI
SCORE2-OP(%)	0.684	0.022	<0.0001	0.640-0.727
Age (years)	0.662	0.022	<0.0001	0.619-0.705
24h SBP (mmHg)	0.647	0.023	<0.0001	0.600-0.694
QKDh (%)	0.693	0.023	<0.0001	0.647-0.738
SCORE2-OP<=5% 53 events
SCORE2-OP(%)	0.614	0.037	0.002	0.542-0.686
Age (years)	0.594	0.036	0.009	0.523-0.666
24h SBP (mmHg)	0.650	0.040	<0.0001	0.571-0.729
QKDh (%)	0.687	0.040	<0.0001	0.609-0.765
SCORE2-OP<=10% 105 events
SCORE2-OP(%)	0.613	0.027	<0.0001	0.560-0.666
Age (years)	0.592	0.027	0.001	0.540-0.644
24h SBP (mmHg)	0.602	0.030	0.001	0.543-0.662
QKDh (%)	0.652	0.030	<0.0001	0.593-0.710

Yes there is potential conflict of interest.

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Arterial Stiffness (From Monitoring of QKD Interval) Predict the Occurrence of Cardiovascular Events and Total Mortality

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