Dr Sivabaskari Pasupathy

Coronary artery disease (CAD) is a condition in which there is an inadequate supply of blood and oxygen to the myocardium. It mostly results from occlusion of the coronary arteries and results in a demand-supply mismatch of oxygen. It is a cause of major morbidity and mortality in Australia and worldwide. The diagnosis and management of acute and chronic obstructive CAD are well established in clinical guidelines and often involve coronary angiography to determine the severity of CAD and its management. However, 30-50% of these coronary angiogram procedures demonstrate No Obstructive CAD to account for the patient’s symptoms. These patients are now labeled as NOCA (Non-Obstructive Coronary Artery) syndromes, and have typically been overlooked and misdiagnosed as ‘non-cardiac chest pain’. However, studies have demonstrated that the symptoms may arise from coronary vasomotor disorders not evident on coronary angiography. We have created the term MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries) to highlight the acute NOCA syndromes and the term INOCA (Ischaemic with Non-Obstructive Coronary Arteries) to describe the chronic NOCA syndromes. In both of these NOCA syndromes, coronary vasomotor disorders (ie large vessel coronary spasm and/or coronary microvascular dysfunction) may be responsible for the clinical presentation. Our group is recognized as an international leader in this field. 

Project 1

Title: Coronary Angiogram Database of South Australia (CADOSA): Improving health outcomes in patients undergoing coronary angiography

Description: Coronary angiography is the clinical benchmark technique in the assessment of coronary artery disease with more than 6,000 performed in South Australia each year. Despite its diagnostic benefits in identifying the presence of coronary disease, its benefit to the patient has been less rigorously studied and will be the focus of this project. CADOSA is an internationally renowned clinical registry incorporating global links with organizations including the American College of Cardiology National Cardiovascular Data Registry and the International Consortium of Health Outcomes Measurement (ICHOM).

Projects Available: Honours and HDR

Location: Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital

Special Requirements: DCSI Clearance, Vaccinations

Project 2

Title: Clinical and Vasomotor Studies of Patients with Myocardial Infarction and Non-Obstructive Coronary Arteries (MINOCA)

Description: Approximately 5-10% of patients who experience a myocardial infarct do not have significant coronary artery disease, prompting the clinical question of what is the underlying mechanism. This project will (i) integrate with established registry studies to assess clinical outcomes and health status of MINOCA patients and (2) utilise invasive and non-invasive clinical techniques to elucidate potential mechanisms that may be responsible for the myocardial infarct.

Projects Available: Honours and HDR

Location: Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital

Special Requirements: DCSI Clearance, Vaccinations

Project 3

Title: Anti anginal efficacy of treatment strategies.

Description:  Randomised, double-blind, placebo-controlled crossover study assessing the anti-anginal benefits and impact on the health status of in ANOCA patients experiencing angina.

Projects Available: Honours and HDR

Location: Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital

Special Requirements: DCSI Clearance, Vaccinations

More information about the project areas is below. 

Angina with Non Obstructive Coronary Arteries (ANOCA)

Angina is chest pain attributable to myocardial ischaemia. Typically, it arises from coronary artery stenoses that obstruct blood flow and can be readily visualized by coronary angiography. These coronary stenoses are located in the large coronary arteries (1-5mm in diameter) and can be effectively treated with reperfusion therapies such as percutaneous coronary intervention and/or coronary artery bypass grafting, as well as medical management. However, angina may also arise from constriction of the coronary microscopic blood vessels (<0.5mm in diameter; ie coronary microvascular dysfunction) or the large epicardial coronary arteries ( ≥ 0.5mm in diameter; ie coronary artery spasm). These large and microscopic vascular dysfunctions may be due to a dysfunctional blood vessel lining (the endothelium).

Since the advent of coronary angiography, our understanding of large-vessel coronary artery disease has dramatically improved, as have our therapies for this condition. However, in 30% of patients with angina, angiography does not reveal obstructive CAD and the myocardial ischemia may be due to vasospastic angina (large vessel coronary artery spasm) or microvascular angina (coronary microvascular dysfunction. Collectively, these patients are labeled as ANOCA (Angina with Non-Obstructive Coronary Arteries) with at least 1,800 patients/year being afflicted within South Australia. These patients are significantly disabled with impaired quality of life and have limited available effective therapies, except for calcium channel blockers in vasospastic angina. There is a need to develop novel therapies tha effectively target coronary vasomotor dysfunction.

Project 1: ZIANOCA Trial (Recruiting)

Zinc (Zn), an essential micronutrient, is critical to the functioning of many metalloenzymes and transcription factors. Zinc deficiency can exacerbate or complicate disease in multiple organ systems. We have demonstrated the importance of Zn homeostasis for the vasculature, including potentiating vasodilator responses via the nitric oxide production and inhibiting endothelin-1-induced constriction. We have recently conducted the first systematic study in Australian cardiac patients, showing a high prevalence of Zn deficiency (29% of 400 patients assessed), associated with worse disease. ZIANOCA trial (The efficacy of Zinc in ANOCA trial) is a Randomised, double-blind, placebo-controlled crossover study assessing the anti-anginal benefits and impact on health status of Zn gluconate 30mg once daily in ANOCA patients experiencing angina at least 3 times/week.

Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA)

Our understanding of heart attack acute myocardial infarction (AMI) has evolved considerably over the past 50 years, which has given rise to innovative therapies that have improved patient outcomes. Each year, 55,000 Australians suffer an AMI whereby treatment is centered around a prompt diagnosis of coronary artery blockages followed by coronary interventions to re-open the artery. However, in 10% of myocardial infarction patients (6,000 annually), a blockage is not identified and so the cause and management for patients are unclear. During my Ph.D., I generated the first landmark systematic review publication characterizing these patients (Circulation). These presentations are referred to as MINOCA and is now an established clinical entity. However, in clinical practice, the MINOCA diagnosis is often neglected as patients are considered to be “false positive infarcts”. Importantly, the management of these intriguing patients is predicated upon their initial recognition and subsequent evaluation to elucidate the pathophysiological processes responsible for their presentation.

WHAT is MINOCA? 

1. AMI as per the “Fourth Universal definition of MI” Criteria.
2. Nonobstructive coronary arteries on angiography: the absence of obstructive disease on angiography (ie, no coronary artery stenosis ≥50%) in any major epicardial vessel.
3. No specific alternate diagnosis for the clinical presentation: Alternate diagnoses include but are not limited to non-ischemic causes such as sepsis, pulmonary embolism, and myocarditis.

Specific causes of MINOCA Presentations: Atherosclerotic vs Nonatherosclerotic Causes of Myocardial Necrosis

• Plaque disruption: approximately 1/3 of MINOCA undergoing intravascular ultrasound testing.
• Coronary Spasm: approximately 50% of MINOCA undergoing provocative spasm testing.
• Microvascular Dysfunction: needs to be studied in the MINOCA population
• Coronary embolism/Thrombosis: inherited hypercoagulable states in patients with MINOCA, especially in younger women
• Spontaneous Coronary Artery Dissection: Rare and Should be suspected mainly in young women

WHY Diagnose MINOCA?

Because MINOCA is a new diagnostic syndrome, the question arises as to why it should be created. There are 3 key reasons for establishing this new clinical entity, which includes (1) ensuring its clinical recognition, (2) prompting the evaluation of its underlying cause, and (3) the guarded prognosis.

• Clinical Recognition Some clinicians consider coronary angiography as the gold standard test for establishing a diagnosis of AMI. For example, acute ST-elevation MI (STEMI) registry studies have labeled patients presenting with acute ST elevation and non-obstructive CAD on angiography as a “false-positive STEMI diagnosis”. In some cases this may be appropriate if the ECG is misinterpreted. However, if the patient exhibits new ST elevation with a significant troponin rise and non-obstructive CAD on angiography, they should be diagnosed as MINOCA. Labeling such patients as “false-positive” AMI will result in these patients being dismissed as having a cardiac event and therefore discharged without further evaluation or appropriate treatment. In contrast, a diagnosis of MINOCA should flag these patients as requiring further cardiac assessment.
• Evaluating the Underlying Cause As listed above in the specific causes of MINOCA, a diagnosis of MINOCA should be a “working diagnosis”, flagging the necessity to evaluate the patient for the potential underlying cause of this presentation.
• Guarded Prognosis The prognosis of patients with MINOCA is unclear and likely to be heterogeneous, considering the diverse mechanisms responsible for the syndrome. Pooled analysis of 8 studies that followed up patients with MINOCA suggests an in-hospital all-cause mortality of 0.9% (95% confidence interval (CI): 0.5%, 1.3%) and 4.7% (95% CI: 2.6%, 6.9%) at 12 months.  Analysis of AMI registries that compared patients with an AMI associated with obstructive CAD with those with MINOCA suggests that the latter have a more favorable prognosis. However, it is disconcerting that patients with stable chest pain (who have not experienced a recent AMI) in the absence of obstructive CAD, have an annual all-cause mortality of 0.3%. Moreover, in the prospectively conducted Korean MI Registry, the MINOCA patients had the equivalent 12-month all-cause mortality to those with an AMI associated with single- or double-vessel CAD. Hence patients with MINOCA should receive the same clinical attention as AMI patients who have single- or double-vessel disease and not merely dismissed as having an insignificant clinical condition.

MINOCA RESEARCH AT UNIVERSITY OF ADELAIDE 

1. MINOCA-BAT (MINOCA-Beta blockers and/or ACE-I/ARB Therapy) Trial (Recruiting): Stemming from AMI management guidelines, the European Society of Cardiology Position Paper on MINOCA recommended beta blockers, ACE inhibitors, dual antiplatelet agents and statins as empiric therapeutic strategies. Observational data from the SWEDEHEART Registry supports the use of ACEI/ARB and statins, with equivocal data for beta-blockers and no benefit from dual antiplatelet therapies. Given the inherent risk of residual confounding in observational studies, the results need to be prospectively validated in a randomised clinical trial. This led to the present pragmatic international multicentre MINOCA-BAT trial. In this trial, it is hypothesized that long-term treatment with ACEI/ARBs and/or beta-blockers will reduce the risk of all-cause death, myocardial infarction, stroke or heart failure in patients with MINOCA and preserved ejection fraction. The MINOCA-BAT Study is an investigator-initiated, registry-based, pragmatically-designed, international, multicentre, open-labelled, 2x2 factorial design, randomised controlled trial.

2. Post Infarct Angina in MINOCA Trial (Recruiting): over a quarter of MINOCA patients continue to experience chest pain (Post-Infarct Angina) over the next 12 months, with an initial prevalence higher than patients with MI and obstructive coronary artery disease (MI-CAD). Post Infarct angina in MINOCA aims to determine whether oral beta-blockade and/or ACEI/ARB in MINOCA patients with post-infarct angina impacts on post-infarct angina at 12 months, where angina frequency is assessed with the Seattle Angina Questionnaire (SAQ).

3. MINOCA CATH study (In Progress): The overall purpose of this project is to identify the prevalence of ischaemic mechanisms in patients with MINOCA. Identifying these ischaemic mechanisms requires invasive coronary assessment with the findings have major implications in affected patients. For example, those with inducible spasm require calcium channel blockers as a cornerstone therapy, patients with plaque disruption would benefit from statin therapy, those with coronary emboli should have anti-thrombotic therapy, and those with coronary microvascular dysfunction may benefit from therapies targeting the microcirculation. The project will specifically evaluate the following pathophysiological mechanisms based upon local experience and safety considerations: (i) coronary microvascular dysfunction, (ii) plaque disruption, and (iii) plaque associated thrombi.

4. MINOCA Health Status Assessments (In Progress): Coronary Angiogram Database of South Australua or CADOSA is a unique registry that collects clinical details on all patients undergoing coronary angiographyat South Australian public hospitals with data collected by trained staff dedicated to this task. Since commencing in 2012, there are over 30,000 patient records, including patients MINOCA. The data collected includes detailed chest pain history, risk factors, past history, medications and angiographic findings. In addition, the SAQ-7, PHQ-9, and EQ5D are established and validated health status instruments that respectively document angina frequency (including the impact of angina on physical limitations and quality of life), depression, and generic quality of life. These are collected at baseline,1, and 12 months via CADOSA registry. 

Coronary Slow Flow Phenomenon (CSFP)

Coronary microvascular dysfunction is an ‘abnormal coronary microvascular resistance (either arteriolar or pre-arteriolar) that is clinically evident as an inappropriate coronary blood flow response, impaired myocardial perfusion and/or myocardial ischaemia that cannot be accounted for by abnormalities in the epicardial coronary arteries.’ Typically, it clinically manifests as angina but its diagnosis may be overlooked if the clinician is not vigilant to its potential presence. Coronary microvascular dysfunction (CMD) may occur in the context of myocardial disease (eg myocarditis or hypertrophic cardiomyopathy), epicardial coronary artery disease (eg atherosclerotic obstructive coronary artery disease or acute myocardial infarction), or associated with iatrogenic conditions (eg the no-reflow phenomenon, post-percutaneous coronary intervention angina). Moreover coronary microvascular dysfunction may occur in the absence of these conditions, such as the primary coronary microvascular disorders (syndrome X, microvascular angina, microvascular spasm and the coronary slow flow phenomenon). Although CMD is frequently encountered in clinical practice, its management is challenging since many conventional anti-anginal agents primarily target the large epicardial coronary vessels and thus have limited impact on CMD.

What is coronary slow flow?

Nearly 50 years ago, Tambe and colleagues initially described this angiographic entity in patients with angina symptoms where they noted the injected contrast during coronary angiography moved very slowly through the coronary arteries, and aptly named “coronary slow flow phenomenon”. The prevalence is estimated at approximately 1-6% of elective angiograms. The condition was largely neglected until Professor John Beltrame identified the distinct clinical features associated with this intriguing entity and thus concluded the coronary slow flow phenomenon was a new coronary disorder rather than angiographic curiosity. Evidence suggests that the coronary slow flow phenomenon leads to clinical manifestations of ischemia, arrhythmias, acute coronary syndromes and even sudden cardiac death.

How is coronary slow flow diagnosed?

Coronary slow flow phenomenon is usually identified subjectively by visual judgment.

• Thrombolysis in myocardial infarction (TIMI) flow grade reflects the speed and completeness of the passage of the injected contrast through the coronary tree. In the setting of coronary slow flow, diagnosis can be made on the basis of TIMI 2 flow grade (ie: requiring ≥ 3 beats to opacify the vessel).
• Corrected TIMI frame count (CTFC) facilitates the standardization of TIMI flow grades and flow assessment. It represents the number of cine-frames required for contrast to first reach standard distal coronary landmarks. TIMI frame count > 27 frames have been frequently used to diagnose slow flow.

What is the medical management for the coronary slow flow phenomenon?

Although coronary slow flow phenomenon patients have good overall prognosis, ongoing anginal episodes result in considerable impairment of their quality of life. Professor Beltrame has been long fighting the battle of identifying appropriate management for these patients, in particular, therapies that limiting the anginal episodes. His group has shown dipyridamole and mibefradil has some benefit in this setting, yet larger studies are required to confirm these findings. Currently available anti-anginal agents are of limited clinical value. To date, no large trial testing pharmacological approaches has been conducted, and the evidence available is derived from small studies, some with inhomogeneous inclusion criteria.

CSFP RESEARCH AT THE UNIVERSITY OF ADELAIDE 

1. Ticagrelor In Coronary Microvascular Dysfunction (TIC) Trial (Completed):  The CSFP is a primary coronary microvascular disorder that is frequently associated with recurrent chest pain and poorly controlled with conventional anti-anginal agents. Ticagrelor has potential anti-anginal benefits for patients with the CSFP since it may ameliorate the associated coronary microvascular dysfunction via its effects on endogenous adenosine levels. A previous study utilizing another agent that increased adenosine levels (dipyridamole), showed a trend towards improvement in the CSFP patients but the study was constrained by the poor tolerance of this agent due to headaches (an effect that is not problematic with ticagrelor). The primary objective of this trial is to assess the effect of ticagrelor 90mg bd on angina frequency in patients with the CSFP who experience angina at least 3 times/week.

2. Zibotentan in CSFP Trial (Completed): Studies conducted both at the University and at other sites, have implicated ET-1, a potent microvascular vasoconstrictor) in the pathogenesis of the CSFP. Key supporting findings include: (i) intracoronary ET-1 infused in animal models reproduces the angiographic findings of the CSFP, (ii) ET-1 levels are elevated in patients with the CSFP, (iii) an endothelin gene mutation is strongly linked to the CSFP, (iv) intravenous ET-1 infusion in healthy humans replicates physiological parameters associated with the CSFP and (v) subcutaneous microvessels from CSFP patients exhibit a selective hyper-responsiveness to ET-1. Furthermore, our previously conducted randomised, double-blind, placebo-controlled, cross- over trial evaluating the anti-anginal benefits of bosentan (a combined ET-A/ET-B receptor blocker) in patients with the CSFP showed a nonsignificant trend for anti-anginal benefit compared to placebo. This finding may reflect (a) a type II error due to an insufficient sample size, and/or (b) use of a combined ET-A/B receptor blocker rather than a specific ET-A receptor blocker. Hence a sufficiently powered study using a specific ET-A blocker may produce more favourable results. Zibotentan is a potent ET-A receptor blocker with no effect on the ET-B receptor. Moreover, it will be the first study to confirm the anti-anginal benefits of selective endothelin receptor blockade and may have implications for broader coronary artery disease conditions. The primary objective is to assess the effect of Zibotentan 10mg once daily/mane on angina frequency in patients with the CSFP who experience angina at least 3 times/week.