Abstract
Background
Patients with angina and coronary microvascular dysfunction, without evidence of structural or epicardial coronary disease (Type I CMVD) remain without evidence based treatment options. Previous work has demonstrated that ranolazine can improve angina frequency and stability among patients with Type 1 CMVD; however, the mechanism remains unclear. Therefore, the objective of this pilot project was to assess the impact of ranolazine on Type I CMVD as measured using an invasive tool to measure global resistance (index of microcirculatory resistance (IMR)).
Methods
Patients with Type 1 CMVD diagnosed using IMR were enrolled and treated with ranolazine 1000 mg BID. Coronary angiography and IMR were performed at baseline and on treatment after four weeks. The primary outcome measure was change in IMR pre- and post-treatment. Secondary outcome measures, improvement in angina and activity level, were assessed using the Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI) and Metabolic equivalent for Task (MET) scores.
Results
A total of 7 patient were enrolled and completed the study. Mean age was 57.6 ± 7.5, 43% were female and 43% were Hispanic. Mean baseline IMR was 37.25 ± 16.27 which decreased to 19.48 ± 5.69 ( p = 0.02; (−48% Δ) after treatment with ranolazine. Four of the five SAQ domains improved on treatment with significant improvement in physical limitation ( p = 0.001), angina frequency ( p = 0.04), angina stability ( p = 0.05) and disease perception ( p = 0.001). Non-significant improvements in activity were also seen in both the DASI and MET scores.
Conclusion
Among patients with Type 1 CMVD, our pilot data suggest favorable changes in IMR, anginal symptoms and activity status with ranolazine treatment. These findings support further evaluation of the effects of ranolazine on microcirculatory function and angina symptoms in a larger cohort of patients with Type 1 CMVD.
Highlights
- •
Coronary microvascular dysfunction (CMVD) occurs in a heterogeneous group of patients. Type I CMVD occurs in the absence of obstructive epicardial coronary artery disease or structural heart disease.
- •
This pilot study explored the use of ranolazine among patients with Type 1 CMVD and assessed the direct impact of ranolazine therapy on microcirculatory resistance.
- •
Index of microcirculatory resistance (IMR) is an invasive tool used to measure global myocardial resistance.
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Among the 7 patients enrolled with an abnormal IMR, treatment with ranolazine for four weeks was associated with an improvement in IMR, measures of angina severity and exercise tolerance.
- •
Based on these data, a larger scale randomized trial would be feasible and important in addressing the need for proven targeted therapies for CMVD.
1
Introduction
Patients presenting with signs and symptoms of myocardial ischemia in the absence of obstructive epicardial coronary artery disease (CAD) represent up to 10% of patients undergoing coronary angiography . This patient population remains incompletely defined and without clear recommendations for further work-up and/or evidence based treatment. A subset of these patients are presumed to have coronary microvascular dysfunction (CMVD) as a cause for the symptoms and clinical presentation .
CMVD occurs in a heterogeneous group of patients which can be subdivided into the following: Type 1: without evidence of structural or epicardial coronary disease; Type 2: with evidence of structural or valvular heart disease; Type 3: In the presence of epicardial CAD; and Type 4: Iatrogenic. . Unlike obstructive epicardial CAD, where the link between ischemia and angiographic coronary anatomy lends a target for revascularization therapy, treatment of the various disorders of the microcirculation is still in evolution. Patients with Type 1 CMVD remain challenging and current management strategies center on symptom relief and risk factor modification . Ranolazine has been shown to improve symptoms of angina and cardiac MRI based perfusion compared to treatment with placebo among patients with Type 1 CMVD and an impaired coronary flow reserve ; however, whether this symptomatic improvement is due to actual improvement in coronary microvascular function remains unknown.
The main goal of this pilot proposal was to study the feasibility of evaluating the impact of ranolazine on CMVD function in a group of patients with Type 1 CMVD using IMR—a novel invasive tool for the specific assessment of the microcirculation.
2
Methods
This was a single center, prospective pilot study assessing the effect of treatment with ranolazine on coronary microvascular dysfunction.Approval was obtained from the institutional research board and all patients provided informed consent prior to enrollment into the study. All patients undergoing diagnostic coronary angiography from 2013 to 2016 were screened for inclusion in the study. Those meeting inclusion/exclusion criteria were enrolled. Demographic data were collected at the time of inclusion and patients completed a baseline Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI) and Metabolic Equivalent for Task (MET) which was repeated at the completion of the study. Once enrolled, patients were started on oral treatment with ranolazine 500 mg BID which was titrated to 1000 mg BID after 7 days. Treatment duration was four weeks and patients were scheduled for a follow-up angiogram with IMR testing at the end of the treatment period.
Inclusion criteria included patients with signs and symptoms of ischemia without flow limiting angiographic CAD (<50% angiographic epicardial coronary stenosis) who underwent invasive testing for coronary microvascular dysfunction using index of microcirculatory resistance (IMR). Patients with IMR > 20 U were considered for enrollment into the trial.
Ischemia was defined as chest pain with 1) dynamic ischemic ECG changes (t wave inversions or >1 mm ST depressions); 2) chest pain with ≥1 mm downsloping or flat ST segment depression during exercise or recovery; 3)≥2 mm ischemic ST depression at a low workload (stage 2 or less or ≤130 beats/min) or early onset (stage 1) or prolonged ST depression duration (>5 min) or multiple leads (>5) with ST depression during exercise treadmill test; and 4) nuclear stress perfusion defect >10% or stress echocardiogram with stress induced wall motion abnormality. Patients were excluded if they were younger than age 18 years, were pregnant or breastfeeding, or had any of the following: flow limiting and/or obstructive epicardial CAD (>50%), life expectancy <6 months, a recent (<1 week) myocardial infarction or positive biomarkers, severe aortic stenosis, contraindications to IMR testing including inability to utilize antithrombotic therapy and/or intravenous adenosine or contraindications to ranolazine therapy.
2.1
Index of microcirculatory resistance (IMR)
IMR is defined as hyperemic distal coronary pressure divided by the inverse of hyperemic mean transit time. IMR is based on the assumption that at peak hyperemia the variability of resting vascular tone and hemodynamics will be eliminated, and the minimum microvascular resistance will be achieved. Studies have correlated IMR value <20 to normal microvascular resistance .
Coronary physiologic indexes are measured in a stenosis free area of the left anterior descending coronary artery when possible, or in the left circumflex artery as a secondary choice. Appropriate coronary guide catheter is used to engage left main coronary artery. After adequate heparinization, a temperature sensor/pressure tipped guideword (Radi pressure wire, St Jude Medical Systems) is advanced through the coronary guide catheter and placed and secured at least 3 cm distal to guide catheter in the coronary artery. Room temperature normal saline (3cm 3 ) is injected into the guide catheter and a baseline mean transit time is obtained using thermodilution. This is repeated three times to obtain an average baseline transit time. Next, intravenous adenosine (140 μg per kilogram of body weight per minute) is infused to induce maximal coronary hyperemia. After 2 min of adenosine infusion, 3 cm 3 of room temp normal saline is injected into the coronary artery and hyperemic transit time is obtained. This is performed at 120, 150 and 180 s after initiation of adenosine and averaged to obtain a mean hyperemic transit time. In addition, simultaneous hyperemic pressure gradient is measured in the proximal and distal vessel. Once data are obtained, the following calculations are made:
2.2
SAQ, DASI and MET
Patient completed the SAQ questionnaire at the time of enrollment and after four weeks of treatment. SAQ assesses physical limitation, angina stability, angina frequency, treatment satisfaction and disease perception. Overall scores for each category were compared before and after treatment. DASI and MET scores were also calculated at baseline and 4 weeks after treatment.
2.3
Statistical methods
Detailed demographic and invasive hemodynamic data were collected in all patients at baseline and after treatment. Continuous variable are reported as mean ± SD and were compared using paired Student t -test. Categorical variables are represented as percentages and were compared using Fishers testing. SAQ score was calculated using the recommended formula and values were compared pre- and post-treatment. Similarly, pre- and post-treatment DASI and METS were compared using paired Student t -test. p Value ≤0.05 was considered statistically significant.
2
Methods
This was a single center, prospective pilot study assessing the effect of treatment with ranolazine on coronary microvascular dysfunction.Approval was obtained from the institutional research board and all patients provided informed consent prior to enrollment into the study. All patients undergoing diagnostic coronary angiography from 2013 to 2016 were screened for inclusion in the study. Those meeting inclusion/exclusion criteria were enrolled. Demographic data were collected at the time of inclusion and patients completed a baseline Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI) and Metabolic Equivalent for Task (MET) which was repeated at the completion of the study. Once enrolled, patients were started on oral treatment with ranolazine 500 mg BID which was titrated to 1000 mg BID after 7 days. Treatment duration was four weeks and patients were scheduled for a follow-up angiogram with IMR testing at the end of the treatment period.
Inclusion criteria included patients with signs and symptoms of ischemia without flow limiting angiographic CAD (<50% angiographic epicardial coronary stenosis) who underwent invasive testing for coronary microvascular dysfunction using index of microcirculatory resistance (IMR). Patients with IMR > 20 U were considered for enrollment into the trial.
Ischemia was defined as chest pain with 1) dynamic ischemic ECG changes (t wave inversions or >1 mm ST depressions); 2) chest pain with ≥1 mm downsloping or flat ST segment depression during exercise or recovery; 3)≥2 mm ischemic ST depression at a low workload (stage 2 or less or ≤130 beats/min) or early onset (stage 1) or prolonged ST depression duration (>5 min) or multiple leads (>5) with ST depression during exercise treadmill test; and 4) nuclear stress perfusion defect >10% or stress echocardiogram with stress induced wall motion abnormality. Patients were excluded if they were younger than age 18 years, were pregnant or breastfeeding, or had any of the following: flow limiting and/or obstructive epicardial CAD (>50%), life expectancy <6 months, a recent (<1 week) myocardial infarction or positive biomarkers, severe aortic stenosis, contraindications to IMR testing including inability to utilize antithrombotic therapy and/or intravenous adenosine or contraindications to ranolazine therapy.
2.1
Index of microcirculatory resistance (IMR)
IMR is defined as hyperemic distal coronary pressure divided by the inverse of hyperemic mean transit time. IMR is based on the assumption that at peak hyperemia the variability of resting vascular tone and hemodynamics will be eliminated, and the minimum microvascular resistance will be achieved. Studies have correlated IMR value <20 to normal microvascular resistance .
Coronary physiologic indexes are measured in a stenosis free area of the left anterior descending coronary artery when possible, or in the left circumflex artery as a secondary choice. Appropriate coronary guide catheter is used to engage left main coronary artery. After adequate heparinization, a temperature sensor/pressure tipped guideword (Radi pressure wire, St Jude Medical Systems) is advanced through the coronary guide catheter and placed and secured at least 3 cm distal to guide catheter in the coronary artery. Room temperature normal saline (3cm 3 ) is injected into the guide catheter and a baseline mean transit time is obtained using thermodilution. This is repeated three times to obtain an average baseline transit time. Next, intravenous adenosine (140 μg per kilogram of body weight per minute) is infused to induce maximal coronary hyperemia. After 2 min of adenosine infusion, 3 cm 3 of room temp normal saline is injected into the coronary artery and hyperemic transit time is obtained. This is performed at 120, 150 and 180 s after initiation of adenosine and averaged to obtain a mean hyperemic transit time. In addition, simultaneous hyperemic pressure gradient is measured in the proximal and distal vessel. Once data are obtained, the following calculations are made:
2.2
SAQ, DASI and MET
Patient completed the SAQ questionnaire at the time of enrollment and after four weeks of treatment. SAQ assesses physical limitation, angina stability, angina frequency, treatment satisfaction and disease perception. Overall scores for each category were compared before and after treatment. DASI and MET scores were also calculated at baseline and 4 weeks after treatment.
2.3
Statistical methods
Detailed demographic and invasive hemodynamic data were collected in all patients at baseline and after treatment. Continuous variable are reported as mean ± SD and were compared using paired Student t -test. Categorical variables are represented as percentages and were compared using Fishers testing. SAQ score was calculated using the recommended formula and values were compared pre- and post-treatment. Similarly, pre- and post-treatment DASI and METS were compared using paired Student t -test. p Value ≤0.05 was considered statistically significant.
3
Results
A total of 7 patients were enrolled. Baseline demographics are shown in Table 1 . Overall, study population consisted of more men and Caucasians. Majority had a history of hypertension and or dyslipidemia.
| N = 7 | |
|---|---|
| Female sex (%) | 43 |
| Age | 57.6 ± 11.25 |
| BMI | 31.4 ± 10.23 |
| Race (%) | |
| Caucasian | 57 |
| Hispanic | 43 |
| Cardiac risk factors | |
| Hypertension (%) | 71 |
| Dyslipidemia (%) | 57 |
| Positive family history (%) | 14 |
| Diabetes mellitus (%) | 14 |
| Lipids | |
| LDL | 72.5 ± 14.4 |
| HDL | 35.3 ± 10.1 |
| Triglycerides | 287.3 ± 110.5 |
| Cath data | Pre | Post |
|---|---|---|
| Access | ||
| Radial artery | 7 | 6 |
| Femoral artery | 0 | 1 |
| Coronary artery disease | ||
| Mild luminal irregularities (<30%) | 6 | 6 |
| Non-obstructive (30–50%) | 1 | 1 |
| Vessel studied | ||
| LAD | 7 | 7 |
| LCX | 0 | 0 |
| RCA | 0 | 0 |
| Total contrast (ml) | 67 ± 25 | 29.3 ± 11.7 |
| Fluoroscopy time | 6.44 ± 2.92 | 4.92 ± 1.90 |
| Complications (%) | 0 | 0 |
Invasive hemodynamic data for each patient are shown in Tables 2A and 2B . On an individual patient level, each patient had a numeric improvement in IMR. Comparison of baseline and post treatment hemodynamics is shown in Table 3 . Baseline mean IMR was 37.25 ± 16.27. After treatment, a numerical, non-statistically significant improvement in hyperemic transit time and a statistically significant improvement in hyperemic distal pressure was observed. This resulted in significant improvement in IMR compared to baseline (−48% Δ). There was no significant difference in left ventricular filling pressures after treatment. There was a numerical improvement in CFR which did not reach statistical significance. Mean FFR was lower in patients post treatment however given the angiographic absence of obstructive epicardial CAD this change was most likely secondary to lower hyperemic pressures. SAQ scores before and after treatment are shown in Fig. 1 . There was statistically significant improvement in 4 out of 5 categories of the questionnaire. Fig. 2 shows change in DASI and MET scores from baseline to post-treatment.
| Baseline | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline transit time | Hyperemic transit time | ||||||||||
| #1 | #2 | #3 | Mean | #1 | #2 | #3 | Mean | FFR | CFR | IMR | |
| Pt 1 | 1.54 | 1.48 | 1.59 | 1.54 | 0.37 | 0.49 | 0.36 | 0.41 | 0.92 | 3.8 | 34.4 |
| Pt 2 | 1.56 | 1.51 | 1.30 | 1.46 | 0.62 | 0.61 | 0.64 | 0.62 | 0.89 | 2.3 | 27.3 |
| Pt 3 | 1.88 | 1.68 | 1.69 | 1.75 | 0.36 | 0.35 | 0.34 | 0.35 | 0.95 | 4.9 | 26.3 |
| Pt 4 | 2.49 | 2.48 | 2.48 | 2.49 | 0.47 | 0.58 | 0.61 | 0.55 | 0.84 | 4.5 | 26.9 |
| Pt 5 | 1.22 | 1.25 | 1.28 | 1.25 | 0.17 | 0.23 | 0.26 | 0.22 | 0.96 | 5.7 | 25.1 |
| Pt 6 | 1.74 | 1.79 | 1.61 | 1.71 | 0.97 | 0.92 | 0.83 | 0.91 | 0.93 | 1.9 | 64.6 |
| Pt 7 | 1.67 | 1.70 | 1.81 | 1.73 | 0.74 | 0.72 | 0.87 | 0.78 | 0.85 | 2.2 | 56.2 |
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