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Phosphodiesterase type 5 inhibition may reduce diastolic function in women with ischemia but no obstructive coronary artery disease

  • Michael D. Nelson1, 2, 3,
  • Puja K. Mehta1,
  • Janet Wei1,
  • Behzad Sharif2,
  • Louise E. J. Thomson4,
  • Daniel Berman4,
  • Debiao Li2 and
  • C. Noel Bairey Merz1Email author
Journal of Medical Case Reports201711:144

https://doi.org/10.1186/s13256-017-1307-2

Received: 17 January 2017

Accepted: 3 May 2017

Published: 22 May 2017

Abstract

Background

Ischemia, in the absence of obstructive coronary artery disease, is prevalent in women, and associated with increased risk for major cardiovascular events. Coronary microvascular dysfunction is prevalent in these patients, and associated with impaired diastolic function. Despite our general understanding, however, optimal treatment of this cohort remains elusive.

Methods

To address this knowledge gap, we performed an open-label treatment trial to assess whether phosphodiesterase type 5 inhibition improves coronary microvascular perfusion and diastolic function in women with signs and symptoms of ischemia but no evidence of obstructive coronary artery disease. Left ventricular morphology and function, along with myocardial perfusion reserve index, were assessed by contrast-enhanced cardiac magnetic resonance imaging.

Results

A total of five women enrolled of which four completed the trial, while one was withdrawn by the investigators after developing dyspnea 1 week after treatment. Her symptoms resolved after cessation of the study medication. In contrast to our hypothesis, phosphodiesterase type 5 inhibition reduced the rate of circumferential strain in diastole in all four women who completed the trial (that is, diastolic dysfunction). This impairment could not be explained by changes in heart rate, contractility, blood pressure, or preload, and was not associated with a change in myocardial perfusion reserve index. Frequency of angina also tended to increase with treatment, with the greatest increase occurring in the patient with the greatest impairment in diastolic strain.

Conclusions

Taken together, these data question the efficacy of phosphodiesterase type 5 inhibition to treat women with ischemic heart disease, and highlight the need for further investigation.

Keywords

Women’s ischemic syndromeCoronary microvascular dysfunctionDiastolic dysfunctionMyocardial perfusion reserve indexPhosphodiesterase type 5 inhibition

Background

Ischemia, in the absence of obstructive coronary artery disease (CAD), is prevalent in women, and associated with increased risk for major cardiovascular events, including myocardial infarction, stroke, heart failure, and sudden cardiac death [1]. Sex-specific research initiatives, including the Women’s Ischemia Syndrome Evaluation (WISE) study sponsored by the National Heart, Lung, and Blood Institute (NHLBI), have established coronary microvascular dysfunction (CMD) and diastolic dysfunction as important etiologic features of this disease [2, 3]. Despite these advancements, effective treatment remains elusive [4].

Phosphodiesterase (PDE) 5 is expressed in vascular smooth muscle cells and regulates vasorelaxation by catabolizing cyclic guanosine monophosphate (cGMP), the downstream target of nitric oxide. PDE5 is upregulated in stress states [5], and thus could contribute to the pathophysiology of ischemic heart disease in women. Accordingly, we sought to determine whether PDE5 inhibition improves CMD-related perfusion and diastolic function in women with signs and symptoms of ischemia but no obstructive CAD.

Methods

Patients were recruited from the WISE-Coronary Vascular Dysfunction study (NCT00832702), which is a NHLBI-sponsored investigation designed to improve diagnostic testing and advance new hypotheses relative to the pathophysiology of ischemic heart disease in women. Women undergoing clinically ordered coronary angiography for suspected ischemia, but without obstructive CAD [6], were recruited. Exclusion criteria included: age <18 years, body mass index (BMI) ≥44 kg/m2, irregular heartbeat, renal failure, concurrent use of nitrates, alpha-adrenergic receptor blockers, or PDE inhibitors, as well as any contraindication to magnetic resonance imaging (MRI).

Patients were treated for 2 weeks in an open-label, non-randomized protocol with the PDE5 inhibitor tadalafil or sildenafil, as per the ordering physician’s instructions (Table 1). In all cases, the final capsule was ingested the night before the follow-up MRI.
Table 1

Patient characteristics, medical history, treatment history, and medication usage

 

Patient #

1

2

3

4

5

 Age, years

55

67

56

65

82

 Body mass index, kg/m2

23

26

21

29

19

 Heart rate, bpm

53

63

80

48

41

 Systolic blood pressure, mmHg

126

96

153

112

100

 Diastolic blood pressure, mmHg

53

53

81

59

53

 LV end-diastolic pressure, mmHg

15

17

---

20

---

Medical history

 Hypertension

---

Y

Y

Y

Y

 Dyslipidemia

Y

Y

---

Y

---

 Diabetes mellitus

---

---

---

Y

---

 Tobacco smoking

---

---

---

---

---

 Myocardial infarction

---

---

---

Y

---

PDE5-inhibitor

 Drug

Tadalafil

Tadalafil

Tadalafil

Sildenafil

Sildenafil

 Dose

5 mg

20 mg

5 mg

20 mg TID

10 mg TID

 Frequency

Every 3 days

Every 3 days

Every 3 days

Daily

Daily

Concomitant medications

 Antiplatelet

Aspirin

Aspirin

Aspirin

Aspirin

Aspirin

 Beta-blocker

Carvedilol

Atenolol

---

Carvedilol

Atenolol

 Calcium channel blocker

---

---

Diltiazem

---

---

 Statin

Pitavastatin

Rosuvastatin

---

Atorvastatin

---

 Diuretic

---

HCTZ

---

---

HCTZ Furosemide

 ACE-I/ARB

---

Ramipril

Losartan

Lisinopril

Losartan

 Other

Levothyroxine

Amitriptyline

---

Metformin

Levothyroxine

 Other

Prometrium (progesterone)

---

---

---

Dronedarone

 Other

Estradiol

---

---

---

---

ACE-I/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, bpm beats per minute, HCTZ hydrochlorothiazide, LV left ventricular, PDE5 phosphodiesterase 5, TID three times a day, Y, Yes. Patient 5 was withdrawn by the investigators after developing dyspnea 1 week after treatment

Cardiac MRI was performed at baseline and after 2 weeks of treatment (Siemens 3 T Verio; Erlangen, Germany). Imaging included cines for morphological and functional analysis (four chamber), mid-ventricular short-axis tissue tagging for strain analysis (HARP, Diagnosoft; Durham, NC, USA) [2], and first-pass perfusion imaging (base, mid, and apex; 0.05 mmol/kg gadolinium) at rest and in response to 140 mcg/kg per minute adenosine stress for calculation of myocardial perfusion reserve index (MPRI) [6]. Image analysis for MPRI was performed manually using a DICOM viewer (OsiriX by Pixmeo, Bernex, Switzerland).

Angina was assessed before and after treatment using the Seattle Angina Questionnaire [7].

Individual data are presented wherever possible. Data comparing the treatment effect are presented as mean ± standard error. Linear regression was used to determine the relationship between diastolic function and angina frequency. Due to the small sample size, statistical analysis was not performed.

Results

Patient characteristics are reported in Table 1. A total of five women enrolled, four completed the trial, while one was withdrawn by the investigators after developing dyspnea 1 week after treatment. Her symptoms resolved after cessation of the study medication.

The major novel finding of this investigation was that PDE5 inhibition reduced the rate of circumferential strain in diastole in all four women who completed the trial (that is, diastolic dysfunction; Fig. 1). This impairment could not be explained by: changes in heart rate, that is, 58 ± 6 beats per minute (bpm) versus 61 ± 6 bpm; contractility, that is, left ventricular (LV) ejection fraction 70 ± 1% versus 67 ± 1% and peak circumferential strain −20.7 ± 1.0% versus −20.2 ± 1.4%; or preload, that is, LV end-diastolic volume 108 ± 8 ml versus 109 ± 3 ml and left atrial volume 56 ± 10 ml versus 61 ± 11 ml; and was not associated with a change in MPRI 2.32 ± 0.10 versus 2.39 ± 0.06 (pre versus post).
Fig. 1

Phosphodiesterase 5 inhibition worsens diastolic function and symptoms of angina in women with ischemic syndrome. Left: Magnetic resonance tissue tagging was performed on two consecutive mid-short axis slices before and after treatment, and analyzed using commercially available software to assess the rate of circumferential strain in diastole. Individual data are shown, illustrating a reduction in all four patients who completed the trial. Group data (mean and standard error) are also reported (black markers). Right: Relationship between changes in self-reported angina frequency (Seattle Angina Questionnaire) and the change in diastolic circumferential strain rate. PDE5 phosphodiesterase 5

The frequency of angina also tended to increase with treatment, with the greatest increase occurring in the patient with the greatest impairment in diastolic strain (Fig. 1).

Discussion

In contrast to our hypothesis, PDE5 inhibition appears to worsen left ventricular relaxation in women with angina but no evidence of obstructive CAD. That one patient developed dyspnea while on the drug is consistent with the diastolic changes observed in the other four patients, and raises concern about the safety of PDE5 inhibition in this population. Our results add to a growing body of literature questioning the safety [8] and efficacy [9] of PDE5 inhibition to treat heart disease, currently an off-label indication (other than pulmonary hypertension).

The mechanism responsible for the reduction in diastolic function remains unknown. We did not observe frank hemodynamic changes, arguing against extrinsic factors. It is therefore interesting to speculate that adverse cellular signaling may have played a role, especially since the two patients with the greatest impairment/symptoms (P4 and P5) were treated with sildenafil, which is far less selective for PDE5 and also inhibits PDE1, which hydrolyzes cyclic adenosine monophosphate (cAMP) as well as cGMP.

This study is not without limitation however. For example, the small sample size and lack of a control group limits the broad application and statistical verification of these results. Moreover, participants were not randomized, nor were they blinded to the treatment. Despite these limitations, however, the uniform nature of our results warrants serious consideration and future investigation. In particular, a randomized placebo-controlled trial in a larger study sample is needed to fully elucidate the therapeutic efficacy of PDE5 inhibitors in CMD.

Conclusion

Taken together, these data question the efficacy of phosphodiesterase type 5 inhibition to treat women with ischemic heart disease, and highlight the need for further investigation.

Abbreviations

bpm: 

Beats per minute

CAD: 

Coronary artery disease

cGMP: 

Cyclic guanosine monophosphate

CMD: 

Coronary microvascular dysfunction

LV: 

Left ventricular

MPRI: 

Myocardial perfusion reserve index

MRI: 

Magnetic resonance imaging

NHLBI: 

National Heart, Lung, and Blood Institute

PDE: 

Phosphodiesterase

WISE: 

Women’s Ischemia Syndrome Evaluation

Declarations

Acknowledgements

Not applicable.

Funding

This work was supported by contracts from: the National Heart, Lung and Blood Institute nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164; grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, R01HL133616,1R03AG032631 from the National Institute on Aging; GCRC grant MO1-RR00425 from the National Center for Research Resources; the Linda Joy Pollin Women’s Heart Health Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA; and the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA. MD Nelson was supported by the Canadian Institutes for Health Research, the American Heart Association (16SDG27260115), and the Harry S. Moss Heart Trust.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors’ contributions

MDN was involved in data analysis and interpretation and drafting the manuscript. PKM was involved in the conception of the study, data collection, and data interpretation. JW was involved in the conception of the study, data collection, and data interpretation. BS was involved in the conception of the study, data collection, data analysis, and data interpretation. LEJT was involved in data interpretation and drafting the manuscript. DB was involved in data interpretation and drafting the manuscript. DL was involved in data interpretation and drafting of the manuscript. CNBM was involved in the conception of the study, data collection, data interpretation, and drafting of the manuscript. All authors read and approved the final manuscript.

Competing interests

Nelson, none. Mehta, Gilead Sciences Inc. Wei, none. Sharif, none. Thomson, none. Berman, none. Li, none. Bairey Merz, Research Triangle Institute International, UCSF, Kaiser, Gilead Sciences Inc. (grant review committee), Garden State AHA, Allegheny General Hospital, PCNA, Mayo Foundation (lectures; symposiums), Bryn Mawr Hospital, Victor Chang Cardiac Research Institute (Australia), Duke (Consulting), Japanese Circ Society, U of New Mexico, Emory, Practice Pont Communications (lectures), Vox Media (lectures), WISE CVD, FAMRI, RWISE, Normal Control, Microvascular, NIH-SEP.

Consent for publication

Not applicable.

Ethics approval and consent to participate

All participants provided written informed consent to participate. The study was approved by the Cedars-Sinai Medical Center Intuitional Research Ethics Board.

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Authors’ Affiliations

(1)
Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute
(2)
Biomedical Imaging Research Institute, Cedars-Sinai Medical Center
(3)
Applied Physiology and Advanced Imaging Laboratory, University of Texas at Arlington
(4)
S. Mark Taper Foundation Imaging Center, Cedars-Sinai Medical Center

References

  1. Jespersen L, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33(6):734–44.View ArticlePubMedGoogle Scholar
  2. Nelson MD, et al. Diastolic dysfunction in women with signs and symptoms of ischemia in the absence of obstructive coronary artery disease: a hypothesis-generating study. Circ Cardiovasc Imaging. 2014;7(3):510–6.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Wenger NK. Women and coronary heart disease: a century after Herrick: understudied, underdiagnosed, and undertreated. Circulation. 2012;126(5):604–11.View ArticlePubMedGoogle Scholar
  4. Marinescu MA, et al. Coronary microvascular dysfunction, microvascular angina, and treatment strategies. JACC Cardiovasc Imaging. 2015;8(2):210–20.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Lu Z, et al. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation. 2010;121(13):1474–83.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Thomson LE, et al. Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women’s Ischemia Syndrome Evaluation. Circ Cardiovasc Imaging. 2015;8(4):e002481.View ArticlePubMedGoogle Scholar
  7. Spertus JA, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995;25(2):333–41.View ArticlePubMedGoogle Scholar
  8. Leung DG, et al. Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Ann Neurol. 2014;76(4):541–9.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Redfield MM, et al. PhosphdiesteRasE-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure (RELAX) trial: rationale and design. Circ Heart Fail. 2012;5(5):653–9.View ArticlePubMedPubMed CentralGoogle Scholar

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© The Author(s). 2017

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