Coronary Venous Pressure and Microvascular Hemodynamics in Patients With Microvascular Angina

This randomized clinical trial investigates the effect of coronary venous pressure on myocardial resistances in patients with microvascular disease.


Signature of the Principal Clinical Investigator
I have read this protocol, appendices and amendment(s), if applicable, and agree to adhere to the requirements.I will provide copies of this protocol and all pertinent information to the study personnel under my supervision.I will discuss this material with them and ensure they are fully informed regarding the device and the conduct of the studies.The primary analysis will be performed as withinsubject-comparison of the primary outcome between each of the two groups (sham or balloon).Effect size assumed for estimation of sample size: We expect a difference of the balloon versus sham treatment of 9 units and a within-subjects standard deviation of 13 units.Therefore, the expected effect size is 0.69.Safety: The safety and efficacy of all devices has been previously shown in large clinical trials.To be allocated to trial (up to n =25) To be analysed (up to n =25)

PROTOCOL SUMMARY
The aim of this study is to test whether an increase in coronary sinus pressure leads to a change in coronary microvascular resistances in patients with angina pectoris and with an indication to measurement of microvascular function as per clinical guidelines.
All patients with a clinical indication for the assessment of microvascular function will be invited to participate and will sign the informed consent at least 24 hours before the study.
Patients with an index of microvascular resistances >25 (i.e.evidence of microvascular dysfunction) will undergo study-specific procedures in the same session (i.e.no additional invasive procedure is required for the study).
Study-specific procedures include the repetition of the assessment of microvascular resistances without (sham condition) versus with coronary sinus occlusion (balloon).
Coronary sinus occlusion will be achieved by inflating a balloon sized to ~70% of the diameter of the coronary sinus.Since the implantation of a coronary sinus reducer is a therapeutic option for this type of patients, also this procedure (inflation of an undersized balloon in the coronary sinus) provides clinically relevant information (sizing of the vessel, effect on microvascular resistances and feasibility of the intervention).
The primary goal of the study is: -To study the effect of coronary sinus occlusion on microvascular resistances at rest and during hyperemia.

BACKGROUND
Microvascular angina still represents a major clinical challenge whose importance is acknowledged in the most recent chronic coronary syndromes guidelines 1 .In particular, there is a strong disagreement on its classification, on the several mechanisms behind its pathophysiology 2 , and the therapeutic alternatives available remain unsatisfactory.
Despite these uncertainties, there is a consensus that this condition is clinically relevant as it affects up to two-thirds of patients who suffer from stable angina and either have no epicardial coronary stenosis at angiography or have combined epicardial and microvascular disease 3 .
Seite 13 von 24 Microvascular angina caused by a dysfunctional microvascular bed cannot be treated by standard revascularization therapies and the pharmacological strategies (e.g.nitrates, cachannel blockers, ranolazine) available also provide limited benefit.As a consequence, the old hypothesis of improving myocardial perfusion by diverting blood from the coronary venous system to an ischemic region ("venous retroperfusion") has again gained attention during recent years.This therapy was proposed as early as 1953 and is based on the concept that an elevation in backward pressure in the coronary venous system provokes dilatation of the subendocardial arterioles, resulting in a relative reduction of vascular resistance in this area and a redistribution of blood flow to these ischemic subendocardial layers 4 .Numerous studies confirm the efficacy of this approach for the therapy of patients who have angina and are not candidates for "traditional" revascularization 4 .
The study presented here aims to investigate the effect of an increase in coronary sinus pressure on microvascular function in the acute setting, a potentially new therapeutic concept.
Initial evidence from animal studies and a series of patients appears to support the hypothesis that coronary sinus occlusion (CSO) improves microvascular function: Ido et al. 10 demonstrated that coronary sinus occlusion lead to dilatation of the subendocardial arterioles, resulting in a significant reduction of vascular resistance in this area and a redistribution of blood flow to these ischemic subendocardial layers.In a small case series by Giannini et al. 11 , patients with microvascular angina showed a clinical improvement after coronary sinus occlusion, an effect similar to that shown in the randomized, sham-controlled trial COSIRA 12 (improvement of 2 CCS angina classes in 35% of the patients).In the paper by de Maria et al 13 , percutaneous-intermittent CSO (PICSO) improved microvascular perfusion and resistances in patients with no reflow after ST-elevation myocardial infarction.Finally, we recently provided mechanistic evidence that CSO might improve microvascular function in a patient with evidence of severe microvascular dysfunction: in a recent publication (Gori T Eurointervention online), we described a case of a patient with microvascular angina that benefited from the implantation of the Reducer.This 61-year old patient with a history of insulin-dependent diabetes, hypertension, and multiple PCIs underwent implantation of a coronary sinus Reducer for chronic angina refractory to maximal therapy.His symptoms included a CCS III angina leading to 4 hospitalizations in the 6 months before Reducer implantation.In order to better understand the pathophysiology of his symptoms, a full hemodynamic assessment was performed.The fractional flow reserve (FFR) in the left anterior descending (LAD) was 0.87, witnessing the absence of epicardial disease.In contrast, the IMR was 63, documenting increased microvascular resistances as a mechanism of his symptoms.Based on this evidence, and on compassionate grounds, a coronary sinus Reducer was implanted.After implantation, the "trans-sinus" gradient was 3mmHg.FFR and resting full-cycle ratio (RFR) were unchanged (0.93 and 0.85), but IMR dropped to 37. Since implantation (currently 12 months follow-up at the time of this writing), the patient has never been admitted again to hospital and is symptom-free.
Seite 14 von 24 Although this is just preliminary data, they suggest that the redistribution of blood from the subepicardial to the subendocardial space might be associated with a drop in total microvascular resistances and therefore relief of symptoms.

Hypothesis
The hypothesis of the study is that occlusion of the coronary sinus will be associated with a decrease in the index of microvascular resistances.

Study design
The study is a single-center, cross-over sham controlled randomized trial to investigate the effect of coronary sinus occlusion on microvascular resistances.

Trial Endpoints
The primary analysis will be on the per-protocol principle (i.e.including all patients who are not protocol violators).A separate analysis will be performed on an intention-to-treat basis (i.e.all randomized patients randomized to a treatment arm).

Primary endpoint
1. Index of coronary microvascular resistances (IMR) in sham versus balloon condition.

Key Secondary endpoints:
changes in physiological parameters

Hemodynamic measurements
Coronary angiography and pressure wire assessments of coronary stenoses will be conducted as per clinical indication using standard methods.This assessment is commonly performed in the diagnostic algorithm of patients with chronic coronary syndromes without coronary stenoses.In this study, only patients in whom these assessments are planned will be included, such that all methods are used as clinically indicated as part of the normal routine.
As per standard procedures, intracoronary nitrates will be administered before each measurement when blood pressure is above 100mmHg systolic.Pressure wire normalization will be performed at the coronary ostia before each measurement and the presence of drift will be checked at each measurement.The distal position (constant across measurements) of the pressure wire will be documented fluoroscopically.

Study Procedures
Patients enrolled in the study will undergo these procedures as clinically indicated: -Microvascular assessment will be performed in the left anterior descending coronary artery using the wire-based thermodilution method.This assessment of coronary hemodynamics will be performed as clinically indicated, according to guideline recommendations.
-Patients with FFR<0.80 and a focal stenosis (i.e.patients who can be treated with stent implantation) and/or patients with IMR<25 (i.e.without microvascular dysfunction) will be excluded from the study -A 7-9mm balloon (sized to 70% of the coronary sinus) will be advanced in the coronary sinus, with access through the femoral vein.Microvascular function measurements will be made twice (in a random, cross-over design) during incomplete balloon occlusion ("balloon") and with the deflated balloon in the right atrium ("sham").The inflation of the balloon is a study-specific procedure.However, this procedure provides the following information that is important for the treatment of the patient: 1. Whether the IMR drops during coronary sinus occlusion.If this is the case (as in the patient described above), implantation of a coronary sinus reducer is indicated as it would be expected to result in the reduction of angina symptoms.If the inflation of the balloon does not lead to a drop in IMR, then a coronary sinus reducer should not be implanted.
2. In case implantation of a coronary sinus reducer is planned, the balloon allows sizing of the coronary sinus.This increases the safety of the implantation, since the most common complication during sinus reducer implantation is undersizing (resulting in device embolism) or oversizing (resulting in sinus venosus rupture).

Hemodynamic recordings
Pressure wire recordings will be performed using the 0.014-inch pressure wire (Pressure Wire X, Abbott Vascular, St Clara, USA).Analysis will be performed offline using the Coroflow software (Coroventis Research AB Uppsala, Sweden).
For FFR measurements, the pressure wire will be advanced distal into the left anterior descending coronary artery (LAD).The pressure gradient between catheter (Pa, aortic pressure) and distal (wire-measured) pressure (Pd, pressure distal) will be assessed at rest and during adenosine-induced hyperemia (140microgr/kg/min i.v., papaverine 14mg i.c. in case of asthma.If the hyperemic Pd/Pa ratio (FFR, fractional flow reserve) is <0.80, a pull-back recording will be performed to look for focal stenoses.
During hyperemia, three boli of saline will be injected through the guiding catheter to assess parameters of microvascular function.All files will be coded and extracted for study purposes by blinded staff at the end of the study.

Risk associated with participation in the study
All measurements (including hemodynamic measurements) are applied as clinically indicated and according to CE certificate and the instruction for use.The intervention applied in the study is limited to the repetition of the measurement of coronary physiology and the expansion of the angioplasty balloon as described above.Vascular access is performed using the femoral vein; the risks correspond to those of a routinely performed venous puncture.The measurement might have clinical relevance, since "responders" would be expected to profit more from the sinus reducer.Measurements do not require X-Rays per se.The expansion of the balloon is incomplete (only 70% of the vessel diameter) and performed using low pressure (2-4ATM).The risk of trauma is thereby minimal.
Therapies will be based on evidence-based guideline recommendation.Thus, it is not to be expected that the participation in the study will lead to unneeded or harmful therapeutic interventions.

Study population
The study will be conducted in patients with chronic coronary syndrome (including patients with anginal equivalents) and reversible ischemia on non-invasive testing.In the case of therapy-refractory symptoms, the indication for the implantation of a coronary sinus reducer was already clinically established in advance.There must be an indication for cardiac revascularization and an evidence of pure or mixed microvascular disease (index of microvascular resistances (IMR>25).FFR and the further haemodynamic measurements are performed routinely in our laboratory.

Inclusion criteria
Patients must meet ALL of the inclusion criteria: Chronic coronary syndrome (including patients with anginal equivalents); Reversible ischemia on non-invasive testing, indication to cardiac catheterization; Indication to the assessment of microvascular function (note: patients will be asked for participation and consented prior to the first measurement of microvascular function, which will be conducted as per clinical indication; only those with evidence of pure or mixed microvascular disease (index of microvascular resistances IMR>25 will proceed into the study); Willingness to participate and ability to understand, read and sign the informed consent;

Exclusion criteria
Patients will be excluded from eligibility for study enrollment if ANY of the following criteria applies to the patient: Likewise, patients unable to consent, e.g. for a neurological damage, are treated as not being able to give informed consent and are excluded for eligibility for study enrollment.

Recruitment
Patients will be enrolled among those treated at Zentrum für Kardiologie, Kardiologie 1 of the Universitätsmedizin Mainz.

Patients
The decision to perform the hemodynamic assessment of the lesion will be taken before, and independently of, the participation of the patient in the study.
Consent will be obtained by study physicians before beginning of the procedure.
It is not planned to recruit patients who are not already in medical treatment in the center of cardiology of the university hospital Mainz and, therefore, it is not planned to create any recruiting material, e.g. for promotion of the study.

Pre-interventional Procedures
Per standard clinical practice, the following baseline procedures will be performed prior to enrolment: − Medical history and physical examination, including (among others) pulses, blood pressure, height and weight (body mass index; BMI).

Randomization
Randomization will be performed after informed consent and if all inclusion criteria and no exclusion criteria are met.
Patients will be randomized 1:1 to one of the two study arms.
Randomization will be done by using a computer-generated random sequence (Medcalc, Mariakerke, BE).

Important note:
The inflation of the balloon in the coronary sinus is a study-specific procedure, but it provides information (feasibility of coronary sinus cannulation/sizing/effect of coronary sinus occlusion on microvascular resistances) which is important for the treatment of the patient (i.e.whether implantation of a sinus reducer is indicated).All procedures are conducted based on the clinical indication, using CE-marked devices, and according to universally accepted standards.

Post-interventional procedures
After intervention, patients will be treated according to guidelines by the responsible doctor as per standard practice.
The medication treatment after intervention will be selected according to current guidelines and depending on indication of coronary intervention and severity of disease.Until discharge, patients will be treated according to routine practice, incorporating patients´ individual comorbidities.
In case additional an (staged) revascularization is deemed necessary at the time of randomization, it can be performed during index hospitalization or later and patients should be treated according to current guidelines.

Risks and benefits
Risks are linked with any intracoronary procedures and it is not expected that participation in the study will affect them.Access to the coronary sinus is performed through the femoral vein, which will be punctured as part of the study.The risks are similar to those of venous vessel puncture and are considered to be relatively low.The angioplasty balloon is expanded incompletely and at low pressure, so there is no relevant risk of vessel injury.

Risks
Risks linked with any intracoronary procedure: There is no benefit for the individual patients participating in the study.

Study insurance
Since all procedures (except for randomization) are clinically indicated and acknowledged in the current literature, a study insurance is not planned.
Seite 24 von 24 research.Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports.All parties should adhere to accepted guidelines for ethical reporting.Negative and inconclusive as well as positive results must be published or otherwise made publicly available.Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication.
Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.
The PI of this study, recognizing the seminal importance of this investigation, is committed to the unrestricted and widespread dissemination of all primary and secondary endpoint results and tertiary analyses.At the conclusion of the study, a abstract reporting the primary results will be prepared by the Principal Investigators and presented at an annual scientific meeting (e.g., Transcatheter Cardiovascular Therapeutics, EuroPCR, the American Heart Association, the American College of Cardiology, or the European Society of Cardiology meeting).A publication will similarly be prepared for publication in a reputable scientific journal.
Following analysis and presentation of the primary endpoint results, active participation of all study group members, will be solicited for data analysis and abstract and manuscript preparation and therefore included as co-authors.Submission of all abstracts and publications regarding the primary endpoint and secondary endpoints from the study requires approval by the Principal Investigators after review by all members of the study group.

I
will conduct the studies in accordance with the protocol, the Declaration of Helsinki, Good Clinical Practice guidelines as well as local regulations, and I accept respective revisions to the protocol approved by authorized personnel of the Sponsor and by regulatory authorities.I agree to report every occurring Adverse Event and Device Deficiency according to the timelines and regulations indicated in the CIP.Mainz, 25 th August 2020 City, Date Signature of Principal Investigator

4 .
Pa and Pd at rest and during hyperemia (aortic and coronary pressure); 5. Hyperemic Tmn; 6. RRR: Resistance Reserve Ratio (a marker of microvascular reactivity); 7. CFR: coronary flow reserve; 8. CFR_norm: CFR normalized by FFR; 9. PB-CFR: Pressure bounded; Note: all these parameters are assessed during an FFR/IMR measurement as clinically indicated in this patient population and do not require additional procedures or imply additional risks.
Previous CABG with patent grafts to the left anterior descending coronary artery Epicardial coronary disease (FFR <0.80 with evidence of a focal stenosis) in the left anterior descending territory Second and third degree atrioventricular block Severe valvular heart disease Any cardiomyopathy; pulmonary or renal disease Inability to provide informed consent Any disease reducing life expectancy Patients unable to understand the scope of the study/unable to consent Patients unable to understand the scope of the study are classified as not able to give informed consent and are excluded for eligibility for study enrollment.