Professor C Noel Bairey Merz

Important advances in the study of Womens Heart Disease

Twenty-five years ago, 1 in 3 women died of heart disease – today the number is 1 in 4. This is progress, of course, but it is not enough. Too many women are still being diagnosed with tests designed for men and treated with drugs tested on men. Too many women with chest pain or other relevant symptoms are being told they don’t have heart disease. Thanks to you, our philanthropic family, we are changing this reality, with research that is influencing guidelines and policies now going out across the globe to help women everywhere.

At the Barbra Streisand Women’s Heart Center, we are moving forward on several fronts simultaneously.  We are advancing the largest-ever clinical trial evaluating treatment for ischemia (reduced blood flow) and chest pain in women with open coronary arteries–a condition we call no obstructive coronary artery disease (INOCA). We also completed a pilot study testing the use of a patient’s own specialized stem cells to improve outcomes for INOCA, and we are happy to report the initial findings are very positive.

Of special note, our research has yielded possible insights into why women tend to develop different types of heart disease at different times than men, showing for the first time that women’s blood vessels appear to age at a faster rate. We also pushed forward investigations into coronary microvascular dysfunction (CMD), heart failure with preserved ejection fraction (HFpEF), pregnancy and heart disease, and increased heart risk in young women, among other pressing research.

This past year, we also saw the birth of an important multidisciplinary initiative at Cedars-Sinai that seeks to address and upturn gender bias in medicine. 

Professor John Beltrame

MINOCA: What is it and why is it important?

Myocardial Infarction with Non-obstructive Coronary Arteries (MINOCA) is a clinical diagnosis for patients who have experienced a heart attack (myocardial infarction) but without significant coronary artery narrowing (ie <50% lesions on coronary angiography) to account for the heart attack. The term was first coined in 2013 in an editorial but widespread interest rapidly evolved following a seminal study detailing its prevalence, clinical characteristics, potential causes and prognosis. Subsequently, professional cardiology societies have released position papers and the term has been included in the latest universal definition of myocardial infarction.

What are the characteristics?
Patients with MINOCA account for approximately 5-10% of patients with an acute heart attack. Compared to patients who have myocardial infarction with obstructive coronary artery disease (MI-CAD), patients with MINOCA tend to be younger, less likely to have high cholesterol levels and women are over-represented. The cause of the heart attack in patients with MINOCA can include erosions of the coronary artery wall, coronary spasm or conditions associated with increased clotting risk. The 12-month prognosis in MINOCA is better than patients who have MI-CAD but not as reassuring as those who have not experienced a heart attack.

Why is it important to diagnose?
Prior to the term ‘MINOCA’ being developed, patients with these clinical characteristics were considered as ‘false positive’ heart attacks (ie not ‘real heart attacks’). Hence a common scenario experienced by these patients was being told in the emergency department they ‘had experienced a heart attack and required a coronary angiogram’ but when this was normal, they were typically told they ‘hadn’t had a heart attack’; clearly patients (and clinical staff) were often confused with their diagnosis. Introducing the term ‘MINOCA’ has achieved several important goals including (a) providing the patient with an established diagnosis, thereby recognising they have had a heart attack, (b) acknowledging the patient’s prognosis is guarded but better than those with obstructive coronary artery disease, (c) emphasising that ‘MINOCA is a working diagnosis’ and that the underlying cause of the heart attack needs to be identified, and (d) enabling clinical research studies to be undertaken on this defined disorder. With regard to the last goal, the first prospective clinical trial in MINOCA is currently in progress and seeks to determine if conventional cardioprotective agents used in MI-CAD are beneficial in patients with MINOCA. This clinical trial and other research studies will continue to improve our understanding and management of MINOCA.

You can read our summary sheet on MINOCA here

Professor Colin Berry

Diagnosis and treatment of Microvascular and Vasospastic angina

Angina is a symptom involving chest tightness, chest pain, with or without breathlessness, dizziness or weakness. Angina is triggered by a lack of blood supply to the heart. Usually, doctors look at angina in terms of finding blockages in the main heart arteries, but angina may also occur due to problems with the small vessels which are typically less than half a millimetre in size. In the UK, angina affects around 2 million people, at least one third of whom may have angina due to small vessel problems including microvascular angina, vasospastic angina, or both.

Microvascular angina is caused by abnormalities of the small vessels in the heart. The walls of the blood vessels themselves become stiff or thicken or the inside of the blood vessel becomes narrower. In some individuals the blood vessels go into spasms temporarily causing the blood vessel to narrow. These problems may limit blood supply to the heart causing anginal chest symptoms during exercise and at other times for example during cold weather or with emotional stress and even at rest.

The pain experienced by patients with microvascular angina can be disabling and as bad or even worse than other types of angina. The psychological burden of patients living with poorly controlled chronic and debilitating acute pain is profound. This along with the inability to carry out normal day to day activities leads to a poor quality of life for many individuals living with microvascular angina.

These conditions are generally under-diagnosed. The standard test in the NHS is a coronary angiogram, however, the small vessels are too small to be seen, hence doctors are not well placed to make the diagnosis. In fact, until recently, there has been no clinical evidence to support the notion that using tests of small vessel function would make any difference to the wellbeing of patients.

You can find our Summary sheet on Coronary Artery Spasm here
You can find our summary sheet on Microvascular Angina here

Professor Paolo Camici

Diagnostic Flowcharts in Coronary Microvascular Dysfunction

Currently available techniques do not allow direct visualisation of the coronary microcirculation in vivo. Assessment of coronary microcirculatory function can be done invasively and non-invasively using techniques that rely on the functional integrity of the coronary microcirculation. A standard criterion for MVA is the documentation of a reduced CFR and/or the occurrence of microvascular spasm (Table 2). The choice of testing modality relates to availability and expertise and suspected mechanism. For the assessment of CFR, noninvasive myocardial blood flow measurements using PET assessment of myocardial perfusion with CMR during maximal hyperemia induced by administration of vasodilators, or coronary flow velocity measurements using transthoracic Doppler echocardiography, can also be used. The latter is measured by pulsed wave Doppler echocardiography, using a sample volume of ~3–4 mm3 positioned on the colour signal of the artery. The measurements are usually done in the distal part of the left anterior descending coronary artery as this portion of the vessel allows proper visualisation due to the proximity of the artery to the chest wall. The pattern of coronary blood flow velocity is biphasic, with a larger diastolic than systolic component; for this reason, only the diastolic component is usually measured. PET allows determination of CFR by quantification of myocardial blood flow per gram of tissue both at rest and during pharmacological vasodilatation.

Many patients with CMD will undergo invasive coronary angiography and this provides the opportunity for the assessment of flow reserve using invasive techniques normally available in the catheterization laboratory. These include measurement of coronary flow velocity reserve using a Doppler flow wire or of coronary blood flow reserve using a combined pressure/thermodilution wire. These techniques have been extensively validated and have been shown to be safe. Independent of the technique used, CFR values below or equal to 2.0 or 2.5, depending on the methodology used, are indicative of CMD. Recently, Doppler-derived hyperemic microvascular resistance and thermodilution-derived index of microvascular resistance have emerged as new techniques for assessment of CMD. The guarded prognosis of patients with confirmed CMD justifies an invasive approach to establish an unequivocal diagnosis of this condition.

Coronary microvascular spasm, which is different from focal epicardial coronary artery spasm (as seen in Prinzmetal’s variant angina), can be inferred during angiographic studies in patients with chest pain despite angiographically unobstructed coronary arteries using intracoronary acetylcholine testing. Investigation is needed to determine the sensitivity and specificity of microvascular spasm using acetylcholine as several reports have shown a high sensitivity and specificity (i.e. 90% and 99%, respectively) for intracoronary acetylcholine testing in patients with suspected epicardial spasm. In patients with non-diagnostic acetylcholine-test results for microvascular spasm (e.g. reproduction of symptoms during the test without signs of ischemia or signs of ischemia without symptoms, transient metabolic alterations (e.g. coronary sinus lactate production, low oxygen saturation) may be indicative of CMD.

Dr Ailsa Care

CAS/CMVD from a GP Perspective

As a GP, through my training, I was never taught anything about CAS/CMVD. The only condition I knew anything about was Prinzmetals angina which I was led to believe was uncommon. 

I have been lucky enough to care for a patient with both CAS and CMVD and be part of her journey from presentation through investigation to diagnosis and treatment. The journey has not been an easy one and for myself as a GP it has involved questioning the opinion of a consultant cardiologist, who advised my patient it was not a cardiac chest pain, and referring for a second opinion. 

I am very happy to be involved with INOCA and helping to raise the awareness of these under-recognised conditions amongst the medical profession, particularly GPs. I believe that if CAS/CMVD are considered as potential diagnoses by GPs in patients presenting with atypical chest pain then this can be flagged on a referral letter and the appropriate investigations done. Hopefully this would reduce the time from presentation to diagnosis significantly. 

Professor Filippo Crea

Heart Failure with Preserved Ejection Fraction – HFpEF

Microvascular angina (MVA)  and heart failure with preserved ejection fraction (HFpEF)  are two diseases that have overlapping clinical presentations and high prevalence among post-menopausal women. Furthermore, no therapeutic intervention has hitherto been proven to improve patient outcome; similarly, symptomatic treatment is largely empirical. Based on the above considerations, the question arises as to whether these parallel ‘tales’ of MVA and HFpEF represent two extreme clinical presentations of a disease continuum (Figure). This tantalizing question is justified by the results of recent studies showing that CMD can be demonstrated not only in MVA but also in HFpEF.

The hypothesis of a common soil for these two conditions appears to be endorsed by the clinical observation that dyspnoea is present in a large proportion of patients with MVA and, vice versa, angina-like symptoms are reported in about 50% of those with HFpEF. Several factors have been reported to predispose to CMD, including traditional risk factors such as smoking, hypertension, and diabetes as well as chronic inflammatory diseases, such as chronic obstructive pulmonary disease, chronic kidney disease, and auto-immune conditions. CMD is well documented in MVA and responsible for the reduced coronary flow reserve (CFR) frequently observed in this condition. Recent studies suggest that CMD might play a key role also in HFpEF. Indeed, endothelial activation/dysfunction reduces nitric oxide (NO) bioavailability, cyclic guanosine monophosphate content, and protein kinase G in adjacent cardiomyocytes. These considerations advocate action to develop appropriate diagnostic and therapeutic strategies for tackling these ‘new’ disease epidemics in the years to come.

Professor Thomas Lüscher

Takotsubo

Professor Mario Marzilli

Myocardial Ischaemia – From Disease to Syndrome

“ Many, many years ago lived an emperor, who thought so much of new clothes that he spent all his money in order to obtain them; his only ambition was to be always well dressed …”. This is how began a tale written in 1837 by Christian Andersen. The story was about people that deny even the most obvious evidence and pretend not to see what is in front of their eyes just to follow the prevailing trend and for the fear to contradict the ‘Emperor’.

Current Cardiology is reminiscent of that old tale, with a diffuse reluctance to accept:

a. Lack of prognostic benefit with a routine invasive strategy in patients with chronic ischemic syndromes.

b. Persistence of angina in a substantial fraction of patients after stenosis removal.

c. Low prevalence of obstructive coronary atherosclerotic lesions in patients with typical angina and/or documented myocardial ischemia.

d. High rate of peri and post-procedural complications of PCI.

This evidence strongly challenges the “stenocentric” conception of myocardial ischemia and explains why Guidelines recommended, since long ago, to consider revascularization only in patients with angina despite optimal medical therapy, and why, more recently, they have officially acknowledged that  myocardial ischemia is a complex, multifactorial, dynamic, life long condition. This new understanding of myocardial ischemia has prompted a change in name for this condition: from disease to syndrome.

This new, revolutionary conception offers both challenges and opportunities to Cardiologists and patients as well. Diagnostic, therapeutic, and prognostic processes have all to be reconsidered and redesigned. Detecting an atherosclerotic obstruction can no longer be accepted as a surrogate for diagnosing myocardial ischemia and absence of coronary obstructions should no longer be considered enough to rule out myocardial ischemia. Most recent epidemiologic reports suggest that the probability of a stenosis is lower than 30% in male patients with typical angina and even lower in female patients. The obvious conclusion of these figures is that typical angina is associated in the majority of patients with non-obstructive mechanisms (INOCA) and that, even when an obstruction is present, other mechanisms may also be present, and be responsible for post-PCI angina.

Signs and symptoms of transient myocardial ischemia should be searched and documented for a definite diagnosis. The identification of the mechanism(s) responsible for ischemia in a specific patient is the second step in the management of a patient and is essential to plan a tailored treatment.

These conceptions are not really new. The role of functional mechanisms (vasospasm), the relevance of microvascular function/dysfunction, even the possibility that non-vascular mechanisms may precipitate myocardial ischemia have all been proposed decades ago.  Unfortunately, the Cardiology community has reacted with scepticism or overt disbelief, but in the meantime the body of evidence supporting the multifactorial nature of myocardial ischemia has become overwhelming and can no longer be overlooked.

Dr Haseeb Rahman

Coronary Microvascular Dysfunction

Until recently, angina was believed to be exclusively associated with narrowings in the main coronary arteries visible during angiography. However approximately half of all patients with angina will have apparently normal coronary arteries and we are increasingly recognising the health burden associated with coronary microvascular dysfunction and coronary spasm.

Our research group’s expertise with novel coronary physiology tools, including catheter laboratory exercise combined with cross-discipline collaboration at King’s College London, has led to many recent advances in the field of coronary microvascular dysfunction. We have implemented national protocols to facilitate routine diagnosis of these conditions whilst establishing a concerted research effort. Our ongoing research efforts have led to greater recognition, diagnosis, understanding and hopefully better therapies for these common yet poorly understood conditions.

Christine Whitten MD

Anaesthesiologist

Coronary Microvascular Disease, for example I.N.O.C.A., causes disruption of blood and oxygen supply in the microcirculation. Its common for pulse oximeter readings in these patients to be normal during an acute flare up. This can mislead attending staff to believe that the oxygen supply is at a good level and that there is no problem. It confuses patients who ask: “How can I have a normal oxygen saturation while at the same time my heart muscle lacks enough oxygen (is ischemic)”? Despite the current widespread use of pulse oximetery to measure hemoglobin oxygen saturation (O2 Sat), many people don’t fully understand what it does and does not measure. To better understand how oxygen saturation can be normal, while at the same time the heart or other organs may not be getting enough oxygen, we need to review:

What is hemoglobin (Hgb)

What oxygen saturation is, and is not

The concept of oxygen supply and demand

How oxygen saturation can be misinterpreted