The present study protocol proposes a novel cGMP Enhancing Therapeutic Strategy (cGETS) to 1) enhance plasma levels of cGMP, 2) to increase cGMP-related control of the myocardial response to low dose dobutamine stress testing, 3) to improve…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Hemodynamics during low dose dobutamine stress testing
2) Extent of diastolic dysfunction determined by echocardiography
3) Magitude of LV hypertrophy
Secondary outcome
1) Plasma levels of cGMP
Background summary
Most trials testing modern heart failure therapy in patients with heart failure
and preserved ejection fraction (HFpEF) had a neutral outcome in contrast to
the positive outcome observed with similar pharmacotherapy in patients with
heart failure and reduced ejection fraction (HFrEF). The main reason for this
discrepancy is failure of modern heart failure therapy to sufficiently address
pathophysiological mechanisms driving left ventricular (LV) remodeling in
HFpEF. LV remodeling substantially differs between HFpEF and HFrEF. In HFpEF,
the left ventricle is concentrically remodeled with normal LV cavity size,
increased wall thickness and increased LV mass/volume ratio whereas in HFrEF,
the left ventricle is eccentrically remodeled with LV dilatation, normal or
decreased wall thickness and low LV mass/volume ratio. Similar findings are
also observed at the microscopic and ultrastructural level with enlarged, stiff
cardiomyocytes in HFpEF and small, more compliant cardiomyocytes in HFrEF.
A recent study identified important differences of myocardial cyclic guanosine
monophosphate (cGMP) - protein kinase G (PKG) signaling between HFpEF and HFrEF
phenotypes. In HFpEF patients, myocardial PKG activity and cGMP level were
respectively two and eight times lower than in HFrEF patients. The lack of cGMP
in HFpEF resulted from high nitrosative/oxidative stress and low natriuretic
peptide level respectively related to obesity and low LV wall stress because of
concentric LV remodeling. Low myocardial PKG activity had previously been shown
to favour maladaptive concentric LV remodeling and to increase cardiomyocyte
stiffness. Furthermore, the increased stiffness of HFpEF cardiomyocytes was
corrected in-vitro by administration of PKG.
Study objective
The present study protocol proposes a novel cGMP Enhancing Therapeutic Strategy
(cGETS) to 1) enhance plasma levels of cGMP, 2) to increase cGMP-related
control of the myocardial response to low dose dobutamine stress testing, 3) to
improve diastolic LV dysfunction, 4) to regress myocardial hypertrophy and 5)
to improve symptoms in HFpEF patients. cGETS intends to raise myocardial cGMP
level through concerted upregulation of cGMP production by soluble (s) and
particulate (p) guanylate cyclase (sGC and pGC respectively) and downregulation
of cGMP breakdown by phospodiesterase 5A (PDE5A).
Study design
Upregulation of cGMP production in HFpEF patients will be achieved through
simultaneous administration of angiotensin converting enzyme inhibitors (ACEi)
and statins. In case patients concomitantly suffer of type 2 diabetes mellitus,
which is either untreated or solely treated with metformin, sitagliptin is also
started. Downregulation of cGMP breakdown will be achieved through
administration of the PDE5A inhibitor sildenafil. Through concerted
upregulation of cGMP production and downregulation of cGMP breakdown, cGETS
hopes to substantially raise myocardial cGMP level, which is eight times lower
in HFpEF. This is expected to result in a modified myocardial response to low
dose dobutamine stress testing, in less diastolic LV dysfunction through
destiffening of cardiomyocytes, in regression of hypertrophy and in improvement
of exercise tolerance.
Intervention
HFpEF patients will be recruited from out-patient clinics. The diagnosis of
HFpEF will be established in accordance to the recommendations of the European
Society of Cardiology. Patients have to be overweight or obese (BMI >25 kg/m2)
with evidence of systemic (RR > 140/90 mmHg or use of antihypertensive
medications) and pulmonary hypertension (pulmonary artery systolic pressure
(PASP) > 35 mmHg), clinically justifying the combined treatment strategy in
cGETS. The echocardiogram used to establish the diagnosis of HFpEF will be
regarded as the recruitment visit echocardiogram (recruitment visit
echocardiography). Included patients will be started on ACEi/sartan or will
drugs dosages be optimized in patients already treated with ACEi/sartan.
Patients not yet receiving ACEi will be started on 4 mg perindopril daily.
Patients already using 4 mg perindopril will be uptitrated to 8 mg perindopril.
Patients using lisinopril will be uptitrated to 40 mg (SID) if tolerated.
Patients using ramipril will be uptitrated to 10 mg (SID). Patients using
enalapril or captopril will be switched to perindopril because of the more
convenient dosage schedule of perindopril (SID) compared to enalapril (BID) or
captopril (TID). Patients who cannot tolerate an ACEi will be treated with
candesartan.
At baseline, an echocardiogram will be performed. Additional baseline
investigations (blood sampling, low dose dobutamine stress testing and cardiac
MRI) will also be performed. In addition, hemodynamic measurements obtained
with a Nexfin device will be recorded during the echocardiography. During this
baseline visit, the patient will receive a single, oral dose of sildenafil
(100mg) as a safety control of drug tolerance. 1 hour after intake, the
echocardiography will be repeated to observe potential differences in diastolic
function.
In addition to ACEi or ARB treatment, the cyclic GMP enhancing strategy will
consist of the following interventions:
1) Initiation or uptitration of statin therapy: Patients not yet on statin
therapy will be started on atorvastatine 40 mg (SID). Patients on rosuvastatine
will be uptitrated to a dose of 20 mg. Patients on simvastatine will be
uptitrated to 80 mg. Pravastatine will be switched to atorvastatine 40 mg.
2) Initiation of sitagliptin in case of untreated DMII or DMII solely treated
with metformin. Sitagliptin eligible patients will be treated with sitagliptin
100 mg once daily.
After a month, during the second visit, the non-invasive imagaging and blood
sample are repeated and the patient again will receive a single, oral dose of
100mg of sildenafil as a safety control of drug tolerance. After 1 hour, the
echocardiography is repeated. If sildenafil improves diastolic distensibility
at the second challenge and the drug is well tolerated, the patient enters the
chronic treatment phase of the study, which will take 1 month and consists of
additional treatment with sildenafil 3x50mg/day. After this phase, the
aforementioned procedureds will be repeated.
Study burden and risks
The nature and extent of the burden and risk are limited and related to the
non-invasive nature of investigations. There is a small risk of a local
hematoma after venapuncture. During low-dose stress echocardiography, no
harmful effects of dobutamine are expected.
The cyclic GMP enhancing therapies can have side-effects, of which the most
common are:
- Sildenafil (1-10% of patients): headache, hypotension, blushing, dizziness,
nausea, palpitations.
- Atorvastatine (1-10%): headache, muscular of articular pain, nausea,
obstipation, diarrea, dyspepsia.
- Sitagliptine (1-10%): hypoglycaemia, nausea.
Van der Boechorststraat 7
Amsterdam 1081 BT
NL
Van der Boechorststraat 7
Amsterdam 1081 BT
NL
Listed location countries
Age
Inclusion criteria
HFpEF patients over 18 years old and concomitant arterial hypertension, overweight or obesity and pulmonary hypertension will be recruited from the outpatient clinic.
Exclusion criteria
* A history of acute coronary syndrome, coronary revascularization, evidence of reversible ischaemia or stroke within the previous 6 months.;* Valvular disease (more than moderate mitral or aortic regurgitation or greater than mild aortic or mitral stenosis).;* Hypertrophic, or infiltrative or inflammatory myocardial disease (e.g., amyloid, sarcoid).;* Pericardial disease, cor pulmonale or primary pulmonary arteriopathy.;* Use of nitrates or anticipated future need for nitrate therapy.;* Previous statin-induced myopathy or hypersensitivity reaction to statins or PDE5 inhibitors.;* Neuromuscular, orthopedic, or other non-cardiac condition that prevents the individual from exercise testing on a bicycle ergometer or from walking in a hallway.;* Non-cardiac condition that limits life expectancy to less than 1 year at the time of study entry, based on the judgment of the physician.;* History of reduced ejection fraction (less than 50%).;* Implanted metallic device that will interfere with MRI examination (in people without atrial fibrillation).;* Severe kidney dysfunction (estimated glomerular filtration rate [GFR] less than 20 ml/min/1.73m2 by modified modification of diet in renal disease [MDRD] equation).;* Pregnant or not using an effective form of contraception.;* Hemoglobin level of less than 10 g/dL (=6.2 mmol/l).;* Taking alpha antagonists or cytochrome P450 3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, saquinavir, cimetidine, or serum protease inhibitors for HIV).;* Retinitis pigmentosa, previous diagnosis of nonischemic optic neuropathy, untreated proliferative retinopathy, or unexplained visual disturbance.;* Sickle cell anemia, multiple myeloma, leukemia, or penile deformities that increase the risk for priapism (e.g., angulation, cavernosal fibrosis, Peyronie's disease).;* Severe liver disease (aspartate aminotransferase [AST] level greater than three times the normal limit, alkaline phosphatase or bilirubin greater than two times the normal limit).;* In being consistent with American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, people with dyspnea and risk factors for coronary artery disease should have had a stress test and those people with a clinically indicated stress test demonstrating significant ischemia in the 1 year before study entry will be excluded.;* Previous or planned heart transplantation.;* Chronic muscle disease or an unexplained creatine kinase level of more than 2.5 times of the normal range.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002877-71-NL |
| CCMO | NL40842.029.12 |