Coronary Microvascular Dysfunction, Metabolic Syndrome
Conditions
Keywords
Cardiac Magnetic Resonance Imaging
Brief summary
Coronary vascular dysfunction is one of the "final common pathways" for the impact of multiple cardiovascular risk factors. The investigators will conduct a randomized, double-blind placebo-controlled study in individuals with the metabolic syndrome and baseline coronary vascular dysfunction to evaluate the impact of vericiguat, a stimulator of soluble guanylyl cyclase, on coronary vascular function using non-invasive cardiac magnetic resonance imaging.
Detailed description
Despite advances in medical therapy for the prevention of coronary artery disease, such as the treatments for high blood pressure and elevated cholesterol, several hundred thousand Americans continue to experience heart attacks every year. This may be related to risk factors which are not now identified and therefore treated. Endothelial dysfunction indexes the adverse impact of multiple risk factors and thus provides the opportunity to evaluate the benefit of an intervention which may improve function. Forty-five participants with metabolic syndrome and coronary vascular dysfunction will be randomized in a 2:1 ratio to receive vericiguat or placebo. Following randomization, the participants will undergo a study drug titration phase as follows: Initial 2.5 mg/day for two weeks, then 5 mg/day for two weeks, and then 10 mg/day for two weeks. This titration protocol is the one stated in the FDA package insert for vericiguat. The vericiguat formulary will be an FDA approved version obtained by the Johns Hopkins Medical Institutions Pharmacy from Merck (manufacturer of vericiguat) and will be maintained by the Johns Hopkins Investigational Drug Service until it is administered. Cardiac MRI with isometric handgrip exercise, as well as echocardiography and blood studies will be used to assess coronary vascular and cardiac function and biomarkers indicative of nitric oxide pathways and factors impacting that pathway. The same procedures will be repeated at the end of the 6-10 week study drug administration period with an identical protocol, with special attention taken on the MRI to interrogate the same coronary segments as those studied at baseline.
Interventions
DRUGVericiguat
Up-titration will be performed as guided by the evaluation of blood pressure and clinical symptoms
DRUGPlacebo
Administered the same way
Sponsors
Johns Hopkins University
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Double-blind, placebo controlled trial
Eligibility
Sex/Gender
ALL
Age
35 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age range 35-85 years * Presence of the metabolic syndrome defined by the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) definition, with at least three of the following five criteria: * waist circumference \> 40 inches (men) or \>35 inches (women) * blood pressure \>130/80 mmHg * fasting triglyceride (TG) level \>150 mg/dL * fasting high-density lipoprotein (HDL) cholesterol level \<40mg/dL in men or \<50mg/dL in women * Fasting blood glucose \>100 mg/dL, or hemoglobin A1c greater or equal to 5.7% * Either one of the following: * Men ≤ 40 or women ≤ 50 years of age with no history or symptoms of ischemic heart disease, or * Men \>40 or women \>50 years of age with either one of the following * a coronary angiography within the past 24 months showing no significant coronary artery disease in a t least one major vessel, defined as \>50% stenosis of the left main coronary artery and/or \>70% stenosis of another major coronary vessel, or * a coronary artery calcium score obtained within the prior 24 months or if no prior calcium scan, one performed as a research study following consent with a Agatston score \<10 in at least one major coronary vessel. * IHE-induced %-change in coronary flow ≤13%
Exclusion criteria
* Systolic blood pressure \<110 mm Hg * Current or anticipated use of long-acting nitrates, soluble guanylate cyclase (sGC) stimulators, or phosphodiesterase type 5 (PDE5) inhibitors * Hematocrit \<30% * Unable to understand the risks, benefits, and alternatives of participation so as to provide informed consent * Women who are pregnant. * Women with reproductive capacity not using an acceptable form of contraception * History of claustrophobia * Inability to lie flat and still for 45 minutes * Presence of non-magnetic resonance (MR)-compatible objects or devices, such as intra-orbital debris, intra-auricular implants, intra-cranial clips, an implanted defibrillator or a pacemaker * History as a machinist, welder, metal worker or a similar activity that poses the risk of metal exposure to the eyes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Coronary Cross-sectional Area (in mm²) Within the Vericiguat Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The difference in absolute change in coronary cross-sectional area (in mm²) from rest to isometric handgrip exercise (IHE) in the group randomized to vericiguat from that measured at baseline, prior to the initiation of vericiguat, to that measured at the end of the study drug administration period, six weeks following initiation of the titrated dose, as assessed by MRI. |
| Relative Change in Coronary Cross-sectional Area (as Percentage) Within the Vericiguat Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The difference in relative change in coronary cross-sectional area (in %) from rest to isometric handgrip exercise (IHE) in the group randomized to vericiguat from that measured at baseline prior to the initiation of vericiguat, to that measured at the end of the study drug administration period, six weeks following initiation of the titrated dose, as assessed by MRI. |
| Absolute Change in Coronary Cross-sectional Area (in mm²) Between the Vericiguat Group and the Placebo Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The difference in absolute change in coronary cross-sectional area (in mm²) from rest to isometric handgrip exercise (IHE) as assessed by MRI. |
| Difference in Percent Change in Coronary Cross-sectional Area (as Percentage) Between the Vericiguat Group and the Placebo Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The difference in percentage change in coronary cross-sectional area (%) from rest to isometric handgrip exercise (IHE) between the vericiguat and placebo groups, as assessed from the baseline MRI to the follow-up MRI, six weeks following initiation of the titrated dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Interleukin 1 (IL-1) Measured Using Blood Samples (in pg/mL) | Baseline and 6 weeks following initiation of up-titrated dose | IL-1 (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. |
| Changes in Interleukin 6 (IL-6) Measured Using Blood Samples (in pg/mL) | Baseline and 6 weeks following initiation of up-titrated dose | IL-6 (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. |
| Changes in Interleukin 10 (IL-10) Measured Using Blood Samples (in pg/mL) | Baseline and 6 weeks following initiation of up-titrated dose | IL-10 (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. |
| Changes in Tumor Necrosis Factor (TNF)-Alpha Measured Using Blood Samples (in pg/mL) | Baseline and 6 weeks following initiation of up-titrated dose | TNF-alpha (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. |
| Changes in High Sensitivity C-Reactive Protein (hsCRP) Measured Using Blood Samples (in mg/L) | Baseline and 6 weeks following initiation of up-titrated dose | hsCRP (in mg/L), an inflammatory marker, will be measured in blood samples to assess changes from baseline. |
| Changes in Cyclic Guanosine Monophosphate (cGMP) Measured Using Blood Samples (in Pmol/mL) | Baseline and 6 weeks following initiation of up-titrated dose | cGMP (in pmol/mL), a mediator in the nitric oxide pathway, will be measured in blood samples to assess changes from baseline. |
| Changes in Left Ventricular Ejection Fraction (as Percentage) as Assessed by Echocardiography | Baseline and 6 weeks following initiation of up-titrated dose | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on left ventricular ejection fraction (%). |
| Changes in e' Velocities (in cm/s) as Assessed by Echocardiography | Baseline and 6 weeks following initiation of up-titrated dose | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on e' velocities (in cm/s). |
| Changes in E/e' Ratio as Assessed by Echocardiography | Baseline and 6 weeks following initiation of up-titrated dose | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on the E/e' ratio. |
| Changes in Left Atrium Volume Index (in mL/BSA) as Assessed by Echocardiography | Baseline and 6 weeks following initiation of up-titrated dose | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on the left atrium volume index (in mL/BSA). |
| Changes in Peak Tricuspid Regurgitation (TR) Velocity (in m/s) as Assessed by Echocardiography | Baseline and 6 weeks following initiation of up-titrated dose | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on peak TR velocity (in m/s). |
| Changes in Strain (as Percentage) as Assessed by Echocardiography | Baseline and 6 weeks following initiation of up-titrated dose | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on strain (as percentage). |
| Absolute Change in Coronary Flow (in mL/Min) Within the Vericiguat Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The absolute changes in coronary flow (in mL/min) with isometric handgrip exercise (IHE) in the group randomized to vericiguat from that measured at baseline, prior to the initiation of vericiguat, to that measured at the end of the study drug administration period as assessed by MRI. |
| Relative Change in Coronary Flow (as Percentage) Within the Vericiguat Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The relative changes in coronary flow (as percentage) with isometric handgrip exercise (IHE) in the group randomized to vericiguat from that measured at baseline, prior to the initiation of vericiguat, to that measured at the end of the study drug administration period as assessed by MRI. |
| Absolute Change in Coronary Flow (in mL/Min) Between the Vericiguat Group and the Placebo Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The absolute changes in coronary flow (in mL/min) with isometric handgrip exercise (IHE) in the vericiguat group as compared to the placebo group as assessed by MRI. |
| Relative Change in Coronary Flow (as Percentage) Between the Vericiguat Group and the Placebo Group as Assessed by Magnetic Resonance Imaging (MRI) | Baseline and 6 weeks following initiation of up-titrated dose | The relative changes in in coronary flow (as percentage) with isometric handgrip exercise (IHE) in the vericiguat group as compared to the placebo group as assessed by MRI. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORThorsten M Leucker, M.D., Ph.D.
Johns Hopkins University
Participant flow
Pre-assignment details
A total of 45 participants were enrolled (provided written informed consent) and underwent screening MRI. 11 participants were excluded from the study before assignment to veiciguat or placebo: six had normal coronary endothelial function, image quality was poor in two, one experienced claustrophobia, one withdrew and one was lost to follow-up. 34 participants were subsequently randomized.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 11 |
| other Total, other adverse events | 11 / 23 | 9 / 11 |
| serious Total, serious adverse events | 0 / 23 | 0 / 11 |
Outcome results
None listed