Association Between Coronary Flow Reserve and BH4 Levels in High CV Risk

Study to Investigate the Association Between Coronary Flow Reserve and BH4 Levels in Patients With High Cardiovascular Risk

To determine if there is a relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels in patients with high cardiovascular risk .

Study Overview

• Status: Completed
• Conditions: Hypertension,Essential
• Intervention / Treatment: Diagnostic test: Echo stress dipyridamole

Detailed Description

Primary parameter :

relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels in patients with hypertension and concomitant cardiovascular risk factors.

Secondary parameter:

Levels of cGMP in platelets.

4. Study design

Three parallel groups of patients (n=15 per group):

• Group 1 with normal coronary flow reserve (CFR ≥2.5)

• Group 2 with reduced coronary flow reserve (CFR≤2.0)

  o Group 3 control subjects (without a high risk profile according to ESC score chart http://www.heartscore.org. ) matched for age (between 40 and 80 years of age)

• and gender. 1/3 enrolled patients must be diabetic (Type2 diabetes)

• Study Type: Observational
• Enrollment (Actual): 55

Contacts and Locations

Study Locations

• Italy
  • Bergamo, Italy, 24127
    • ASST Papa Giovanni XXIII
  • Milan, Italy, 20132
    • IRCCS Ospedale San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Symptomatic (angina symptoms both typical and atypical ) patients referred to the hospital with hypertension plus risk factors: diabetes, hypercholesterolemia, smoking, chronic renal failure

Description

Inclusion Criteria:

• o men and women (females of childbearing potential must be using highly effective contraceptive precautions such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner)

  • Females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test
  • between 40 and 80 years of age
  • documented history of hypertension
  • smokers/non smokers R
  • type 2 diabetes R
  • Moderate to severe kidney disease (GFR >30 and <60 ml/min/1.73m2 (estimated MDRD) R
  • Hypercholesterolemia R
  • Receiving an optimal standard antihypertensive treatment for at least 6 months, stable for at least 15 days
  • All other concomitant treatments stabilized at least for the preceding 15 days
  • Able to give written informed consent

Exclusion Criteria:

• o Females of childbearing potential not using highly effective contraceptive precautions

  • Patients with obstructive (>50% diameter reduction) CAD on the LAD (based on invasive angiography or coronary CTA) or with evidence of previous myocardial infarction or history of revascularization in the LAD territory.
  • CAD on the RCA or CX with diameter reduction > 50% (based on invasive angiography or coronary CTA) , either native or revascularized (stent)
  • Patients with infectious disease and/or chronic inflammatory diseases
  • Epicardial coronary arteries spasm
  • Patients with severe valve disease and/or significant left ventricular wall motion abnormalities
  • Patients under treatment with non-selective beta blockers including propranolol, nadolol, pindolol, labetalol, penbutolol, sotalol, carvedilol, and timolol.
  • Contraindications to dipyridamole infusion: asthma, bronchospasm, previous < 24 hours ingestion of phylline derivatives (tea, coffee, cola, xanthines and chocolate) sick sinus syndrome, advanced AV block (second and third degree), systolic blood pressure < 90 mmHg, cerebral ischemia, severe sinus bradycardia (heart rate <40/min), use of dipyridamole during the last 24 h, severe atherosclerotic lesions of extracranial artery >75%.
  • Acute treatment or treatment for acute diseases
  • Patients receiving steroidal anti-inflammatory drugs, dietary supplements of folic acid, or antioxidant vitamins.
  • Any condition that may prevent the pt to give informed consent , enter the study or bias the results.
  • Participating into other studies

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy controls	Diagnostic test: Echo stress dipyridamole; Echo stress dipyridamole; Other Names: Blood sample
Hypertensive patients	Diagnostic test: Echo stress dipyridamole; Echo stress dipyridamole; Other Names: Blood sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BH2 and BH4 levels (ng/ml) in plasma and platelets	Blood samples will be withdrawn and subsequently analyzed to assess biopterins BH4 and BH2 ng/mL concentration in plasma and platelets Each will be determined separately from the same sample, by high-performance liquid chromatography followed by serial electrochemical and fluorescent detection.	1 week
Coronary Flow Reserve (CFR) Trans Thoracic Doppler Echocardiography	Measurement of coronary flow reserve of the left anterior descending coronary artery will be carried out with transthoracic Doppler Echocardiography (TDE) and dipyridamole stress. CFR will be calculated as the ratio between stress and resting flow velocity (cm/sec)	1 week
Relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels.	Simple regression analysis or logistic regression will be used to test the relationship between CFR and biopterins values in plasma and platelets.	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of cGMP in platelets	Comparison of levels of cGMP in platelets among normals, patients with normal CFR and patients with reduced CFR	1 week

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Collaborators: Servier
• Investigators: Principal Investigator: Paolo G Camici, MD, IRCCS Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2017
• Primary Completion (Actual): May 31, 2019
• Study Completion (Actual): July 10, 2019

Study Registration Dates

• First Submitted: January 25, 2019
• First Submitted That Met QC Criteria: February 13, 2019
• First Posted (Actual): February 15, 2019

Study Record Updates

• Last Update Posted (Actual): July 12, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Phosphodiesterase Inhibitors; Dipyridamole
• Other Study ID Numbers: CFRBH4_IT1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No