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Puja K Mehta - One of the best experts on this subject based on the ideXlab platform.

  • left ventricular circumferential strain and Coronary Microvascular Dysfunction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd project
    International Journal of Cardiology, 2021
    Co-Authors: Balaji Tamarappoo, Puja K Mehta, Janet Wei, Louise Thomson, Jake T Samuel, Omeed Elboudwarej, Haider Aldiwani, Susan Cheng, Behzad Sharif, Ahmed Albadri
    Abstract:

    Abstract Aims Women with ischemia but no obstructive Coronary artery disease (INOCA) often have Coronary Microvascular Dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical Dysfunction. Methods and results Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) Conclusion The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical Dysfunction in CMD.

  • n terminal pro b type natriuretic peptide and Coronary Microvascular Dysfunction in women with preserved ejection fraction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd study
    PLOS ONE, 2020
    Co-Authors: Erika Jones, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Carl J Pepine, Michael D Nelson, Behzad Sharif, May Bakir, Eileen M Handberg
    Abstract:

    Author(s): Jones, Erika; Wei, Janet; Nelson, Michael D; Bakir, May; Mehta, Puja K; Shufelt, Chrisandra; Minissian, Margo; Sharif, Behzad; Pepine, Carl J; Handberg, Eileen; Cook-Wiens, Galen; Sopko, George; Bairey Merz, C Noel | Abstract: BackgroundWomen with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive Coronary artery disease (CAD), often have Coronary Microvascular Dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population.MethodsWe evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive Coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables.ResultsOverall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = l0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively).ConclusionAmong women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional Coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF.

  • adenosine vs regadenoson pharmacologic stress differs in women with suspected Coronary Microvascular Dysfunction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd study
    Cardiovascular Disorder and Medicine, 2019
    Co-Authors: Puja K Mehta, Chrisandra Shufelt, Eileen M Handberg, Daniel S Berman, Noel Bairey C Merz, Carl J Pepine, Andre Rogatko, Galen Cookwiens, Behzad Sharif, George Sopko
    Abstract:

    Background: Stress cardiac magnetic resonance (CMR) imaging with myocardial perfusion reserve index (MPRI) measurement has emerged as a noninvasive method for assessing Coronary Microvascular Dysfunction (CMD) in the absence of obstructive Coronary artery disease (CAD). Pharmacologic stress with adenosine or regadenoson is typically used with comparable Coronary vasodilation, but higher unadjusted MPRI has been reported with regadenoson in healthy men. This difference has not been assessed in symptomatic or healthy women. Methods: In a prospective cohort study, 139 symptomatic women with suspected CMD and no obstructive CAD underwent stress CMR and invasive Coronary flow reserve (CFR) testing. Adenosine was the default vasodilator (n=99), while regadenoson was used if history of asthma or prior adenosine intolerance (n=40). Stress CMR was also performed in 40 age-matched healthy controls using adenosine (n=20) and regadenoson (n=20). Unpaired t-tests and analysis of covariance were performed to compare MPRI with adenosine and regadenoson in the symptomatic women and healthy controls. Results: Compared to regadenoson cases, adenosine cases had lower invasive CFR (2.64±0.62 vs 2.94±0.68, p=0.01) and pharmacologic heart rate change (28±16 vs 38±15 bpm, p=0.0008). Unadjusted MPRI was lower in the adenosine compared to regadenoson cases (1.73±0.38 vs 2.27±0.59, p<0.0001). When adjusted for heart rate, rate-pressure-product, and invasive CFR, MPRI remained lower in the adenosine cases (p<0.0001). Invasive CFR to adenosine correlated with adenosine MPRI (r 0.17, p=0.02) but not regadenoson MPRI (r -0.14, p=0.19). There was no significant difference in MPRI in the controls who received adenosine vs regadenoson (2.27±0.33 vs 2.38±0.44, p=0.36). Conclusion: In women undergoing stress CMR for suspected CMD, those who received adenosine had lower MPRI than those who received regadenoson. However, there were no differences in MPRI in the healthy controls. These findings suggest there may be physiologic differences in adenosine and regadenoson response in the Coronary microcirculation of symptomatic women.

  • daily activity measured with wearable technology as a novel measurement of treatment effect in patients with Coronary Microvascular Dysfunction substudy of a randomized controlled crossover trial
    JMIR Research Protocols, 2017
    Co-Authors: Kade Birkeland, Raj M Khandwalla, Ilan Kedan, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Eileen M Handberg, Louise Thomson, Daniel S Berman
    Abstract:

    Background: Digital wearable devices provide a “real-world” assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and Coronary Microvascular Dysfunction (CMD) with no obstructive Coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO) [JMIR Res Protoc 2017;6(12):e255]

  • daily activity measured with wearable technology as a novel measurement of treatment effect in patients with Coronary Microvascular Dysfunction substudy of a randomized controlled crossover trial
    JMIR Research Protocols, 2017
    Co-Authors: Kade Birkeland, Raj M Khandwalla, Ilan Kedan, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Eileen M Handberg, Louise Thomson, Daniel S Berman
    Abstract:

    Background: Digital wearable devices provide a “real-world” assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and Coronary Microvascular Dysfunction (CMD) with no obstructive Coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO)

Janet Wei - One of the best experts on this subject based on the ideXlab platform.

  • association of Coronary Microvascular Dysfunction and cardiac bridge integrator 1 a cardiomyocyte Dysfunction biomarker
    Clinical Cardiology, 2021
    Co-Authors: Christine Pacheco, Chrisandra Shufelt, Janet Wei, Eileen M Handberg, John W Petersen, Carl J Pepine, Tara C Hitzeman, Galen Cookwiens, David R Anderson, Tingting Hong
    Abstract:

    BACKGROUND Coronary Microvascular Dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described. HYPOTHESIS We hypothesized that CMD in women with suspected ischemia with no obstructive Coronary artery disease (INOCA) is associated with cardiomyocyte Dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1). METHODS Women with suspected INOCA undergoing Coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in Coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule Dysfunction. RESULTS INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = -0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001). CONCLUSIONS CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.

  • left ventricular circumferential strain and Coronary Microvascular Dysfunction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd project
    International Journal of Cardiology, 2021
    Co-Authors: Balaji Tamarappoo, Puja K Mehta, Janet Wei, Louise Thomson, Jake T Samuel, Omeed Elboudwarej, Haider Aldiwani, Susan Cheng, Behzad Sharif, Ahmed Albadri
    Abstract:

    Abstract Aims Women with ischemia but no obstructive Coronary artery disease (INOCA) often have Coronary Microvascular Dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical Dysfunction. Methods and results Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) Conclusion The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical Dysfunction in CMD.

  • n terminal pro b type natriuretic peptide and Coronary Microvascular Dysfunction in women with preserved ejection fraction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd study
    PLOS ONE, 2020
    Co-Authors: Erika Jones, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Carl J Pepine, Michael D Nelson, Behzad Sharif, May Bakir, Eileen M Handberg
    Abstract:

    Author(s): Jones, Erika; Wei, Janet; Nelson, Michael D; Bakir, May; Mehta, Puja K; Shufelt, Chrisandra; Minissian, Margo; Sharif, Behzad; Pepine, Carl J; Handberg, Eileen; Cook-Wiens, Galen; Sopko, George; Bairey Merz, C Noel | Abstract: BackgroundWomen with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive Coronary artery disease (CAD), often have Coronary Microvascular Dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population.MethodsWe evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive Coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables.ResultsOverall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = l0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively).ConclusionAmong women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional Coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF.

  • five year follow up of Coronary Microvascular Dysfunction and Coronary artery disease in systemic lupus erythematosus results from a community based lupus cohort
    Arthritis Care and Research, 2020
    Co-Authors: Vaneet K Sandhu, Janet Wei, Louise Thomson, Daniel S Berman, Noel Bairey C Merz, Jay N Schapira, Daniel J Wallace, Michael H Weisman, Mariko L Ishimori
    Abstract:

    Objective The present study was undertaken to investigate prospective change in the prevalence of Coronary Microvascular Dysfunction (CMD) and obstructive Coronary artery disease (CAD) in a cohort of subjects with systemic lupus erythematosus (SLE) initially evaluated for anginal chest pain (CP). Prior work documented a relatively high prevalence of CMD in the absence of obstructive CAD in subjects with SLE. Methods Twenty female SLE subjects with CP who underwent stress cardiac magnetic resonance imaging (CMRI) and Coronary computed tomography angiography at baseline were reevaluated at 5 years. Results Seventeen subjects (85%) were available and reenrolled, of which 11 (65%) had persistent CP at follow-up. Fourteen subjects had complete follow-up CMRI, of which 36% (n = 5) demonstrated CMD at follow-up. Further, 25% (1 of 4) of the originally abnormal myocardial perfusion reserve index (MPRI) findings at baseline were lower at follow-up, while 2 additional abnormal MPRI findings at follow-up were noted in previously normal MPRI results. The prevalence of CMD and nonobstructive/obstructive CAD both was unchanged between baseline and follow-up, respectively (both P values not significant). During follow-up, 33% of subjects (5 of 15) had adverse cardiac outcomes, including pericarditis, unstable angina, or intracranial aneurysm clipping procedure. Conclusion At the 5-year follow-up of SLE subjects with CP who were evaluated at baseline and follow-up, a majority had persistent CP, and nearly one-half had similar or worse myocardial perfusion consistent with CMD without obstructive CAD. These findings propose an alternative explanation for CP in SLE subjects compared to the more common SLE-related accelerated obstructive CAD accounting for CP and adverse outcomes. These findings support further studies of CMD as an etiology for cardiac morbidity and mortality in SLE.

  • ambulatory and silent myocardial ischemia in women with Coronary Microvascular Dysfunction results from the cardiac autonomic nervous system study cans
    International Journal of Cardiology, 2020
    Co-Authors: Rajasree Roy, Chrisandra Shufelt, Margo Minissian, Janet Wei, Michael D Nelson, Haider Aldiwani, Navid Darouian, Shilpa Sharma, Tina Torbati, Noel Bairey C Merz
    Abstract:

    Abstract Background Up to two-thirds of patients with obstructive Coronary artery disease (CAD) have silent ischemia (SI), which predicts an adverse prognosis and can be a treatment target in obstructive CAD. Over 50% of women with ischemia and no obstructive CAD have Coronary Microvascular Dysfunction (CMD), which is associated with adverse cardiovascular outcomes. We aimed to investigate the prevalence of SI in CMD in order to consider it as a potential treatment target. Methods 36 women with CMD by Coronary reactivity testing and 16 age matched reference subjects underwent 24-h 12-lead ambulatory ECG monitoring (Mortara Instruments) after anti-ischemia medication withdrawal. Ambulatory ECG recordings were reviewed by two-physician consensus masked to subject status for SI measured by evidence of ≥1 minute horizontal or downsloping ST segment depression ≥1.0 mm, measured 80 ms from the J point. Results Demographics, resting heart rate, and systolic blood pressure were similar between CMD and reference subjects. Thirty-nine percent of CMD women had a total of 26 SI episodes vs. 0 episodes in the reference group (p = 0.002). Among these women 13/14 (93%) had SI, and few episodes (3/26, 12%) were symptomatic. Mean HR at the onset of SI was 96 ± 13 bpm and increased to 117 ± 16 bpm during the ischemic episodes. 87% reported symptoms that were not associated with ST depressions. Conclusions Ambulatory ischemia is prevalent in women with CMD, with a majority being SI, while most reported symptoms were not accompanied by ambulatory ischemia. Clinical trials evaluating anti-ischemic medications should be considered in the CMD population.

Noel Bairey C Merz - One of the best experts on this subject based on the ideXlab platform.

  • specialized proresolving mediators in symptomatic women with Coronary Microvascular Dysfunction from the women s ischemia trial to reduce events in nonobstructive cad warrior trial
    American Journal of Cardiology, 2021
    Co-Authors: Ellen C Keeley, Eileen M Handberg, Noel Bairey C Merz, Christopher R Cogle, Carl J Pepine
    Abstract:

    Resolvins and maresins, members of the specialized proresolving mediator (SPM) family, are omega-3 fatty acid-derived lipid mediators that attenuate inflammation. We hypothesized that they play a role in the pathophysiology of Coronary Microvascular Dysfunction (CMD) in women with ischemia and no obstructive Coronary disease. In a pilot study, we measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid, eicosapentaenoic acid (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid by mass spectrometry in the peripheral blood of 31 women enrolled in the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial who had confirmed CMD assessed by Coronary flow reserve. We compared SPM levels with 12 gender and age-matched reference subjects. Compared with the reference subject group, those with CMD had significantly lower plasma concentrations of resolvin D1 and maresin 1 and significantly higher levels of docosahexaenoic acid and 18-hydroxyeicosapentaenoic acid. In conclusion, insufficient or ineffective SPM production may play a role in the pathophysiology of CMD. If our results are validated in a larger cohort, omega-3 fatty acid supplementation could be tested as a novel treatment for these patients.

  • five year follow up of Coronary Microvascular Dysfunction and Coronary artery disease in systemic lupus erythematosus results from a community based lupus cohort
    Arthritis Care and Research, 2020
    Co-Authors: Vaneet K Sandhu, Janet Wei, Louise Thomson, Daniel S Berman, Noel Bairey C Merz, Jay N Schapira, Daniel J Wallace, Michael H Weisman, Mariko L Ishimori
    Abstract:

    Objective The present study was undertaken to investigate prospective change in the prevalence of Coronary Microvascular Dysfunction (CMD) and obstructive Coronary artery disease (CAD) in a cohort of subjects with systemic lupus erythematosus (SLE) initially evaluated for anginal chest pain (CP). Prior work documented a relatively high prevalence of CMD in the absence of obstructive CAD in subjects with SLE. Methods Twenty female SLE subjects with CP who underwent stress cardiac magnetic resonance imaging (CMRI) and Coronary computed tomography angiography at baseline were reevaluated at 5 years. Results Seventeen subjects (85%) were available and reenrolled, of which 11 (65%) had persistent CP at follow-up. Fourteen subjects had complete follow-up CMRI, of which 36% (n = 5) demonstrated CMD at follow-up. Further, 25% (1 of 4) of the originally abnormal myocardial perfusion reserve index (MPRI) findings at baseline were lower at follow-up, while 2 additional abnormal MPRI findings at follow-up were noted in previously normal MPRI results. The prevalence of CMD and nonobstructive/obstructive CAD both was unchanged between baseline and follow-up, respectively (both P values not significant). During follow-up, 33% of subjects (5 of 15) had adverse cardiac outcomes, including pericarditis, unstable angina, or intracranial aneurysm clipping procedure. Conclusion At the 5-year follow-up of SLE subjects with CP who were evaluated at baseline and follow-up, a majority had persistent CP, and nearly one-half had similar or worse myocardial perfusion consistent with CMD without obstructive CAD. These findings propose an alternative explanation for CP in SLE subjects compared to the more common SLE-related accelerated obstructive CAD accounting for CP and adverse outcomes. These findings support further studies of CMD as an etiology for cardiac morbidity and mortality in SLE.

  • ambulatory and silent myocardial ischemia in women with Coronary Microvascular Dysfunction results from the cardiac autonomic nervous system study cans
    International Journal of Cardiology, 2020
    Co-Authors: Rajasree Roy, Chrisandra Shufelt, Margo Minissian, Janet Wei, Michael D Nelson, Haider Aldiwani, Navid Darouian, Shilpa Sharma, Tina Torbati, Noel Bairey C Merz
    Abstract:

    Abstract Background Up to two-thirds of patients with obstructive Coronary artery disease (CAD) have silent ischemia (SI), which predicts an adverse prognosis and can be a treatment target in obstructive CAD. Over 50% of women with ischemia and no obstructive CAD have Coronary Microvascular Dysfunction (CMD), which is associated with adverse cardiovascular outcomes. We aimed to investigate the prevalence of SI in CMD in order to consider it as a potential treatment target. Methods 36 women with CMD by Coronary reactivity testing and 16 age matched reference subjects underwent 24-h 12-lead ambulatory ECG monitoring (Mortara Instruments) after anti-ischemia medication withdrawal. Ambulatory ECG recordings were reviewed by two-physician consensus masked to subject status for SI measured by evidence of ≥1 minute horizontal or downsloping ST segment depression ≥1.0 mm, measured 80 ms from the J point. Results Demographics, resting heart rate, and systolic blood pressure were similar between CMD and reference subjects. Thirty-nine percent of CMD women had a total of 26 SI episodes vs. 0 episodes in the reference group (p = 0.002). Among these women 13/14 (93%) had SI, and few episodes (3/26, 12%) were symptomatic. Mean HR at the onset of SI was 96 ± 13 bpm and increased to 117 ± 16 bpm during the ischemic episodes. 87% reported symptoms that were not associated with ST depressions. Conclusions Ambulatory ischemia is prevalent in women with CMD, with a majority being SI, while most reported symptoms were not accompanied by ambulatory ischemia. Clinical trials evaluating anti-ischemic medications should be considered in the CMD population.

  • treatment of Coronary Microvascular Dysfunction
    Cardiovascular Research, 2020
    Co-Authors: Noel Bairey C Merz, Carl J Pepine, Hiroki Shimokawa, Colin Berry
    Abstract:

    Patients with ischemia and non-obstructive Coronary artery (INOCA) often have Coronary Microvascular Dysfunction (CMD), and they are at high risk for adverse cardiac events. Nevertheless, the management of CMD represents a major unmet need because the lack of large, randomized studies makes it difficult to generate evidence-based recommendations. Recently, it was demonstrated that stratified medical therapy guided by an interventional diagnostic procedure improves health status of patients with INOCA. Accordingly, the latest guidelines state that treatment of CMD should address the dominant mechanism of microcirculatory Dysfunction. In patients with impaired microcirculatory conductance and a negative acetylcholine (ACh) provocation test, beta-blockers, ACE inhibitors, and statins, along with lifestyle modifications and weight loss, are indicated. On the other hand, patients developing ECG changes and angina in response to ACh testing but without severe epicardial Coronary vasoconstriction (all suggestive of Microvascular spasm) may be treated mainly by calcium channel blockers. However, in patients with INOCA, Coronary functional abnormalities, including epicardial Coronary spasm, reduced Microvascular vasodilatation, and increased Microvascular resistance, frequently coexist in various combinations. Thus, in everyday clinical practice, a combination of several types of vasodilators, such as a beta-blocker and a long-acting dihydropyridine calcium channel blocker, should constitute the second step when a single drug fails to success. In cases with refractory symptoms which seriously limit life quality, analgesic drugs or non-pharmacological interventions, including rehabilitation exercise programs, spinal cord simulation, and/or psychological treatments, might be helpful. In this section, we will discuss the treatment options for CMD, taking into consideration currently accepted pathogenic mechanisms of the disorder.

  • adenosine vs regadenoson pharmacologic stress differs in women with suspected Coronary Microvascular Dysfunction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd study
    Cardiovascular Disorder and Medicine, 2019
    Co-Authors: Puja K Mehta, Chrisandra Shufelt, Eileen M Handberg, Daniel S Berman, Noel Bairey C Merz, Carl J Pepine, Andre Rogatko, Galen Cookwiens, Behzad Sharif, George Sopko
    Abstract:

    Background: Stress cardiac magnetic resonance (CMR) imaging with myocardial perfusion reserve index (MPRI) measurement has emerged as a noninvasive method for assessing Coronary Microvascular Dysfunction (CMD) in the absence of obstructive Coronary artery disease (CAD). Pharmacologic stress with adenosine or regadenoson is typically used with comparable Coronary vasodilation, but higher unadjusted MPRI has been reported with regadenoson in healthy men. This difference has not been assessed in symptomatic or healthy women. Methods: In a prospective cohort study, 139 symptomatic women with suspected CMD and no obstructive CAD underwent stress CMR and invasive Coronary flow reserve (CFR) testing. Adenosine was the default vasodilator (n=99), while regadenoson was used if history of asthma or prior adenosine intolerance (n=40). Stress CMR was also performed in 40 age-matched healthy controls using adenosine (n=20) and regadenoson (n=20). Unpaired t-tests and analysis of covariance were performed to compare MPRI with adenosine and regadenoson in the symptomatic women and healthy controls. Results: Compared to regadenoson cases, adenosine cases had lower invasive CFR (2.64±0.62 vs 2.94±0.68, p=0.01) and pharmacologic heart rate change (28±16 vs 38±15 bpm, p=0.0008). Unadjusted MPRI was lower in the adenosine compared to regadenoson cases (1.73±0.38 vs 2.27±0.59, p<0.0001). When adjusted for heart rate, rate-pressure-product, and invasive CFR, MPRI remained lower in the adenosine cases (p<0.0001). Invasive CFR to adenosine correlated with adenosine MPRI (r 0.17, p=0.02) but not regadenoson MPRI (r -0.14, p=0.19). There was no significant difference in MPRI in the controls who received adenosine vs regadenoson (2.27±0.33 vs 2.38±0.44, p=0.36). Conclusion: In women undergoing stress CMR for suspected CMD, those who received adenosine had lower MPRI than those who received regadenoson. However, there were no differences in MPRI in the healthy controls. These findings suggest there may be physiologic differences in adenosine and regadenoson response in the Coronary microcirculation of symptomatic women.

Eileen M Handberg - One of the best experts on this subject based on the ideXlab platform.

  • specialized proresolving mediators in symptomatic women with Coronary Microvascular Dysfunction from the women s ischemia trial to reduce events in nonobstructive cad warrior trial
    American Journal of Cardiology, 2021
    Co-Authors: Ellen C Keeley, Eileen M Handberg, Noel Bairey C Merz, Christopher R Cogle, Carl J Pepine
    Abstract:

    Resolvins and maresins, members of the specialized proresolving mediator (SPM) family, are omega-3 fatty acid-derived lipid mediators that attenuate inflammation. We hypothesized that they play a role in the pathophysiology of Coronary Microvascular Dysfunction (CMD) in women with ischemia and no obstructive Coronary disease. In a pilot study, we measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid, eicosapentaenoic acid (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid by mass spectrometry in the peripheral blood of 31 women enrolled in the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial who had confirmed CMD assessed by Coronary flow reserve. We compared SPM levels with 12 gender and age-matched reference subjects. Compared with the reference subject group, those with CMD had significantly lower plasma concentrations of resolvin D1 and maresin 1 and significantly higher levels of docosahexaenoic acid and 18-hydroxyeicosapentaenoic acid. In conclusion, insufficient or ineffective SPM production may play a role in the pathophysiology of CMD. If our results are validated in a larger cohort, omega-3 fatty acid supplementation could be tested as a novel treatment for these patients.

  • association of Coronary Microvascular Dysfunction and cardiac bridge integrator 1 a cardiomyocyte Dysfunction biomarker
    Clinical Cardiology, 2021
    Co-Authors: Christine Pacheco, Chrisandra Shufelt, Janet Wei, Eileen M Handberg, John W Petersen, Carl J Pepine, Tara C Hitzeman, Galen Cookwiens, David R Anderson, Tingting Hong
    Abstract:

    BACKGROUND Coronary Microvascular Dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described. HYPOTHESIS We hypothesized that CMD in women with suspected ischemia with no obstructive Coronary artery disease (INOCA) is associated with cardiomyocyte Dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1). METHODS Women with suspected INOCA undergoing Coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in Coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule Dysfunction. RESULTS INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = -0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001). CONCLUSIONS CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.

  • n terminal pro b type natriuretic peptide and Coronary Microvascular Dysfunction in women with preserved ejection fraction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd study
    PLOS ONE, 2020
    Co-Authors: Erika Jones, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Carl J Pepine, Michael D Nelson, Behzad Sharif, May Bakir, Eileen M Handberg
    Abstract:

    Author(s): Jones, Erika; Wei, Janet; Nelson, Michael D; Bakir, May; Mehta, Puja K; Shufelt, Chrisandra; Minissian, Margo; Sharif, Behzad; Pepine, Carl J; Handberg, Eileen; Cook-Wiens, Galen; Sopko, George; Bairey Merz, C Noel | Abstract: BackgroundWomen with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive Coronary artery disease (CAD), often have Coronary Microvascular Dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population.MethodsWe evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive Coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables.ResultsOverall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = l0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively).ConclusionAmong women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional Coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF.

  • adenosine vs regadenoson pharmacologic stress differs in women with suspected Coronary Microvascular Dysfunction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd study
    Cardiovascular Disorder and Medicine, 2019
    Co-Authors: Puja K Mehta, Chrisandra Shufelt, Eileen M Handberg, Daniel S Berman, Noel Bairey C Merz, Carl J Pepine, Andre Rogatko, Galen Cookwiens, Behzad Sharif, George Sopko
    Abstract:

    Background: Stress cardiac magnetic resonance (CMR) imaging with myocardial perfusion reserve index (MPRI) measurement has emerged as a noninvasive method for assessing Coronary Microvascular Dysfunction (CMD) in the absence of obstructive Coronary artery disease (CAD). Pharmacologic stress with adenosine or regadenoson is typically used with comparable Coronary vasodilation, but higher unadjusted MPRI has been reported with regadenoson in healthy men. This difference has not been assessed in symptomatic or healthy women. Methods: In a prospective cohort study, 139 symptomatic women with suspected CMD and no obstructive CAD underwent stress CMR and invasive Coronary flow reserve (CFR) testing. Adenosine was the default vasodilator (n=99), while regadenoson was used if history of asthma or prior adenosine intolerance (n=40). Stress CMR was also performed in 40 age-matched healthy controls using adenosine (n=20) and regadenoson (n=20). Unpaired t-tests and analysis of covariance were performed to compare MPRI with adenosine and regadenoson in the symptomatic women and healthy controls. Results: Compared to regadenoson cases, adenosine cases had lower invasive CFR (2.64±0.62 vs 2.94±0.68, p=0.01) and pharmacologic heart rate change (28±16 vs 38±15 bpm, p=0.0008). Unadjusted MPRI was lower in the adenosine compared to regadenoson cases (1.73±0.38 vs 2.27±0.59, p<0.0001). When adjusted for heart rate, rate-pressure-product, and invasive CFR, MPRI remained lower in the adenosine cases (p<0.0001). Invasive CFR to adenosine correlated with adenosine MPRI (r 0.17, p=0.02) but not regadenoson MPRI (r -0.14, p=0.19). There was no significant difference in MPRI in the controls who received adenosine vs regadenoson (2.27±0.33 vs 2.38±0.44, p=0.36). Conclusion: In women undergoing stress CMR for suspected CMD, those who received adenosine had lower MPRI than those who received regadenoson. However, there were no differences in MPRI in the healthy controls. These findings suggest there may be physiologic differences in adenosine and regadenoson response in the Coronary microcirculation of symptomatic women.

  • daily activity measured with wearable technology as a novel measurement of treatment effect in patients with Coronary Microvascular Dysfunction substudy of a randomized controlled crossover trial
    JMIR Research Protocols, 2017
    Co-Authors: Kade Birkeland, Raj M Khandwalla, Ilan Kedan, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Eileen M Handberg, Louise Thomson, Daniel S Berman
    Abstract:

    Background: Digital wearable devices provide a “real-world” assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and Coronary Microvascular Dysfunction (CMD) with no obstructive Coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO) [JMIR Res Protoc 2017;6(12):e255]

Louise Thomson - One of the best experts on this subject based on the ideXlab platform.

  • left ventricular circumferential strain and Coronary Microvascular Dysfunction a report from the women s ischemia syndrome evaluation Coronary vascular Dysfunction wise cvd project
    International Journal of Cardiology, 2021
    Co-Authors: Balaji Tamarappoo, Puja K Mehta, Janet Wei, Louise Thomson, Jake T Samuel, Omeed Elboudwarej, Haider Aldiwani, Susan Cheng, Behzad Sharif, Ahmed Albadri
    Abstract:

    Abstract Aims Women with ischemia but no obstructive Coronary artery disease (INOCA) often have Coronary Microvascular Dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical Dysfunction. Methods and results Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) Conclusion The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical Dysfunction in CMD.

  • five year follow up of Coronary Microvascular Dysfunction and Coronary artery disease in systemic lupus erythematosus results from a community based lupus cohort
    Arthritis Care and Research, 2020
    Co-Authors: Vaneet K Sandhu, Janet Wei, Louise Thomson, Daniel S Berman, Noel Bairey C Merz, Jay N Schapira, Daniel J Wallace, Michael H Weisman, Mariko L Ishimori
    Abstract:

    Objective The present study was undertaken to investigate prospective change in the prevalence of Coronary Microvascular Dysfunction (CMD) and obstructive Coronary artery disease (CAD) in a cohort of subjects with systemic lupus erythematosus (SLE) initially evaluated for anginal chest pain (CP). Prior work documented a relatively high prevalence of CMD in the absence of obstructive CAD in subjects with SLE. Methods Twenty female SLE subjects with CP who underwent stress cardiac magnetic resonance imaging (CMRI) and Coronary computed tomography angiography at baseline were reevaluated at 5 years. Results Seventeen subjects (85%) were available and reenrolled, of which 11 (65%) had persistent CP at follow-up. Fourteen subjects had complete follow-up CMRI, of which 36% (n = 5) demonstrated CMD at follow-up. Further, 25% (1 of 4) of the originally abnormal myocardial perfusion reserve index (MPRI) findings at baseline were lower at follow-up, while 2 additional abnormal MPRI findings at follow-up were noted in previously normal MPRI results. The prevalence of CMD and nonobstructive/obstructive CAD both was unchanged between baseline and follow-up, respectively (both P values not significant). During follow-up, 33% of subjects (5 of 15) had adverse cardiac outcomes, including pericarditis, unstable angina, or intracranial aneurysm clipping procedure. Conclusion At the 5-year follow-up of SLE subjects with CP who were evaluated at baseline and follow-up, a majority had persistent CP, and nearly one-half had similar or worse myocardial perfusion consistent with CMD without obstructive CAD. These findings propose an alternative explanation for CP in SLE subjects compared to the more common SLE-related accelerated obstructive CAD accounting for CP and adverse outcomes. These findings support further studies of CMD as an etiology for cardiac morbidity and mortality in SLE.

  • daily activity measured with wearable technology as a novel measurement of treatment effect in patients with Coronary Microvascular Dysfunction substudy of a randomized controlled crossover trial
    JMIR Research Protocols, 2017
    Co-Authors: Kade Birkeland, Raj M Khandwalla, Ilan Kedan, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Eileen M Handberg, Louise Thomson, Daniel S Berman
    Abstract:

    Background: Digital wearable devices provide a “real-world” assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and Coronary Microvascular Dysfunction (CMD) with no obstructive Coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO) [JMIR Res Protoc 2017;6(12):e255]

  • daily activity measured with wearable technology as a novel measurement of treatment effect in patients with Coronary Microvascular Dysfunction substudy of a randomized controlled crossover trial
    JMIR Research Protocols, 2017
    Co-Authors: Kade Birkeland, Raj M Khandwalla, Ilan Kedan, Chrisandra Shufelt, Puja K Mehta, Margo Minissian, Janet Wei, Eileen M Handberg, Louise Thomson, Daniel S Berman
    Abstract:

    Background: Digital wearable devices provide a “real-world” assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and Coronary Microvascular Dysfunction (CMD) with no obstructive Coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO)

  • myocardial tissue deformation is reduced in subjects with Coronary Microvascular Dysfunction but not rescued by treatment with ranolazine
    Clinical Cardiology, 2017
    Co-Authors: Chrisandra Shufelt, Puja K Mehta, Janet Wei, Jaime L Shaw, Michael D Nelson, Galen Cookwiens, Behzad Sharif, Louise Thomson
    Abstract:

    Background Patients with Coronary Microvascular Dysfunction (CMD) often have diastolic Dysfunction, representing an important therapeutic target. Ranolazine—a late sodium current inhibitor—improves diastolic function in animal models and subjects with obstructive Coronary artery disease (CAD). Hypothesis We hypothesized that ranolazine would beneficially alter diastolic function in CMD. Methods To test this hypothesis, we performed retrospective tissue tracking analysis to evaluate systolic/diastolic strain, using cardiac magnetic resonance imaging cine images acquired in a recently completed, randomized, double-blind, placebo-controlled, crossover trial of short-term ranolazine in subjects with CMD and from 43 healthy reference controls. Results Diastolic strain rate was impaired in CMD vs controls (circumferential diastolic strain rate: 99.9% ± 2.5%/s vs 120.1% ± 4.0%/s, P = 0.0003; radial diastolic strain rate: −199.5% ± 5.5%/s vs −243.1% ± 9.6%/s, P = 0.0008, case vs control). Moreover, peak systolic circumferential strain (CS) and radial strain (RS) were also impaired in cases vs controls (CS: −18.8% ± 0.3% vs −20.7% ± 0.3%; RS: 35.8% ± 0.7% vs 41.4% ± 0.9%; respectively; both P < 0.0001), despite similar and preserved ejection fraction. In contrast to our hypothesis, however, we observed no significant changes in left ventricular diastolic function in CMD cases after 2 weeks of ranolazine vs placebo. Conclusions The case-control comparison both confirms and extends our prior observations of diastolic Dysfunction in CMD. That CMD cases were also found to have subclinical systolic Dysfunction is a novel finding, highlighting the utility of this retrospective approach. In contrast to previous studies in obstructive CAD, ranolazine did not improve diastolic function in CMD.