INTERNATIONAL JOURNAL OF CARDIOLOGY AND CARDIOVASCULAR MEDICINE (ISSN:2517-570X)

Background: Identifying therapeutic agents to reduce the morbidity and mortality and symptom burden of women with microvascular angina (MVA) remains a priority. The aim of this study was to investigate the effects of nebivolol, a cardioselective beta-blocker with nitric oxide mediated vasodilatory effects, on angina, health-related quality of life, and cardiopulmonary function of women with MVA.

Methods and Results: In this study, women with MVA underwent cardiopulmonary exercise testing and completed the Seattle Angina Questionnaire and Short-Form 36 version 2. Subjects were then started on nebivolol (5-10 mg daily) and repeat testing performed at 12 weeks. Anginal stability improved significantly (29.2 ± 18.8 vs. 83.3 ± 25.8, p=0.034). There was also a trend towards improvement in anginal frequency and quality of life. Despite expected lower peak heart rate (pHR) (145 ± 17 vs. 119 ± 11 beats/min, p<0.001, -18%) the peak O₂ pulse was significantly higher (11.0 ± 2.5 vs. 13.1 ± 2.3 mL/beat, p< 0.01, +20%) and the peak oxygen consumption (peak VO₂ ) was unchanged (22.9 ± 6.3 vs. 22.0 ± 4.8 mL/kg/min, p=0.41).

Conclusions: Nebivolol improved anginal stability without impairment in peak VO₂. Further research is needed to identify the mechanism by which the nitric oxide mediated vasodilatory effects of nebivolol relate to enhanced peak O₂ pulse and whether this finding reflects improved stroke volume or peripheral oxygen extraction. 

Microvascular angina; Nebivolol; Cardiopulmonary exercise testing

Although women have less obstructive coronary artery disease (CAD) then men, women continue to have a greater burden of symptoms, more ischemia and a higher rate of adverse outcomes compared to age-matched male counterparts [1]. This has led to the recognition of microvascular angina (MVA) as an alternative to the flow limiting atherosclerotic CAD mechanism [2]. Identifying effective therapeutic agents to improve the morbidity and mortality of women suffering from MVA remains a priority. Nebivolol has antioxidant and vasodilator properties via its effect on nitric oxide bioactivity. Its subsequent endothelial effects make it a potential therapeutic agent for MVA [3].

The aim of this study was to investigate the effects of nebivolol on angina, the healthrelated quality of life, and cardiopulmonary function of women with MVA.

This was a 12-week, open-label, interventional study conducted at the Massachusetts General Hospital. The Partners Human Research Committee approved this project and all participants provided written informed consent.

Women between the ages of 40-80 years with coronary microvascular dysfunction were included in the study. Men were excluded from this study, as primary coronary microvascular dysfunction primarily occurs in women, with more data in this population subset required. The diagnosis of coronary microvascular dysfunction was determined by the presence of (a) rest and/or exertional chest tightness, (b) a history of either an elevated troponin level, positive stress test (electrocardiogram criteria or imaging) or a diagnosis of microvascular angina by their primary cardiologist, and (c) non-obstructive CAD (<50% epicardial obstruction) by either diagnostic catheterization with coronary angiography or computed tomography angiography. Exclusion criteria for the study included intolerance or contraindication to beta-blocker therapy, the inability to exercise, left ventricular systolic function <40%, Prinzmetal’s angina, myocardial bridging, decompensated heart failure,severe hepatic impairment, significant renal disease or neurologic disease, and current malignancy. Women on hormone replacement therapy or of child-bearing age not on an adequate birth control method were also excluded from the study.

Enrolled subjects underwent a washout period during which beta-blockers, ranolazine, and long-acting nitrates were discontinued. A standardized regimen of amlodipine (2.5-10 mg daily) plus PRN sublingual nitrates was then initiated. After 4 weeks on the standardized regimen, subjects underwent baseline testing which included cardiopulmonary exercise testing (CPET) as well as completion of the Seattle Angina Questionnaire (SAQ) and the Short-Form 36 Version 2 (SF-36v2) health survey. Subjects were then started on open label nebivolol (5-10 mg daily) which was uptitrated as tolerated. After 12 weeks of treatment, repeat testing was performed on nebivolol. Patients were monitored for potential nebivolol adverse reactions including: bradycardia, presyncope and fatigue.

Continuous variables were reported as the mean ± standard deviation (SD) and categorical data presented as frequency and percentage of the sample. Comparisons between baseline and posttreatment SAQ scores, SF-36v2 scores, and CPET variables were performed using a paired t-test for normally distributed variables or a Wilcoxon signed-rank test for non-normally distributed variables. Normality was defined by the Shapiro-Wilk test. For categorical variables, data were compared using a chi-squared test. All statistical tests were two-sided and p-values <0.05 were considered significant. 

Twelve women were enrolled in the study. Seven patients completed both baseline and post-treatment CPET testing of which one patient did not complete post-treatment study questionnaires. The mean age was 61.6 ± 10.0 years and 85.7% were postmenopausal. The most common cardiovascular risk factors were postmenopausal state, hypertension, family history of premature CAD, followed by tobacco use, dyslipidemia, and obesity. Of the patients who completed the study, all underwent cardiac catheterization of which 5 patients had normal epicardial coronary arteries and 2 patients were found to have non-obstructive coronary artery disease. A total of 2 patients had undergone percutaneous coronary intervention but had patent epicardial coronary arteries at time of study inclusion. One patient had a history of a previous myocardial infarction with preserved ejection fraction. Reasons for which enrolled patients were withdrawn from the study included the inability to be weaned off baseline medications in preparation to start the standardized regimen (n=1), markedly abnormal baseline CPET testing warranting further care by primary cardiologist (n=1), the inability to complete CPET testing by the study close out date (n=1), and patient personal preference (n=2). There were no serious adverse events during the duration of the study.

SAQ results are presented in Table 1. After 12 weeks of treatment, SAQ anginal stability scores were significantly higher (29.2 ± 18.8 vs. 83.3 ± 25.8, p=0.034). There was also a trend towards a higher (improved) anginal frequency score (70.0 ± 15.5 vs. 80.0 ± 20.0, p=0.076) as well as quality of life score (51.4 ± 23.2 vs. 62.5 ± 33.6, p=0.10). There was no statistically significant difference observed between baseline and post-treatment physical limitation and treatment satisfaction scores.

After 12 weeks of treatment, there were no significant differences observed between baseline and post-treatment scores for all health related quality of life domains of the SF-36v2 survey.

Key CPET finding are presented in Table 2. After 12 weeks of treatment with nebivolol, peak heart rate (pHR) was significantly lower (145 ± 17 vs. 119 ± 11 beats/min, p<0.001, -18%) as well as resting heart rate (83 ± 16 vs. 66 ± 9 beats/min, p<0.002, -20%). Peak O₂ pulse was significantly higher (11.0 ± 2.5 vs. 13.1 ± 2.3 mL/ beat, p<0.01, +20%) and peak oxygen consumption (peak VO₂ ) was unchanged (22.9 ± 6.3 vs. 22.0 ± 4.8 mL/kg/min, p=0.41, -3.9%). The changes observed in all other CPET variables including exercise duration were not statistically significant.

To the best of our knowledge, this is the first study to examine the effects of nebivolol therapy on angina, the health-related quality of life, and cardiopulmonary function in women with MVA. The findings from this study demonstrated that after treatment with nebivolol, angina stability was significantly improved in women with MVA. Furthermore, there was a trend towards improvement in anginal frequency and quality of life.

We also examined the impact of nebivolol on cardiopulmonary function in women with MVA by performing CPET testing at baseline followed by post-treatment testing. As the subjects, did not undergo any exercise training (endurance or strength) as part of the study protocol, any improvement in peak VO₂ was not expected. Nebivolol treatment did result in a significant reduction in pHR consistent with beta-1 adrenergic receptor blockade. However, surprisingly there was not an associated impairment in peak VO₂ as has been previously reported with other beta-blockers, primarily non-cardio selective beta-blockers [4]. The increase in peak O₂ pulse observed post-treatment as compared to baseline suggests that peak VO₂ was preserved either by improvement of cardiac stroke volume or enhancement of peripheral oxygen extraction.

Similarly, to many of the other published studies assessing the efficacy of therapeutic agents in MVA patients, the primary limitations of this study was the small sample size as well as the relatively short term follow-up period. The main recruitment difficulty encountered in this study was successfully enrolling eligible patients willing to undergo a washout period followed by a standardized medication regimen. Another barrier to recruitment includes the reduced awareness for this disorder by physicians in general, thereby reducing the pool of eligible patients. Lastly, patients themselves are often resistant to treatment as women are often too engrossed and occupied as the primary caregiver for their households to manage their own health issues. Furthermore, this study was neither blinded nor placebo-controlled. However, despite its limitations, to the best of our knowledge this study is the first to date to examine the effects of nebivolol therapy on angina, health-related quality of life, and cardiopulmonary function in women with MVA. Furthermore, given the current limited understanding of MVA and scarceness of targeted, effective therapies this study provides valuable insight to inform future investigations.

The treatment of MVA remains largely empirical due to limited outcomes data regarding symptom alleviation as well as major adverse cardiac outcomes reduction. Women with MVA continue to report more frequent angina and worse quality of life. They frequently seek medical attention for the evaluation of cardiovascular symptoms including chest pain and shortness of breath. Consequently, these women incur greater healthcare costs, with more office visits, hospitalizations, and adverse cardiovascular event. In fact, more than one half of women without obstructive CAD continue to have ischemic symptoms that lead to further consumption of resources, most often because of diagnostic uncertainty [5-8].

In the absence of robust outcomes data to drive the care of women with MVA, various treatment strategies have been utilized by healthcare professionals. In addition to focusing on the management of traditional cardiovascular risk factors via lifestyle modifications and pharmacotherapy, some physicians treat women with MVA as they would treat patients with known obstructive CAD, while some, in the setting of angiographically normal appearing coronary arteries and persistent angina, simply opt for reassurance. Nevertheless, given that women with MVA continue to have higher morbidity and mortality, as well as increased resource consumption, there is a widely recognized need for effective therapeutic agents to alleviate symptoms, improve quality of life, decrease resource consumption, and ultimately reduce morbidity and mortality. 

To date, there have not been any interventions that have demonstrated a reduction in adverse cardiac events in women with signs and symptoms of cardiac ischemia and non-obstructive CAD. However, there have been several studies that have demonstrated an improvement in symptomatology with the use of various different antianginal therapies, treatments that effect pain perception, and finally agents that directly target underlying microvascular dysfunction [9]. Although many conventional therapies have been tested, it remains to be determined which is the most effective agent in this patient population in terms of ischemic symptom burden, quality of life, healthcare related costs, and long-term cardiovascular outcomes.

Although several different pathogenic mechanisms have been described in MVA, vascular endothelial dysfunction and inflammation are believed to play major role. Endothelial dysfunction is believed to lead to a reduction in plasma NO levels in patients with MVA and ultimately a reduction in coronary vasodilation [10,11]. Given our current pathophysiologic understanding of MVA, the potential for nebivolol to serve as an effective therapy secondary to its NO-mediated vasodilatory effects has started to be preliminarily explored over the last several years. One previous study demonstrated that treatment with nebivolol resulted in an improvement in endothelial function and NO release [12]. Another study showed that nebivolol improved exercise parameters, as well as endothelial function, more effectively than beta blockade with metoprolol, among patients with persistent angina and non-obstructive CAD [13]. Based on the findings of these previous studies as well as of this present study, nebivolol has shown promise as a therapy for MVA, but future work is needed to further examine its effects in this unique patient population on a larger scale. 

In conclusion, the results from this study suggest that nebivolol is a promising therapeutic agent for women with MVA and suffering from inadequately controlled symptoms. Nebivolol therapy improved angina stability without decreasing peak VO₂. Impairment in peak exercise capacity has been demonstrated with other betablocker therapies and is mediated by pharmacologically induced chronotropic incompetence. The proposed mechanism of action for preservation of peak VO₂ with nebivolol therapy in this study, given the observed augmentation in peak O₂ pulse, is either improvement of cardiac stroke volume or peripheral oxygen extraction. Further work is necessary to determine which of these two mechanisms is responsible, and whether the augmentation in peak O₂ pulse is due to the unique NO-mediated vasodilatory effects of nebivolol. Future research efforts should also focus on further examining the effects of nebivolol treatment on the long-term clinical outcomes of women with MVA.

This study was funded by the Forest Research Institute, an affiliate of Actavis, Inc (now: Allergen), the US marketer of nebivolol.

This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

This study was investigator-initiated and funded by the Forest Research Institute, an affiliate of Actavis, Inc (now: Allergen), the US marketer of nebivolol. Forest did have a role in the study design and assisted with manuscript preparation; however, they were not involved in data collection, data analysis, or interpretation of the results. Statistical analyses were performed by the investigators with assistance from Harvard Catalyst. The decision to submit this manuscript for publication was made by the study investigators. The authors do not have any conflicts of interest to declare with regard to the content of this manuscript and did not receive any financial support from the Forest Research Institute.

1. Sedlak TL, Lee M, Izadnegahdar M, Merz CN, Gao M, et al. Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. Am Heart J. 2013 Jul;166(1):38-44.
2. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001 May;141(5):735- 741.
3. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, doubleblind, crossover study. Circulation. 2001 Jul;104(5):511-514.
4. Gullestad L, Hallen J, Medbø JI, Grønnerød O, Holme I, et al. The effect of acute vs chronic treatment with beta-adrenoceptor blockade on exercise performance, haemodynamic and metabolic parameters in healthy men and women. Br J Clin Pharmacol. 1996 Jan;41(1):57-67.
5. Shaw LJ, Merz CN, Pepine CJ, Reis SE, Bittner V, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women’s Ischemia Syndrome Evaluation. Circulation. 2006 Aug;114(9):894-904.
6. Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. 2010 Jun 22;55(25):2825-2832.
7. Lin FY, Shaw LJ, Dunning AM, Labounty TM, Choi JH, et al. Mortality risk in symptomatic patients with nonobstructive coronary artery disease: a prospective 2-center study of 2,583 patients undergoing 64-detector row coronary computed tomographic angiography. J Am Coll Cardiol. 2011 Jul 26;58(5):510-519.
8. Sharaf B, Wood T, Shaw L, Johnson BD, Kelsey S, et al. Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. Am Heart J. 2013 Jul;166(1):134-141.
9. Marinescu MA, Löffler AI, Ouellette M, Smith L, Kramer CM, et al. Coronary microvascular dysfunction, microvascular angina, and treatment strategies. JACC Cardiovasc Imaging. 2015 Feb;8(2):210-220.
10. Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol. 2002 Nov 1;90(9):974- 982.
11. Hurst T, Olson TH, Olson LE, Appleton CP. Cardiac syndrome X and endothelial dysfunction: new concepts in prognosis and treatment. Am J Med. 2006 Jul;119(7):560-566.
12. Kayaalti F, Kalay N, Basar E, Mavili E, Duran M, et al. Effects of nebivolol therapy on endothelial functions in cardiac syndrome X. Heart Vessels. 2010 Mar;25(2):92-96.
13. Sen N, Tavil Y, Erdamar H, Yazici HU, Cakir E, et al. Nebivolol therapy improves endothelial function and increases exercise tolerance in patients with cardiac syndrome X. Anadolu Kardiyol Derg. 2009 Oct;9(5):371-379.