Resistant Hypertension in Patients With Type-II-Diabetes Mellitus
The risk of cardiovascular disease (CVD) in patients with type-II-diabetes mellitus (type-II-DM)is more than doubled and CVD accounts for 70% of deaths in this group of patients.
Hypertension is a major risk factor for CVD in patients with type-II-DM and a major contributor cardiovascular mortality. Uncontrolled- (UH) and resistant hypertension (RH)are more common in patients with type-II-DM, why further bloodpressure (BP) control is needed.
The prevalence of UH and RH has not been examined in a consecutive Danish outpatient population with type-II-DM.
The purpose of this study is to examine the prevalence of resistant hypertension in patients with type-II-diabetes and to examine the characteristics of patients with resistant hypertension as compared to patients with controlled hypertension with regards to arterial stiffness and diastolic heart function.
The risk of cardiovascular disease (CVD) in patients with type-II- diabetes mellitus (type-II-DM) is more than doubled and CVD accounts for 70% of deaths in this group of patients. Hypertension is a major risk factor for CVD in patients with type-II-DM with a major increase in diabetes-related death as a result. Controlled hypertension as well as uncontrolled- and resistant hypertension is more common in patients with type-II-DM than in the general population and are major contributors to CVD and cardiovascular mortality.
Resistant hypertension is defined as BP above 130 mmHg systolic and / or 80 mmHg diastolic despite treatment with 3 antihypertensive agents or more, of which one should be a diuretic, or controlled BP on four antihypertensive agents or more.
The NHANES study estimated the prevalence of hypertension in patients with type-II-DM to 71% and showed that among those with type-II-DM and hypertension only 31% had controlled BP. It is furthermore estimated that resistant that hypertension is present in up to 30% of a hypertensive population and the ALLHAT trial found that 50% of hypertensives needed treatment with three or more antihypertensive agents.
Type-II-DM promotes both small and large artery disease, whereas hypertension promotes primarily large artery disease. As such type-II-DM and hypertension together may influence the entire vascular system. Type-II-DM is strongly associated with development of heart failure and atherosclerosis and it is therefore important to investigate parameters that reflect arterial stiffness (AS), left ventricular function and degree of atherosclerosis.
AS is an age dependent process, where the arterial wall degenerate and elastic fibers are replaced by collagen fibers. The process is accelerated by cardiac risk factors and increased AS can be regarded as both an individual risk factor and a marker reflecting atherosclerosis.
AS can be estimated by pulse wave analysis (PWA) including pulse wave velocity (PWV).
As blood is pumped out of the heart, a pulse wave is created. The pulse wave propagates along the vessels and is reflected from the arterial wall at sites of increased impedance. In healthy elastic arteries the reflected wave reaches the aorta during diastole resulting in increased coronary perfusion. In stiff arteries the reflected wave propagates faster and reaches the aorta during systole before closure of the aortic valve, thereby increasing pulse pressure, systolic pressure and reducing diastolic pressure and thereby coronary perfusion.
Augmentation Index (AIx) measured using PWA is related to ischemic heart disease (IHD) risk factors, among other hypertension and diabetes, and is an independent predictor of mortality in patients with IHD. It is therefore important to examine the relationship between BP and AS, as it may characterize the patients with uncontrolled and resistant hypertension.
A consequence of increased AS is left ventricular hypertrophy (LVH) and a common echocardiographic finding in patients with hypertension, type-II-DM and LVH, is diastolic dysfunction. This is often seen before the onset of systolic dysfunction and any symptoms of CVD.
The increased left ventricular mass is due to hemodynamic factors as well as non-hemodynamic factors, such as activation of the renin-angiotensin-aldosteron-system (RAAS).
Aldosterone is primarily associated with intravascular volume regulation via genomic effects regulating sodium and potassium uptake and excretion.
The non-genomic effects cause endothelial dysfunction, hypertrophy of vascular smooth muscle cells and fibrosis of the vascular wall. Because of this, aldosterone is thought to induce AS. As the receptor for aldosterone is also present in the cell membrane of myocytes, it is possible that aldosterone promotes LVH.
Coronary artery calcium (CAC) score is closely related to atherosclerosis and is a number reflecting the degree and extent of calcium deposits in the walls of the coronary arteries, as demonstrated by cardiac computed tomography. CAC score represents overall plaque burden and is also an independent predictor of cardiovascular events (CVE) and cardiovascular death in asymptomatic patients. In patients with type-II-DM the extent of CAC score is similar to that of patients with coronary artery disease (CAD). Measurement of CAC score can be used as advanced risk assessment. As CAC score is high in patients with cardiac risk factors it is possible that CAC score is reduced when minimizing cardiac risk factors.
The relationship between BP, AS, left ventricular function and CAC score may provide further methods of risk stratification and new strategies for treatment of uncontrolled and resistant hypertension in patients with type-II-DM.
1. Uncontrolled and resistant hypertension is present in more than 50% of consecutive patients with type-II-DM in an out-patient clinic.
2. Increased AS, diastolic dysfunction and high CAC score are more common in patients with type-II-DM with uncontrolled or resistant hypertension than in patients with controlled BP.
3. AS, diastolic function and CAC are improved with increased control of BP.
4. Treatment of patients with resistant hypertension and type-II-DM with an aldosterone antagonist lowers BP significantly, reduces AS, improves diastolic function and reduces CAC score.
To test these hypotheses we wish to conduct two studies:
1. A descriptive study in which the prevalence of uncontrolled and resistant hypertension in consecutive out-patients with type-II-DM is assessed and compared to data from the Diabetes Database of Southern Denmark and The Danish National Indicator Project (NIP) of diabetes.
2. Assessment of AS, diastolic function and CAC in patients with type-II-DM with uncontrolled and resistant hypertension and the changes in these parameters during intensified treatment. This is compared to patients with controlled BP.
Study 1: Prevalence of uncontrolled hypertension and resistant hypertension in patients with type-II-DM.
Consecutive patients with type-II-DM scheduled for control or their first visit in the diabetic out-patient clinic, OUH Svendborg Hospital are screened and asked for informed consent. Patients are characterized as:
1. BP >/= 130/80 mmHg on less than 3 antihypertensive drugs (uncontrolled hypertension)
2. BP >/= 130/80 mmHg on 3 or more antihypertensive drugs including a diuretic (resistant hypertension).
3. BP < 130/80 mmHg on 4 or more antihypertensive drugs (resistant hypertension)
4. BP < 130/80 mmHg on less than 3 antihypertensive drugs (controlled hypertension which will serve as controls)
Methods Ambulatory BP is measured following guidelines from the Danish Society of Hypertension Study 2: Characteristics of patients with type-II-DM with uncontrolled or resistant hypertension Patients from study 1 will be invited to participate in study 2. Patients from group d will participate as control group and patients from group a, b and c will have their medication changed on an individual basis to obtain their goal for BP reduction.
Medication in groups a, b and c will be changed and/or intensified according to the guidelines from the Danish Society of Hypertension with the following principals:
1. It is recommended that all patients with type-II-DM are treated with an angiotensin-IIreceptor antagonist.
2. All traditional antihypertensive drugs can be used in patients with type-II-DM in order to obtain BP < 130/80 mmHg.
3. If 3 or more antihypertensive drugs are needed one of them should ideally be a diuretic.
Medication will be changed or up titrated during visits after 1, 2, 4 and 6 months. If a patient at one of these visits obtains controlled BP no more changes in medication will be made.
Methods All patients who choose to participate in study 2 will be examined at baseline and after 6 and 12 months using the following measurements.
BP measurement BP will be measured as described in study 1.
PWA is performed at baseline and after 6 and 12 months. All data are recorded digitally, which allows for blinded analysis later. The analysis includes:
- Measurement of PWV. For this we will use the Sphygmocor Pulse Wave Velocity Vx System. Using applanation tonometry we register the pulse wave in the carotid and femoral artery 20 times successively. ECG is recorded simultaneously with the recording of the pulse wave. The time it takes for the pulse wave to propagate from the descendent aorta to the carotid and femoral artery is calculated by registering the time from the R-wave in the ECG to the time when the pulse wave is registered in the carotid and femoral artery. To calculate the time it takes for the pulse wave to propagate through the aorta, the time it takes from the aorta to the carotid artery is subtracted from the time it takes from the aorta to the femoral artery. This leaves the time it takes for the pulse wave to propagate from the sternal notch to the femoral artery. The distance the pulse wave covers is measured on the body surface and calculated as the distance from the sternal notch to the femoral artery subtracted from the distance from the sternal notch to the carotid artery. PWV is then calculated as distance (L) divided by the difference in time (dt).
- PWA. For this we will use the Sphygmocor Px Aortic BP Profile system, where the pulse wave curve is presented using applanation tonometry. Using the validated transfer function the pulse wave curve, registered at the site of the radial artery, can be transferred and express the pulse wave curve in the aorta. The curve has several tops. The first top is created when pulse pressure arises during systole and until the flow is at the maximum. This top is named P2. The pulse pressure and flow then drops shortly until the reflected wave reaches the aorta which makes the pulse pressure rise again to the maximum systolic peak. This top is called P1. The difference between P1 and P2 presents the pressure with which the reflected wave contributes (the augmentation pressure). Pulse pressure is calculated as the difference between diastolic and systolic pressure. The AIx is the ratio between the augmentation pressure and pulse pressure in percent. AIx is a measure of stiffness in aorta.
Echocardiography Echocardiography will be performed at baseline and after 6 and 12 month respectively. All recordings will be stored digitally, which allows for blinded analysis later.
Analysis will include:
1. Pulsed Wave Doppler echocardiography from mitral inflow, analysis of tissue wave Doppler velocities from the mitral ring using both septal and lateral measure points.
2. Regional left ventricular systolic and diastolic function assessed on a segmental basis utilizing strain rate imaging and specletracking.
3. 2 and 3 dimensional assessment of left ventricular systolic and diastolic volume, from which left ventricular ejection fraction is calculated. Assessment of left ventricular ejection fraction utilising wall motion index could be used in patients with previously ischemic heart disease.
CAC score CAC will be measured at baseline and after 12 months. All recordings will be stored digitally, which allows for blinded analysis later.
Analysis will include:
1. CAC score (Agatston score) measured in a non-contrast enhanced scan. Each subject will undergo a heart scan on a MDCT scanner without administration of a contrast agent.
Blood samples will be drawn by a professional bioanalytic according to existing guidelines from department of Clinical Biochemistry at Svendborg hospital. Following analyses are made:
- Blood glucose, HbA1c
- Total Cholesterol, LDL, HDL, triglycerides
- Na, Ka, creatinin, carbamide
- Renin, aldosterone
- Pro-BNP, Hs-CRP
Following samples are made:
- Urine stix measuring albumin, glucose
- Albumin / creatinin ratio
Time Perspective: Prospective
Department of Medical Research, Svendborg Hospital
Results (where available)
- Source: http://clinicaltrials.gov/show/NCT01056367
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
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