Overview

Hypertension remains a global burden in cardiovascular disease leading to stroke, myocardial infarction, and heart failure. Its myocardial complications result from increased mechanical load on the heart. Under physiological conditions of increased myocardial load and resulting myocardial stretch, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) synthesis and secretion occur contributing to maintenance of optimal cardiorenal and blood pressure homeostasis. However, studies indicate that in subjects with cardiovascular diseases the biological structure of these hormones may be altered, thus reducing their favorable protective activities. New studies indicate that early and moderate hypertension is associated with a derangement of the natriuretic peptide system which is characterized by the lack of activation of biologically active ANP and BNP, while severe hypertension is characterized by cardiac release of altered molecular forms of ANP and BNP that have reduced biological properties and/or enhanced degradation.

The broad objective of this proposal is to advance the biology and therapeutics of the NPs with a special focus on the cardiac peptide BNP in human hypertension. Our proposal is based upon the biological properties of BNP (i.e. natriuretic, renin-angiotensin-aldosterone suppressing, vasodilating, anti-fibrotic, anti-hypertrophic and positive lusitropic), its mechanistic role in human hypertension, and thus its potential as an innovative chronic protein therapeutic to enhance the treatment of patients with hypertension. Importantly, BNP is an endocrine hormone normally produced by the human heart, and it has been approved for the treatment of acute heart failure in USA.

Eligibility

Inclusion Criteria:

• Office systolic blood pressure (SBP) ≥ 120 mmHg and treatment with at least one anti-hypertensive medication. Unchanged medication regimen the last two weeks prior to inclusion.
• Average day-time SBP > 115 on a 24-h ambulatory BP measurement at screening.

Exclusion Criteria:

• Congestive Heart Failure (any New York Heart Association class)
• Ejection Fraction ≤ 40 %
• Known, not appropriately treated, secondary hypertension
• Myocardial infarction within 3 months of screening
• Unstable angina within 14 days of screening, or any evidence of myocardial ischemia
• Pulmonary hypertension
• Aortic stenosis with maximum jet velocity > 2,5 m/s
• Other valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis or biopsy proven active myocarditis
• Sustained Ventricular Tachycardia or Ventricular Fibrillation within 14 days of screening
• Sustained Atrial Fibrillation
• Second or third degree atrioventricular block without a permanent cardiac pacemaker
• Cerebrovascular event within 3 months of screening, or other evidence of significantly compromised cerebral perfusion
• Proteinuria defined as albumin:creatinine ratio > 100 (equivalent to an excretion of > 1 g/day)
• Nephrotic syndrome
• Body Mass Index > 35
• Total bilirubin of > 25 µmol/L, aspartate aminotransferase or alanine aminotransferase 1.5 times the upper limit of normal range
• Renal insufficiency assessed by estimated glomerular filtration rate (GFR) < 30 ml/min
• Serum sodium of ≤ 135 mmol/L and ≥ 150 mmol/L
• Serum potassium of ≤ 3.5 mmol/L and ≥ 5.5 mmol/L
• Women taking hormonal contraceptives containing estrogens
• Pregnancy
• Patients on prolonged, i.e. more than 30 days, immunosuppressant therapy
• Patients with known, active malignancies
• Patients with orthostatic hypotension
• Participation in a trial with an investigational product within the previous three months
• Any contraindication listed on the Investigator's Brochure of the Investigational Medicinal Product
• Any reason why, in the opinion of the investigator, the patient should not participate.