Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Double Blind, Active-controlled, Parallel Study to Analyse Effects of the Combination of Aliskiren and Valsartan on the Vascular Structure and Function of Retinal Vessels
Brief Summary: Hypertension affects approximately one fourth of the world population and therefore contributes substantially to the worldwide burden of cardiovascular (CV) disease and end-organ damage.

Changes in small artery structure characterized by an increased wall-to-lumen ratio (WLR) are characteristic feature of target organ damage in hypertension. Of clinical importance, structural arteries of small subcutaneous arteries have been shown to be of prognostic significance, with adverse prognosis in subjects with higher WLR. However, the assessment of arteriolar structure from biopsies of subcutaneous tissue is invasive and impractical in clinical practice. A new approach focuses on retinal arteriolar structural parameters by using scanning laser Doppler flowmetry (SLDF) with automatic full-field perfusion imaging analyses (9). This approach allows the non-invasive assessment of both the outer diameter (OD) and inner diameter (ID) of retinal arterioles in vivo and, thus, analyses vascular remodeling of retinal arterioles by calculating WLR = (OD - ID) / ID).

A crucial role in the efforts of prevention of end-organ damage plays the renin angiotensin system (RAS). The increased mechanical strain on the vasculature at a higher BP can cause injury to the endothelial wall. Activation of the RAS increases BP and stimulates a local inflammatory response to repair the injury. Long-term or repeated response to injury leads to endothelial dysfunction and microvascular damage, and hence end-organ damage.

Combining RAS inhibitors may provide greater end-organ protection than use of either class alone. However, ONTARGET has failed to show superiority of the dual RAS blockade (ACE-I and ARB) in patients at high cardiovascular risk. The combination of ARBs and direct renin inhibitors (DRIs) emerged as the only available, valid and innovative option for blocking the RAS at two different sites (sequential blockade). Indeed, AVOID study and ALLAY study demonstrated that the DRI aliskiren has additional and to some extent blood pressure independent effects on albuminuria and left ventricular hypertrophy, both signs of subclinical organ damage in hypertension, respectively.

However, no data are available with respect to the effects of ARBs and DRIs on vascular properties in the short and long term To close this gab we focus in this study on vascular structural and functional changes since vascular adaptation to high blood pressure occurs in the early phase of hypertensive disease.


Options:
A: Inclusion Criteria:

* Male or female aged 18 to 75 years (females of child bearing potential must be using adequate contraceptive precautions)
* Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at enrolment visit
* Patients with mild to moderate uncomplicated essential hypertension with a trough mean sitting DBP ≥ 90 mmHg and/or SBP ≥ 140 mmHg or pretreated arterial hypertension
* Written informed consent
* Agreement to attend all study visits as planned in the protocol
* Agreement to perform routinely self home blood pressure measurements as well as keep a blood pressure diary throughout the study and to inform the investigator if BP exceeds cutt off criteria given in the ICF

Exclusion Criteria:

* In the investigator's opinion the patient can not be withdrawn from their current antihypertensive medication
* Secondary hypertension (e.g. patients with hyperaldosteronism, pheochromocytoma, renal artery stenosis, renal parenchymal disease, coarctation of the aorta, Cushing's disease syndrome)
* Severe essential hypertension (systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg) or treatment resistant hypertension (3 antihypertensive drugs and still SBP ≥ 140mmHg and/or DBP ≥ 90mmHg)
* History of hypertensive encephalopathy or intracerebral hemorrhage
* Diabetes mellitus Type 1 or Type 2
* History of epilepsia (no retinal exam possible)
* Eye cataract (no retinal exam possible)
* History of the following within the last six months: myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, heart failure
* Presence of significant renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, immunological, haematological or oncological, neurological and psychiatric diseases or dysfunction
* Impaired renal function as shown by estimated GFR (abbreviated MDRD formula) \< 45 ml/min/1.73 m2
* Impaired hepatic function as shown by transaminases higher than three times the upper normal limit
* Known allergy or a known intolerance to any ARB or Aliskiren
* Females who are pregnant or lactating or who are not on an adequate contraception (Pearl-Index ≥ 1 %)
* Use of any investigational drug within 28 days before study entry
* Patients previously enrolled into the study
* History of drug, medication abuse.
* Serious disorders which may limit the ability to evaluate the efficacy or safety of the test drug(s), including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, immunological, haematological or oncological, neurological and psychiatric diseases
* Subject is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
* Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
* Subject unlikely to comply with protocol, e.g. uncooperative attitude, inability to return for follow-up visits and unlikelihood of completing the study
* Subject who do not give written consent, that pseudonymous data will be transferred in line with the duty of documentation and the duty of notification according to § 12 and § 13 GCP-V
B: Inclusion Criteria:

1. Individual has a mean day-time SBP ≥ 135 mmHg, as determined with the use of ABPM, while using 3 or more antihypertensive agents for at least 3 months prior to inclusion or with documented intolerance to 2 or more of the 4 major classes antihypertensive drugs ( ACE/ARB, Calcium channel blocker, Beta Blocker, Diuretic) and no possibility to take 3 anti-hypertensive drugs.
2. Individual is ≥18 years of age.

Exclusion Criteria:

1. Individual is unable or unwilling to sign informed consent.
2. Individual has a treatable secondary cause of hypertension.
3. Individual has an eGFR below 20 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) calculation.
4. Individual has renal artery anatomy that is ineligible for treatment
5. Individual has any serious medical condition, which in the opinion of the investigator, may adversely affect the safety and/or effectiveness of the participant or the study.
6. Individual is pregnant, nursing or planning to be pregnant.
7. Individual has a known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or would be unlikely or unable to comply with study follow-up requirements.
8. Individual is currently enrolled in another investigational drug or device trial.
C: Inclusion Criteria:

* Average SBP \>140mmHg, measured per guidelines
* 24 hour average ABPM daytime SBP \>135mm/Hg
* On stable medication regimen of full tolerated doses of 3 or more antihypertensive meds, with one being a diuretic
* No changes for a minimum of 2 weeks prior to screening
* No planned medication changes for 6 months
* Age 18-80 years
* At minimum, 3 antihypertensive medications must meet one or more of the following full dose criteria:
* Highest labeled dose according to medication's labeling
* Highest usual dose per clinical guidelines-JNC-7
* Highest tolerated dose
* Highest appropriate dose for the patient per the PI's clinical judgment

Exclusion Criteria:

* Hemodynamically or anatomically significant renal artery abnormalities or stenosis \>50% or prior renal artery intervention
* eGFR \< 45 mL/min/1.73m2 (MDRD formula)
* Albumin/creatinine ratio \> 50 mg/mmol
* Type 1 diabetes mellitus
* Known alcohol or drug abuse
* Symptomatic orthostatic hypotension in past year
* Stenotic valvular heart disease for which BP reduction would be hazardous
* MI, unstable angina, or CVA in the prior 6 months
* Known primary pulmonary HTN
* Known pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism or hyperparathyroidism
* Known primary hyperaldosteronism not adequately treated.
D: Inclusion Criteria:

1. Individual is ≥18 and ≤75 years of age
2. More than half a year for definite primary hypertension
3. Individual has a systolic blood pressure ≥160 mmHg (≥150 mmHg for type 2 diabetics) based on an average of three office blood pressure readings measured
4. Individual is adhering to a stable drug regimen, including three or more antihypertensive medications of which one is a diuretic, for a minimum of 14 days prior to enrollment
5. At least 30 seconds on a rhythm strip in an ECG record and at least 1 AF outbreak which was recorded by EGG and Holter during the preceding 6 months
6. Paroxysmal and persistent AF individual
7. Agree to attend experimental clinic and sign written informed consent

Exclusion Criteria:

1. Secondary and white-coat hypertension
2. Permanent AF individual
3. Thrombus in left atrial appendage found by transesophageal echocardiography
4. Individual with severely enlarged left atria ≥55 mm
5. Individual has experienced renal artery stenosis, or a history of prior renal artery intervention including balloon angioplasty or stenting, or ineligible conditions seen on renal artery computed tomography angiogram inspection such as double renal artery on one side, renal artery length ≤2 cm, diameter ≤4 mm, and distortion at incept sect
6. Individual has experienced a definite acute coronary syndrome in the past 3 months, or a cerebrovascular accident and alimentary canal bleeding within 3 months
7. Individual has experienced sick sinus syndrome
8. reversible causes of AF, including alcohol abuse, surgery, electrocution, myocadial infarction, pericarditis, myocarditis, pulmonary embolism or other pulmonary diseases, hyperthyroidism, and other metabolic disorders
9. structural heart diseases such as congenital, valvular heart diseases and kinds of cardiomyopathy
10. Individual is pregnant or nursing
11. Mental disorders - individual cannot complete follow-up or one the researcher thinks is unfit to be included in this study

Answer: A