Physical Examination in Aortic Valve Disease

Physical Examination in Aortic Valve Disease: Do We Still Need it in the Modern Era?

Vol. 18, N° 12 - 26 Feb 2020

Dr. Roxana-Nicoleta Siliste

Assoc. Prof Calin Siliste

Compared to echocardiography, auscultation is of low sensitivity in detecting aortic valve lesions (56.6-73%), but has a high agreement rate between examiners and a high specificity (92-98%). This is why, even in the era of high technology, physical examination still plays a crucial role in the screening, diagnosis and the severity assessment of aortic valve disease. The classic signs such as a "parvus et tardus" carotid pulse, a loud late-peaking systolic murmur in the aortic area or a diminished A2 correlate with the severity of aortic stenosis, while wide pulse pressure and a holodiastolic regurgitant murmur are the hallmark findings in significant chronic aortic regurgitation.

Topic(s):

Valvular Heart Disease

Introduction

Aortic valve disease, especially aortic stenosis (AS), has an increasing prevalence worldwide, so a good screening tool for the selection of patients being referred for further testing and surgical or interventional procedure is always needed. For many years, the physical examination based mostly on cardiac auscultation represented the most useful bedside diagnostic tools for the diagnosis of these diseases. Unfortunately, expertise and proficiency in auscultation has been diminishing in the modern era, since new technologies have been developed.

Increasingly, over the years, cardiac auscultation has tended to be replaced by sophisticated high technology - electronic stethoscopes, handheld ultrasound or echocardiographic evaluation. Until now, there has been no evidence to support the role of auscultatory devices in increasing the sensitivity of auscultation. There were several studies that showed some benefit of handheld ultrasound (HHU) versus physical examination for the diagnosis of different cardiac diseases, but there are no substantial data concerning the role of HHU in the screening of asymptomatic aortic valve lesions. A systematic review by Stanger et al. showed that the sensitivity and specificity of insonation in identifying AS ranged from 62% to 94% and 85% to 98%, respectively, and that these ranges were similar to auscultation [1].

Compared to echocardiography, auscultation is of low sensitivity (56.6-73%) in detecting aortic valve lesions, but with a high agreement rate between examiners and a high specificity (92-98%) [2,3]. The lowest sensitivity was found in subjects with aortic regurgitation (AR), mild valve lesions, as well as in patients with significant lesions and concomitant left ventricle systolic dysfunction [2].  Regarding the value of the diastolic murmur for the diagnosis of AR, older studies have found a sensitivity of 0% to 38% for mild AR and 60% to 80% for moderate or greater AR [4].

With a certain degree of limitation, cardiac auscultation may have a prognostic value in AS. For 35 years, Bodegard et al have followed up a cohort of apparently healthy middle-aged men, including 23.4% of subjects with systolic ejection murmurs. In patients with a low-grade murmur, there was a 4.7-fold, age-adjusted increase in the risk of aortic valve replacement (AVR) compared to an 89-fold increased risk of AVR for those with increased risk of AVR for those with moderate-grade murmur.

The physical examination has also an important role in the preoperative assessment of patients before non-cardiac surgery. The preoperative screening using cardiac auscultation identified 908 out of 3,997 hip fracture patients with an undiagnosed heart murmur, of whom almost a third were diagnosed by echocardiography with significant aortic stenosis, this finding being important for the further perioperative management [6].

Physical Examination in Valvular Aortic Stenosis

Physical examination often provides the first clue to the presence of AS and helps in assessing the severity of the lesion. Precordial palpation, cardiac auscultation and examination of the carotid pulse are very valuable when evaluating a patient with suspicion of AS.

In patients with isolated AS, the precordial apical thrust is accentuated and initially normal in location. In the left lateral decubitus, a bifid apical impulse is sometimes felt: the first impact comes from the left atrial contraction (corresponding to the presystolic gallop) and the second one from the LV contraction. A low-intensity and/or displaced systolic apical impulse could be a sign of low-flow AS or may be caused by other associated cardiac conditions. A thrill may be palpable over the aortic area in significant AS.

The carotid pulse is characterised in normal subjects by a relatively rapid upstroke and a smooth, more gradual downstroke, interrupted only briefly at the pulse peak. These palpable pulsatile changes in the carotid arterial diameter are virtually identical to the intraluminal pressure pulse. In patients with significant AS, the carotid pulse is weak (“pulsus parvus”), rises slowly and has a delayed systolic peak (“pulsus tardus”). The absence of this finding, particularly in an elderly patient with non-compliant vasculature or in patients in a hyperkinetic state, does not exclude severe AS [7].

Cardiac auscultation reveals many important findings that suggest both the diagnosis and the severity of AS. The most important auscultatory findings in AS are: a normal first sound (S1), a soft and single second sound (S2), the presence of an aortic ejection click and the typical basal systolic murmur.

Normally, the murmur is a systolic ejection murmur with onset a short interval after the S1 and the end before S2. When the valve is still flexible the aortic ejection click precedes the murmur. It is commonly heard in the 2nd right intercostal space (the aortic area), but it could also be audible along the left sternal border in the 3rd and 4th interspaces. The murmur is usually harsh and medium-pitched, so it is audible with either the bell or the diaphragm of the stethoscope. It has a characteristic “diamond shape” in the phonocardiogram. Generally, the murmur is loudest in the aortic area, but in 15% of cases it can be better heard at the apex [8]. The murmur is transmitted well and equally to the carotid arteries and both clavicles. Etchells et al showed that the absence of the transmission of the murmur over the right clavicle effectively rules out AS [9]. The murmur may also radiate to the apex, sometimes with a musical quality due to high frequency vibrations, the so-called Gallavardin phenomenon (usually encountered in degenerative AS).

The presence of three or four associated findings - slow carotid artery upstroke, reduced carotid artery volume, maximal murmur intensity at the second right intercostal space, and reduced or absent second heart sound - effectively rules in AS [9].

The AS murmur has to be differentiated from other conditions that could associate a basal systolic murmurs:

• Functional murmurs are generally faint, medium-pitched, very short (proto-, mid- or late-systolic); the S2 is always normal.
• Patients with hypertension or aortic sclerosis could have a similar harsh, medium-pitched murmur, but with a normal or even loud S2.
• In hypertrophic obstructive cardiomyopathy a systolic ejection murmur is heard along the left sternal border and the apex. Typically the murmur is variable, being amplified by exercise, squatting, Valsalva manoeuvre or administration of vasodilator or positive inotropic drugs.
• Supravalvular aortic stenosis produces most of the signs of valvular stenosis, but the systolic click is absent, the S2 is accentuated and the carotid murmurs are very loud.
• The murmur of pulmonic stenosis has similar intensity, configuration and pitch to AS, but it is loudest in the pulmonary area, the S2 is widely split and the murmur extends beyond the S2.
• A similar murmur to that of pulmonic stenosis can be heard in atrial septal defect, but the S2 is wide and with a fixed split.

When the AS murmur radiates to the apex, there are some hints to differentiate it from mitral regurgitation: the apical impulse is normal in location, the S1 is normal, the murmur starts after the S1, it is not holosystolic and it is not transmitted to the axilla.

Clinical Signs Predictive of Severe Aortic Stenosis

The following signs help in the diagnosis of severe AS (Table 1), but no combination of physical findings has both a high sensitivity and specificity, particularly in asymptomatic patients.

Table 1. Clinical Signs Predictive of Severe Aortic Stenosis.

Clinical Signs of Severe Aortic Stenosis	Mechanism	Pitfalls
A loud systolic murmur (grade 4 or greater)	The intensity of the murmur reflects the velocity and turbulence of blood flow across the valve	↓- LV dysfunction ↑-Hyperdynamic states (anaemia, fever, hyperthyroid)
Mid- or late- peaking murmur	It takes longer for blood to eject through a very reduced AV area	Difficult to be assessed clinically, especially in patients with tachycardia, atrial fibrillation, low grade murmur
A diminished or absent S2	The aortic cusps are immobile, so the A2 is faint or even not audible	S2 is increased in associated pulmonary hypertension, other valve heart diseases, hypertensive heart
Paradoxical splitting of S2	LV ejection time is prolonged and AV closes after PV	In LV dysfunction the ejection time does not correlate to the AV area
The disappearance of an ejection click	It occurs at the moment of maximal opening of the AV, when the valve is bicuspid, still flexible	Usually it is not audible
Presystolic gallop (S4)	Forceful atrial contraction into a hypertrophied, non-compliant left ventricle	Other causes of LV hypertrophy Absent in atrial fibrillation
The “parvus et tardus” carotid pulse	Occlusion of more than 75% of the AV orifice produces a plateau pulse and diminished pulse pressure	The pulse pressure increases in patients with non-compliant vasculature or hyperdynamic states

AV: aortic valve; A2: aortic valve closer; LV: left ventricle; PV: pulmonary valve; S2: the second heart sound

The Intensity of the Murmur

Haemodynamic studies have shown that the intensity of the murmur reflects the velocity of blood flow across the valve, so a very loud murmur (grade 4 or greater) has a high specificity for severe AS. In one study, the echocardiographically derived peak gradient, mean gradient and aortic valve area were highly predictive for correctly identifying the degree of severity of the murmur (87%, 81%, and 87%, respectively) [10]. Despite the high specificity, the intensity of the murmur has a low sensitivity in diagnosing severe AS, being dependent on the hemodynamic status. In patients with a low left ventricular (LV) ejection fraction or low stroke volume, the murmur’s intensity decreases and in hyperdynamic states it is frequently augmented.

A Mid- or Late-Peaking Murmur

As aortic stenosis worsens, it takes longer for blood to be ejected through the valve. Thus, mild AS would have an early peaking murmur, while in severe AS the murmur peaks later in systole. Even if it is a highly specific clinical sign for severe AS, the evaluation of the timing of the murmur has a very low reproducibility among examiners. Derived from this clinical finding, time-to-peak-velocity (TPV) is a new echocardiographic variable that is easily measured, reproducible and useful to evaluate AS severity (Figure 1). In the study of Kamimura et al, a TPV cut-off value of 99 msec had the highest sensitivity, specificity, and positive and negative predictive values in detecting severe AS (irrespective of ejection fraction) and also for predicting a poor prognosis in AS patients [11].

Figure 1. Time-to-Peak Velocity Measured by Continuous-Wave Doppler Echocardiography in a Patient with Severe AS and a Late-Peaking Systolic Murmur.

  

A Diminished or Absent S2

In severe AS, the aortic cusps are immobile, so the aortic component of the second sound is faint or even not audible. The real proportion of this feature was not extensively studied.  In a series of 397 patients with AS at their first haemodynamic evaluation, only 9% had an absent S2 [12].

Paradoxical Splitting of the S2

The paradoxical splitting of S2 is present when the transaortic pressure gradient is very high and the aortic valve closes very late, after the pulmonic valve (more obvious during expiration). Haemodynamic studies showed that, in patients with AS, the direct linear relationship between ejection time and stroke volume is totally obliterated and the degree of prolongation of left ventricular ejection time above that predicted from stroke volume is closely correlated with aortic valve area. On the other hand, in patients with failing ventricles, the ejection time was less prolonged, and the duration of ejection was unrelated to the valve area [13].

The Disappearance of the Ejection Click

The ejection click is a high-pitched sound, best heard at the apex that occurs at the moment of maximal opening of the aortic valve (AV), shortly after the S1. The sound occurs in the presence of a dilated aorta or in the presence of a bicuspid or flexible stenotic AV. It disappears in patients with a severe calcific, immobile aortic valve [8].

The Presence of Presystolic Gallop (The Fourth Sound or So-Called Atrial Gallop)

A prominent S4 can be audible and palpable due to forceful atrial contraction into a hypertrophied, non-compliant left ventricle [8]. The presence of an S4 in a young patient with AS indicates a significant AV lesion, but in an elderly or hypertensive person this is not necessarily true because it can be related to the very common diastolic dysfunction.

The “Parvus et Tardus” Carotid Pulse

Occlusion of more than 75% of the aortic orifice produces a plateau pulse and diminished pulse pressure that can be objectified by carotid or peripheral pulse palpation. Of its two components, “pulsus tardus” is the better discriminator, detecting severe AS with a sensitivity of 31% to 90%, and a specificity of 68% to 93% [14]. A prolonged carotid upstroke time was found in 58% to 68% of patients with severe AS, in 33% of patients with moderate AS and only in 3% of patients with mild AS [15]. A recent study demonstrated that the invasively measured time difference between LV and aortic systolic pressure peaks was significantly associated with the severity of AS and AV calcification calculated on multidetector computed tomography (MDCT) [16].

Physical Examination in Valvular Aortic Regurgitation

In patients with AR, the clinical examination focuses on precordial and peripheral pulse inspection and palpation, as well as cardiac auscultation. The typical early diastolic murmur has a high sensitivity and specificity for the diagnosis of AR (76% and 96%, respectively) [4], though its absence does not exclude the diagnosis. An isolated mid-systolic murmur is a more common auscultatory finding by a non-cardiologist in patients with mild to moderate AR [17].

A displaced (laterally and inferior), diffuse and hyperdynamic apical thrust is a frequent finding in significant chronic AR.

The pulse is characterised by a very brisk upstroke, large amplitude, and rapid collapse (known as Corrigan’s pulse or Watson’s water hammer pulse). It is an extreme form of the hyperkinetic pulse, so we have to differentiate it from other hyperdynamic states [7].

Besides the Corrigan Pulse, there is a long list of classic findings related to wide pulse pressure, but their sensibility and specificity is not well established - dancing carotid arteries (also described by Corrigan), de Musset’s sign (head bobbing with systolic pulse), Mueller’s sign (systolic pulsations of the uvula), Becker’s sign (pulsation of the retinal arteries), Landolfi’s sign (pupillary hippus), Traube’s sign (systolic and diastolic “pistol shot” sounds heard while auscultating the femoral artery), Duroziez’s sign (a systolic and diastolic bruit heard when the femoral artery is partially compressed), Quincke’s pulse (systolic pulsations seen upon light compression of the nail bed) and Hill’s sign (the lower limb systolic blood pressure exceeds the upper limb systolic blood pressure by more than 20 mmHg).

Cardiac auscultation in chronic AR reveals a normal S1, a soft, single or accentuated S2, the typical basal diastolic murmur and a faint mid-systolic murmur.

Normally the murmur is an early diastolic regurgitant murmur that immediately follows the 2nd sound. It is heard in the 2nd right or 3rd left intercostal space (the Erb area), but it could commonly be audible along the left sternal border in the 3rd and 4th interspaces in patients with valvular AR. This is a high-pitched, blowing murmur, best heard with the diaphragm of the stethoscope [8]. Occasionally, the murmur can be musical in quality, the so-called diastolic whoop. It is usually protodiastolic and decrescendo in the phonocardiogram, but in severe AR the murmur is holodiastolic. The murmur is transmitted towards the cardiac apex. The intensity is usually low and does not correlate to the severity of the valve lesion. When faint, the murmur can be better heard end-expiratory or with the patient leaning forward.

A mid-systolic murmur is frequent in isolated AR and is caused either by a large ejection volume through the AV or by calcification of the cusps.

All these findings described in chronic AR may not be present in the acute setting of a severe AR. Usually the murmur with acute AR is a low-pitched early diastolic murmur beginning after the S2, and the signs of acute heart failure dominate the clinical picture.

The AR murmur has to be differentiated from other conditions that could associate basal diastolic murmurs:

• Pulmonic regurgitation is indistinguishable in location, timing and quality from the AR murmur, so the distinction is made only by precordial palpation and the lack or presence of peripheral signs.
• Coronary artery stenosis (Dock’s murmur) is a high-pitched early diastolic murmur, best heard in the 2nd or 3rd left space, near the left border; it is not as widespread as AR.

The following clinical findings suggest a severe AR:

1. A Holodiastolic Murmur

The duration and quality of murmur are directly proportional to the severity of AR. In mild AR the murmur is blowing and only early diastolic. In moderate to severe AR the murmur is holodiastolic (>2/3 diastole) and rougher in quality. However, it becomes very soft or even disappears in patients with LV dysfunction.

2. Marked Peripheral Signs

There are only few data about the predictive value of peripheral signs in diagnosing the severity of AR. Sensitivity reported in the literature for Hill’s sign and Duroziez’s murmur is 69% and 88%, respectively [18]. A difference in blood pressures between lower and upper limb (ankle-brachial difference =ABD) >60 mmHg is highly suggestive of severe AR. In a recent study, the ABD determined by using the cardio ankle vascular index was correlated with LV dimensions and the vena contracta of AR measured by Color echo-Doppler [19].

3. The Austin Flint Murmur

The murmur typically begins in mid-diastole, often has a presystolic accentuation, and terminates at the end of diastole. It is low-pitched, with a rough and rumbling quality, and is best heard at the apex. The proposed mechanisms for the presence of this murmur are fluttering of the anterior mitral leaflet due to the regurgitant jet, increased mitral inflow velocity due to narrowing of the valve orifice by the jet, early mitral valve closure caused by high left ventricular end-diastolic (LVED) pressure, and diastolic mitral regurgitation. The sensitivity reported in various studies is 25% to 100%; the specificity is irrelevant since the Austin Flint murmur is by definition only found in AR [18].

4. Signs of LV Dilation and Dysfunction

The systolic apical impulse is laterally and inferiorly displaced, the intensity of the S1 is decreased (due to the elevated LVED pressure and the early closure of the mitral valve) and a protodiastolic gallop (S3 gallop) is usually heard at the apex.

 Conclusion

If we are aware of its limitations and strengths and we succeed in keeping our expertise and proficiency in cardiac auscultation, then clinical examination remains a valuable and cost-effective tool that often enables a rapid, integrative, accurate and patient-orientated diagnosis of aortic valve disease. Although advanced technologies have become part of our daily lives as clinicians, physical examination still plays a crucial role in the screening, diagnosis and evaluation of the severity of aortic valve disease, especially in AS.

References

1. Stanger D, Wan D, Moghaddam N, Elahi N, Argulian E, Narula J, Ahmadi A. Insonation versus Auscultation in Valvular Disorders: Is Aortic Stenosis the Exception? A Systematic Review. Ann Glob Health. 2019;85:104. 
2. Patel A, Tomar NS, Bharani A. Utility of physical examination and comparison to echocardiography for cardiac diagnosis. Indian Heart J. 2017;69:141-5. 
3. Thoenes M, Bramlage P, Zamorano P, Messika-Zeitoun D, Wendt D, Kasel M, Kurucova J, Steeds RP. Patient screening for early detection of aortic stenosis (AS)-review of current practice and future perspectives. J Thorac Dis. 2018;10:5584-94. 
4. Choudhry NK, Etchells EE. Does This Patient Have Aortic Regurgitation? JAMA. 1999;281:2231-8.
5. Bodegard J, Skretteberg PT, Gjesdal K, Pyörälä K, Kjeldsen SE, Liestøl K, Erikssen G, Erikssen J. Low-grade systolic murmurs in healthy middle-aged individuals: innocent or clinically significant? A 35-year follow-up study of 2014 Norwegian men. J Intern Med. 2012;271:581-8. 
6. McBrien ME, Heyburn G, Stevenson M, McDonald S, Johnston NJ, Elliott JR, Beringer TR. Previously undiagnosed aortic stenosis revealed by auscultation in the hip fracture population--echocardiographic findings, management and outcome. Anaesthesia. 2009;64:863-70. 
7. Morris DC. The Carotid Pulse. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 20, pp.312. 
8. Le Blond R, Brown D. Cardiovascular signs. In: DeGowin’s Diagnostic Examination, 10th Edition. New York: McGraw Hill Education; 2015. Chapter 6, pp 308-333.
9. Etchells E, Glenns V, Shadowitz S, Bell C, Siu S. A bedside clinical prediction rule for detecting moderate or severe aortic stenosis. J Gen Intern Med. 1998;13:699-704. 
10. Rama BN, Mohiuddin SM, Esterbrooks DJ, Lynch JD, Holmberg MJ, Mooss AN, Hilleman DE. Correlation of intensity of aortic stenosis murmur by auscultation with echocardiographically determined transvalvular gradients and valve area. Journal of Noninvasive Cardiology. 1999;3:25-31.
11. Kamimura D, Hans S, Suzuki T, Fox ER, Hall ME, Musani SK, McMullan MR, Little WC. Delayed Time to Peak Velocity Is Useful for Detecting Severe Aortic Stenosis. J Am Heart Assoc. 2016;5:3002907. 
12. Lombard JT, Selzer A. Valvular aortic stenosis. A clinical and hemodynamic profile of patients. Ann Intern Med. 1987;106:292-8. 
13. Kligfield P, Okin P. Effect of ventricular function on left ventricular ejection time in aortic stenosis. Br Heart J. 1979;42:438-41.  
14. Steven McGee MD. Pulse rate and contour. In: Evidence-Based Physical Diagnosis (Fourth Edition). Amsterdam, the Netherlands: Elsevier; 2018. Chapter 15, pp. 95-108.
15. Munt B, Legget ME, Kraft CD, Miyake-Hull CY, Fujioka M, Otto CM. Physical examination in valvular aortic stenosis: correlation with stenosis severity and prediction of clinical outcome. Am Heart J. 1999;137:298-306. 
16. Sato K, Kumar A, Jobanputra Y, Betancor J, Halane M, George R, Menon V, Krishnaswamy A, Tuzcu EM, Harb S, Jaber WA, Mick S, Svensson LG, Kapadia SR. Association of Time Between Left Ventricular and Aortic Systolic Pressure Peaks With Severity of Aortic Stenosis and Calcification of Aortic Valve. JAMA Cardiol. 2019;4:549-55. 
17. Heidenreich PA, Schnittger I, Hancock SL, Atwood JE. A systolic murmur is a common presentation of aortic regurgitation detected by echocardiography. Clin Cardiol. 2004;27:502-6. 
18. Babu AN, Kymes SM, Carpenter Fryer SM. Eponyms and the Diagnosis of Aortic Regurgitation: What Says the Evidence? Ann Intern Med. 2003;138:736-742. 
19. Shiraishi H, Shirayama T, Maruyama N, Kaimoto S, Otakara A, Kurimoto R, Nakanishi N, Nakamura T, Yamano T, Matsumuro A, Doi K, Yaku H, Matoba S. Usefulness of peripheral arterial signs in the evaluation of aortic regurgitation. J Cardiol. 2017;69:769-73. 

Categories: iatrika

acute coronary syndromes:

The year in cardiology: acute coronary syndromes: The year in cardiology 2019 

Adrian P Banning, Filippo Crea, Thomas F Lüscher

European Heart Journal, Volume 41, Issue 7, 14 February 2020, Pages 821–832, https://doi.org/10.1093/eurheartj/ehz942

Published:

06 January 2020

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Abstract

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Topic:

• acute coronary syndromes
• st segment elevation myocardial infarction
• cardiology
• heart
• takotsubo syndrome

Issue Section:

 Acute coronary syndromes

Preamble

The management of acute coronary syndromes (ACS) has made enormous progress over the last five decades due to the introduction of defibrillation, beta blockers, thrombolytics, aspirin, primary percutaneous transluminal intervention (PCI), P₂Y₁₂ inhibitors, statins, radial access, and eventually PCSK9 inhibitors, among others.1 However, in spite of all these remedies, there is a remaining acute mortality risk, in particular, in those presenting in cardiogenic shock or after resuscitation and an accruing number of major cardiovascular events (MACE) over the following years.2 Thus, there is an unmet need in the management of ACS. In 2019, there were a number of important papers published in the European Heart Journal and other journals that deepened our knowledge about the spectrum of ACS and their management. Today patients presenting with acute chest pain and changes in the electrocardiogram (ECG) or biomarkers may have ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) caused by atheroma, coronary dissection,3 takotsubo syndrome,4,5 MINOCA (Myocardial infarction with Non-Obstructed Coronary Arteries6), or myocarditis.7

Genetics

Whole-genome sequencing and early acute myocardial infarction

The relative prevalence and importance of monogenic mutations related to familial hyper-cholesterolaemia (FH) and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction (MI) remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. Khera et al.8 performed whole-genome sequencing in 2081 patients hospitalized for early-onset AMI to assess the prevalence and clinical importance of FH mutations and a high polygenic score. They observed an FH mutation in 1.7% of patients and a high polygenic score in 17% of patients, each of which was associated with a greater than three-fold increased odds of early-onset AMI. Beyond clinical risk stratification, the polygenic score may additionally foster insights into the mechanistic underpinnings of AMI. Indeed, this risk associated with a high polygenic score is not the result of a discrete underlying mechanism but rather a quantitative blend of numerous risk pathways.

Pathophysiology

Plaque rupture and healing assessed by optical coherence tomography

The mechanisms and the pathologic substrate of plaque erosion and plaque fissure are different. Indeed, plaques complicated by erosion tend to be matrix-rich, lipid-poor, and usually lack prominent macrophage collections, unlike plaques that rupture, which characteristically have thin fibrous caps, large lipid pools, and abundant foam cells.9 In a prospective study in 211 patients with STEMI who underwent pre-intervention optical coherence tomography (OCT) examination for the culprit lesion, Tan et al.10 found that trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite derived from dietary phosphatidylcholine and choline, were significantly and independently higher in patients with plaque fissure than in those with plaque erosion. The area under the receiver operating characteristic curve for distinguishing plaque rupture from plaque erosion was 0.89. Thus, plasma TMAO has the potential to serve as a novel biomarker for plaque rupture in patients with STEMI and indeed is a prognostic marker in these patients (see below). This might be relevant because risk stratification and management are probably different for plaque fissure and erosion.

Healed plaque ruptures or erosions may be considered as a signature of an aborted ACS. However, the role of plaque healing in the natural history of ischaemic heart disease (IHD) is largely unknown. OCT has been validated for the detection of healed coronary plaques against histology and therefore, offers the opportunity of assessing their clinical relevance. Vergallo et al.11 assessed plaque healing in two groups of patients at the extremes of the clinical presentations of IHD: (a) patients with recurring ACS, defined as history of at least three AMIs or at least four ACS with at least one AMI; (b) patients with long-standing chronic coronary syndromes, defined as a minimum 3-year history of stable angina in the absence of previous ACS. In the first group, non-culprit plaques only were assessed. They found that patients with recurrent ACS had a distinct atherosclerotic phenotype compared with those with chronic coronary syndrome and longstanding angina, including a much lower prevalence of healed coronary plaques, suggesting that plaque healing may play a role in leading the natural history of patients with IHD.

In another OCT study, Fracassi et al.12 assessed plaque healing in the culprit stenosis, among 376 patients with ACS and found plaque healing in more than one-quarter. Such patients more frequently were diabetic or hyperlipidaemic; furthermore, healed plaques frequently showed OCT features of local and systemic inflammation. This suggests that the combination of risk factors and local in addition to systemic inflammation may outweigh the protective mechanism of plaque healing and predispose those plaques to develop occlusive thrombus. Thus, a better knowledge of the mechanisms promoting plaque healing might provide new therapeutic targets to reduce ACS burden in addition to optimal risk factor control.

Mechanisms of coronary microvascular obstruction

The rapid re-opening and stenting of occluded epicardial coronary arteries via emergency PCI have revolutionized STEMI treatment. Despite technical refinements and the introduction of numerous antiplatelet and anticoagulant drugs, more than one-third of patients demonstrate coronary microvascular obstruction (CMVO) which deny the benefit of an apparently successful PCI. The mechanisms of CMVO are still largely unknown, while its prevention and treatment remain an unmet need.

Herring et al.13 found that STEMI patients with the highest neuropeptide Y levels in the coronary sinus had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire, both markers of CMVO. After 2 days, they also had significantly higher levels of myocardial oedema and microvascular obstruction (MVO) on magnetic resonance imaging (MRI), and significantly lower ejection fractions and ventricular dilatation 6 months later. Interestingly, neuropeptide Y (NPY) (100–250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304. Immunohistochemistry of the human coronary microvasculature confirmed the presence of vascular smooth muscle Y₁ receptors. Thus, antagonism NPY might be an attractive future therapeutic target in the prevention of CMVO (Figure 1).

Figure 1

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Neuropeptide-Y following primary percutaneous coronary intervention for ST-elevation myocardial infarction causes vasoconstriction of the coronary microvasculature and is associated with a high index of microcirculatory resistance and low coronary flow reserve, leading to microvascular obstruction, oedema, and eventually a lower ejection fraction and ventricular dilatation. Redrawn with permission from Ref.13

New insight into post-myocardial infarction remodelling

The immune response to AMI involves two equally important, consecutive phases: the inflammatory phase and the reparatory phase. During the inflammatory phase, neutrophils and inflammatory Ly6Chi monocytes are recruited into the ischaemic myocardium. Subsequently, the Ly6Chi monocytes give rise to reparatory Ly6Clo macrophages, with an important role in cardiac recovery. A balance between the two phases is crucial for recovery of cardiac function and patient prognosis. An excessive inflammatory response to AMI amplifies myocardial injury, leading to larger infarcts and loss of function. However, clinical trials testing anti-inflammatory strategies in AMI have so far led to non-significant or even deleterious effects. Ideally, an efficient therapy should inhibit the damaging effects of excessive inflammation, while leaving the repair mechanisms intact.

Alarmins are a group of heterogeneous molecules released from dying cells and activated leucocytes that signal tissue damage and trigger an innate immune response. S100A9 and its dimerization partner S100A8, also called myeloid-related proteins 8 and 14, are proinflammatory alarmins that are readily produced and stored in large amounts in neutrophils and are increased at the site of acute coronary occlusion.14 Marinković et al.15 studied 524 patients with ACS and found that high plasma S100A8/A9 at the time of ACS was associated with lower left ventricular ejection fraction (LVEF) at 1 year and increased hospitalization for heart failure during follow-up. Moreover, in wild-type C57BL/6 mice with AMI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with controls. To mimic the clinical scenario, they further confirmed the effects of the treatment in a mouse model of ischaemia and reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved LVEF. Thus, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients.

Tang et al.16 investigated the effects of gut microbiota on cardiac repair after AMI. C57BL/6J mice were treated with antibiotics 7 days before AMI to deplete mouse gut microbiota. Antibiotic-treated mice displayed drastic, dose-dependent mortality after AMI associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. The physiological status and survival of mice were significantly improved after faecal reconstitution or dietary supplementation with short-chain fatty acids that are altered after antibiotic treatment; this benefits appeared to be mediated by immunomodulatory effects. In addition, supplementing antibiotic-treated mice with a Lactobacillus probiotic before AMI restored yielded cardioprotective effects. Thus, this study uncovers the adverse effects of antibiotics on survival after MI and addresses a promising therapeutic strategy that involves modulation of gut microbiota composition through probiotic supplementation (Figure 2).

Figure 2

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A schematic diagram showing the importance of gut microbiota-derived short-chain fatty acids for maintaining immune composition and repair capacity during homoeostasis. (A) In untreated mice, gut microbiota-derived short-chain fatty acids modulate immune composition and repair capacity during homoeostasis. (B) On antibiotics-mediated dysbiosis, the depletion of the gut microbiota and the short-chain fatty acid products are associated with changes in immune composition and an abolishment of repair response, leading to exacerbated mortality after myocardial infarction. Restoration of the system across each level through the faecal reconstitution of the gut microbiota, dietary supplementation of short-chain fatty acids, or immune cell transplantation results in improved survival. Reprinted with permission from Ref.16

Mechanisms of takotsubo syndrome

In 55 patients with takotsubo syndrome, Scally et al.17 found myocardial macrophage inflammatory infiltrates as assessed by MRI as well as changes in the distribution of monocyte subsets and an increase in systemic pro-inflammatory cytokines. Many of these changes persisted for at least 5 months suggesting a low-grade chronic inflammatory state. Obviously, whether inflammation is a cause or a consequence of the acute takotsubo event remains to be shown. Moreover, whether inflammation is maladaptive and implicated in the persistence in the long-term consequences of this condition is uncertain. Nevertheless, inflammation might play a role in the complex pathogenesis of this syndrome.

Most importantly, novel investigations using functional MRI of the brain suggest that an altered limbic and central autonomic signal processing plays a crucial role in takotsubo and may explain the inappropriately excessive reaction of the sympathetic nervous system to stressful triggers. Thus, takotsubo is indeed by a brain disease and the heart may just represent the target organ.18

Diagnosis

Troponins

Boeddinghaus et al.19 prospectively enrolled patients presenting with symptoms suggestive of AMI in three large diagnostic studies in order to assess the validity of the 0/h-algorithms according to age (<55 years, ≥55 to <70 years, and ≥70 years). Rule-out safety of the ESC high-sensitivity cardiac troponin T (hs-cTnT) 0/1 h-algorithm was very high with a sensitivity of >99.3% in all age-strata, while triage efficacy decreased with increasing age with sensitivity dropping from 93% to 55%. Slightly higher cut-off concentrations optimized for older patients maintained very high safety of rule-out and increased specificity. Findings were confirmed in two validation cohorts and also for hsTnI. While safety of the ESC 0/1 h-algorithms remained very high, increasing age significantly reduced overall efficacy and the accuracy of rule-in. Thus, alternative slightly higher cut-off concentrations may be considered for older patients, although the problem remains for other confounders like chronic kidney disease, chronic heart failure, atrial fibrillation, and others that also need to be incorporated. Twerenbold et al.20 confirmed the excellent applicability, short time to emergency department discharge, and low rate of 30-day MACE associated with the routine clinical use of the ESC 0/1-h-algorithm for the management of patients presenting with acute chest discomfort to the emergency department in a real-world setting.

Finally, important concepts for institutional transition to hs-cTn methodology providing recommendations useful for education before implementation have been reported in an Expert Panel chaired published by Januzzi et al.21

Implantable cardiac alert system

Symptoms remain a poor prompt for ACS. In a multicentre, randomized trial of an implantable cardiac monitor that alerted 907 high-risk ACS patients with rapidly progressive ST-segment deviation randomized to a control (alarms deactivated) or treatment group for 6 months, after which alarms were activated in all subjects.22 Safety revealed a 96.7% freedom from system-related complications. The primary efficacy endpoint of cardiac or unexplained death, new Q-wave MI, and detection to presentation time >2 h following a confirmed occlusive event within 7 days was numerically, but not statistically reduced among patients with activated alarms group. When the observation window was extended to 50, 70, and 90 days in a prespecified analysis to include the majority of confirmed occlusive events in the control group, and an exploratory dual-baseline ECG analysis was used to reduce noise, a significant reduction in the primary endpoint was observed. Moreover, alarms significantly decreased detection to arrival time at a medical facility. This device may be beneficial among high-risk subjects in potentially identifying asymptomatic events.

Risk stratification

Biomarkers

Among 4257 patients of the VISTA-16 trial, initial and subsequent increases in high-sensitivity C-reactive protein (hsCRP) levels during 16 weeks after ACS were associated with a greater risk of the combined MACE endpoint, cardiovascular (CV) death, and all-cause death despite established background therapies.23 Further studies will be required to determine whether initial and serial hsCRP measurements can help guide the use of targeted anti-inflammatory therapies after ACS or whether more specific inflammatory markers will be needed to this end.

Four new biomarkers have been investigated in different trials in the setting of ACS: (a) galectin-3, implicated in fibrosis24; (b) impaired endogenous fibrinolysis25; (c) trimethyllysine and TMAO, gut-microbiota derived metabolite26; (d) serum cholesterol efflux capacity.27 All these biomarkers were found to be independently associated with MACE at follow-up. Again, further studies will be required to establish whether these markers identify patient subsets who need personalized forms of treatment.

Finally, Lindholm et al.28 assessed the association between cystatin-C, growth differentiation factor-15 (GDF-15), hsCRP, hs-TnT and TnI, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and specific causes of mortality among 17 095 ACS patients of the PLATO trial. They found that NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or non-vascular causes and possibly with death due to bleeding. It remains to establish how to these important prognostic information can guide treatment.

Cardiac magnetic resonance and entropy

Entropy is a new late gadolinium-enhanced MRI-derived parameter to evaluate tissue inhomogeneity, independent of signal intensity thresholds. Androulakis et al.29 enrolled 154 consecutive post-AMI patients undergoing late gadolinium-enhanced MRI prior to implantable cardioverter-defibrillator (ICD) implantation. When entropy involved the entire left ventricle (LV), this was associated with mortality. After adjusting for multivessel disease, acute revascularization, and ejection fraction, entropy of the scar was independently associated with the presence of ventricular arrhythmias. The association between LV entropy and mortality may reflect adverse and irreversible, inhomogeneous remodelling of the post-infarct LV and/or possibly fatal arrhythmias. Further studies are warranted to establish whether this new marker can allow a better identification of candidates for ICD after AMI.

Treatment

Ticagrelor compared to prasugrel were studied in the ISAR-REACT 5 study (Figure 3).30 Patients with ACS and a proposed interventional strategy were randomized and the primary composite endpoint was death, MI, or stroke. In these patients with or without STEMI, prasugrel therapy was superior to ticagrelor with no difference in bleeding. These important comparative data are likely to change clinical practice.

Figure 3

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The Kaplan–Meier curves of the ISAR–REACT5 show the cumulative incidence of the primary endpoint, which was a composite of death, myocardial infarction, or stroke at 1 year. The inset shows the same data on an enlarged y axis. Reprinted with permission from Ref.30

Timing of treatment

The optimal timing of administration of dual antiplatelet therapy (DAPT) in STEMI patients was investigated by the Swedish Coronary Angiography and Angioplasty Registry.31 Patients were stratified between either post- or pre-procedure treatment with P₂Y₁₂ receptor antagonists. Of the 44’804 patients 58% had been

on clopidogrel, 35% on ticagrelor, and 5% on prasugrel. There was no survival benefit from pre-treatment or any impact on infarct-related artery patency, stent thrombosis, or bleeding. These data are surprising as a potential impact on early stent thrombosis, in particular, might have been anticipated. Existing Guidelines32 recommend catheter-lab administration of antiplatelet drugs and these data are supportive of that strategy, although Abtan and Steg33 argue that we should continue to give P₂Y₁₂ receptor antagonists as early as possible in probable STEMI patients as there is a strong biological plausibility of likely benefit with no obvious likely detriment.

Whether patients with patients with transient ST-elevation (patients who present initially with ST-elevation on the electrocardiogram but, subsequently, show complete normalization of the ST-segment and relief of symptoms before reperfusion therapy) require immediate revascularization was studied in a trial34 of 142 patients who were randomized to immediate (mean 0.3 h) or delayed angiography (mean 22.7 h). The outcome was infarct size by MRI at Day 4. The observed infarcts were generally small and there was no clear benefit from the immediate strategy, although 4/71 patients required urgent intervention because of further symptoms and ST elevation whilst waiting. Consequently, these data can probably be interpreted as allowing decisions about timing of revascularization in patients with transient STEMI, to be guided by the availability of angiography and careful clinical assessment.

The management of non-culprit lesions in STEMI patients has been extensively discussed over the last years. Small randomized trials have suggested a probable benefit from complete revascularization. The large COMPLETE trial randomized 4041 STEMI patients (Figure 4) to complete or partial revascularization.35 Complete revascularization was superior to culprit-only as it reduced the risk of CV death or AMI. There was also benefit from complete revascularization in reducing ischaemic endpoints. Timing appeared to be less important and deferring any secondary revascularization procedure was safe. Thus, the advantage of complete revascularization will presumably be reflected in subsequent ESC Guidelines.

Figure 4

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The Kaplan–Meier curves show the cumulative incidence of the primary endpoint, which was a composite of death, myocardial infarction, or stroke at 1 year. The inset shows the same data on an enlarged y axis. Reprinted with permission from Ref.35

Can we tailor treatment in acute coronary syndromes?

There remains a desire to tailor drug therapy to the individual patients and perhaps the individual lesion. This strategy would allow pharmaceutical optimization of protection with minimization of side effects or bleeding risk. The CHAMPION PHOENIX trial36 has suggested that complex coronary lesions can be characterized and that it is inadequate treatment of these ‘high risk’ lesions that leads to repeat revascularization or clinical events. Compared with a loading dose of clopidogrel, cangrelor reduced MACE occurring within 48 h after PCI in patients with ACS regardless of baseline lesion complexity. However, the absolute benefit: risk profile for cangrelor was greatest during PCI in complex coronary anatomy. In a substudy of the PROSPECT trial,37 virtual histology and grey scale intravascular ultrasound (IVUS) was a predictor of a suboptimal final angiographic result reflected as a high residual Syntax Score after intervention. A detailed Expert consensus review has provided detail on characterization of acute coronary lesions using IVUS or OCT and suggested a triaged therapeutic approach.38

Unfortunately measuring individuals’ responses to antiplatelet drugs has not shown clinical utility. Randomizing patients to measuring platelet function in the TROPICAL trial39 showed no measurable clinical advantage. Within the trial, those patients with maximal platelet inhibition were predictably most prone to bleeding.

Optimizing treatment in ST-segment elevation myocardial infarction

About one-third of STEMI patients have suboptimal reperfusion after PCI and it is this group of patients that might experience heart failure and premature death. MRI can provide evidence of MVO and myocardial haemorrhage.40 In the DANAMI-3 trial delayed presentation41 as evidenced by prolonged door-to-wire-time predicted adverse clinical outcome, consistent with previous observations using intracoronary physiology measurements suggesting increased risk in these ‘late presenters’.42 Enhanced and continued public information campaigns are required to optimize outcomes in high-risk STEMI patients along with novel adjunctive therapies. In this context, full dose intracoronary tenectaplase was inferior to abciximab in a small randomized trial43 and using low dose intracoronary tenecteplase after reperfusion in the T-time trial also failed to reduce MVO measured using cardiac magnetic resonance imaging (CMRI).44

Hypothesis generating results were presented by the Microvascular Reperfusion Utilizing Sonothrombolysis in Acute Myocardial Infarction (MRUSMI) investigators.45 They randomized STEMI patients to either standard PCI or diagnostic ultrasound transducer guided, high mechanical index impulses during an ultrasound agent transfusion prior to and following PCI. The ultrasounds high mechanical index impulses create microbubble cavitation that induce shear forces, designed to dissolve intracoronary thrombi. The treatment cohort demonstrated higher recanalization (48% vs. 20%) and TIMI 3 flow rates (32% vs. 14%) within the infarcted vessel ST-segment resolution prior to primary PCI occurred more frequently. Furthermore, infarct size as assessed by MRI and TNT peak values was also reduced by the intervention. Optimizing reperfusion for patients with STEMI when there is lot of thrombus is challenging and these preliminary results hint at a possible alternate approach.

Remote preconditioning in STEMI was studied in the CONDI-2/ERIC PPCI trial46 which randomized 5401 patients to standard treatment (including a sham simulated remote ischaemic conditioning at UK sites) or remote ischaemic conditioning (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before primary PCI. Unfortunately, remote ischaemic conditioning did not improve clinical outcomes (cardiac death or hospitalization for heart failure) at 12 months. New approaches and therapies within this area are warranted if this experimentally well-documented concept should ever reach the clinical applicability.

Outcomes

Quality of treatment and outcomes

In a cohort of 389 507 NSTEMI patients, optimal care, defined as the receipt of all eligible treatments, was inversely related to risk status (defined by the GRACE risk score), i.e. 25.6% in low, 18.6% in intermediate, and 11.5% in high-risk patients. At the end of 2.3 years of follow-up, the association between the use of all eligible guideline-indicated treatments and improved survival remained only significant for high-risk NSTEMI.47 Thus, optimal use of guideline-indicated care for NSTEMI was associated with greater survival gains with increasing GRACE risk, but its use paradoxically decreased with increasing GRACE risk, thus leaving room for improvement.

In the SWEDHEART registry, outcomes of patients presenting with NSTEMI followed over 20 years demonstrated a substantial improvement in long-term survival and reduction in the risk of MACE.48 These improvements were associated with the gradual uptake and widespread use of PCI and long-term use of evidence-based medications, consistent with the anticipated effectiveness of their implementation as proposed in guidelines (Figure 5).

Figure 5

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(A and B) Kaplan–Meier estimates of the cumulative incidence of the first coprimary outcome (death from cardiovascular causes or new myocardial infarction) and the second coprimary outcome (death from cardiovascular causes, new myocardial infarction, or ischaemia-driven revascularization), respectively. Insets show the same data on an enlarged y axis. PCI, percutaneous coronary intervention. Reprinted with permission from Ref.48

Take home figure

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The spectrum of acute coronary syndromes encompasses plaque rupture and erosion (=Type 1 myocardial infarction), Type 2 myocardial infarction, epicardial and microvascular coronary spasm, coronary embolism, acute myocarditis, takotsubo syndrome, and coronary dissection.

The value of a cardiac rehabilitation programme was compared in 839 patients who attended a planned programme at discharge after ACS or surgical revascularization, while 441 patients were discharged without it.49 At multivariable Cox proportional hazard analysis, the cardiac rehabilitation programme was an independent predictor of lower occurrence of MACE (hazard ratio 0.55), while in a propensity-matched analysis patients attending the cardiac rehabilitation programme also experienced a lower total mortality (10% vs. 19%) and CV mortality (2% vs. 7%) compared to non-rehabilitated ones. Thus, the positive effects of ambulatory of cardiac rehabilitation are also notable in a real-world population.

Finally, in a cohort study of 123 780 consecutive PCIs from the Pan-London PCI Registry the outcomes pre- and post-public reporting in the UK were compared.50 After public reporting was introduced, patients were older and had more complex medical problems, while in-hospital MACE and MACCE and 30-day mortality rates were significantly lower. These results probably reflect continued improvements in PCI outcomes concomitant with the introduction of public reporting, but the lower reported complication rate could also reflect a change in the documentation of risk factors and a change in operator behaviour. Reassuring, additional data from the UK registry also confirm continued temporal improvement in outcomes in ACS and notably demonstrate no difference in outcome depending on the times of day that treatment occurred. Patients treated as emergencies at night had similar outcomes to those treated within ‘office hours’.

Modes of death after non-ST-segment elevation myocardial infarction

In 66 252 patients with NSTEMI enrolled in 14 TIMI trials, baseline characteristics and modes and timing of death were examined. Of the 2606 patients with known modes of death, 75.1% were related to MACE, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event.51 The most common modes of CV death were sudden death and recurrent AMI (36.4% and 23.4%, respectively). The proportion of CV deaths related to recurrent AMI was higher in the first 30 days than it was after 30 days following NSTEMI (30.6% vs. 18.7%), whereas the proportion of sudden death was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Thus, sudden death represented the largest proportion of CV deaths after 30 days. Further investigations aimed at defining management approaches to reduce sudden death following NSTEMI may be critical to reducing late mortality.

Outcomes of in-hospital acute coronary syndromes

In a cohort study of 1.3 million patients hospitalized in US Veterans Health Administration facilities, an incidence of in-hospital AMI of 4.27 per 1000 admissions and risk factors associated with in-hospital AMI such as history of IHD, elevated heart rate, low haemoglobin level, and elevated white blood cell count were reported.52 Compared with matched controls, mortality was significantly higher for in-hospital AMI. Thus, in-hospital AMI is common and associated with common CV risk factors and markers of acute illness and with high mortality approaching 60% at 1 year. Further studies of in-hospital AMI may yield opportunities to reduce in-hospital AMI risk and improve patient outcomes.

Outcomes of atypical acute coronary syndromes

Spontaneous coronary artery dissection

Spontaneous coronary artery dissection (SCAD) is an underdiagnosed and poorly understood condition and an important cause of AMI in young women.3 In the Canadian multicentre, prospective, observational study of 750 patients, predisposing conditions included fibromuscular dysplasia in 31.1%, systemic inflammatory diseases in 4.7%, peripartum in 4.5%, and connective tissue disorders in 3.6% were noted.53 Most were treated conservatively, while 14% underwent PCI and a few coronary artery bypass surgery. In-hospital composite MACE was 8.8%, but higher in peripartum SCAD (20.6% vs. 8.2%). Overall 30-day MACE was 8.8% with peripartum SCAD and connective tissue disease being independent predictors of 30-day MACE.

Takotsubo syndrome

Two different studies of the InterTak Registry including over 1500 patients with takotsubo syndrome found that both in-hospital cardiac arrest (4.9 of patients)54 or the presence of an associated malignancy (16.6% of patients)55 were associated with worse long-term outcome. Of note, patients with cardiac arrest were more likely to be younger, male, and have apical takotsubo, atrial fibrillation, neurologic comorbidities, physical triggers, longer corrected QT-interval, and lower LVEF, while those with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers.

Myocardial infarction with non-obstructed coronary arteries

The long-term outcome of MINOCA was investigated in a large US Registry of 286 780 AMI admissions of which 5.9% had MINOCA.56 Following risk-adjustment, MINOCA patients had a 43% lower risk of MACE over 12 months compared to those with AMI and coronary artery disease. This pattern was similar for adjusted risks of the MACE components. Thus, MINOCA has an unfavourable prognosis in elderly patients with one in five suffering a major adverse event over 12 months.

Women vs. men

The impact of gender was assessed in 13 451 NSTEMI and STEMI patients undergoing PCI in the Victorian Cardiac Outcomes Registry in Australia.57 Women with STEMI had significant delays in presentation and revascularization with a higher 30-day mortality compared with men, while women with NSTEMI had no delay in presentation or revascularization, with mortality comparable to men. Thus, public awareness campaigns might be needed to address women’s recognition and early action for STEMI.

In a Swiss population of 4360 patients with STEMI ischaemic time in women remained greater than that in men due to persistently greater patient delays.58 In contrast to men, clinical signs of ongoing chest discomfort did not predict delays in women, suggesting that female STEMI patients were less likely to attribute symptoms to a condition requiring urgent treatment.

In a Chinese population of 82 196 patients women hospitalized for ACS less frequently received acute treatments and strategies for secondary prevention than men.59 The observed sex differences in in-hospital mortality were mainly due to worse clinical profiles and fewer evidence-based acute treatments provided to women with ACS.

Finally, Vicent et al.60 in an octogenarian Spanish population of 535 patients with STEMI found that female sex was independently associated with death and hospitalization at 6-month follow-up.

Medicaid beneficiaries vs. privately insured individuals

In 42 645 and 171 545 STEMIs receiving Medicaid or private insurance, respectively,61 in unadjusted analyses, Medicaid beneficiaries had lower rates of coronary revascularization and higher rates of in-hospital mortality compared with privately insured individuals. Similar results were found in a propensity-matched cohorts. Further studies are needed to identify and understand the causes of the variation in STEMI outcomes by insurance status.

Black vs. White patients

In a US cohort of 6402 patients, self-identified black and white patients differed in several clinical and socioeconomic characteristics.62 The higher the prevalence of characteristics associated with being black, the higher the 5-year mortality rate, but no differences were observed between black and white patients with similar characteristics. Thus, a greater prevalence of characteristics associated with black race, but not race itself, was associated with higher mortality risk after AMI.

Conclusions

Important data from large randomized trials have augmented the management of patients presenting with ACS. Importantly, recognition of the clinical spectrum of ACS has expanded in recent years and atypical forms, besides the classical STEMI and NSTEMI, such as takotsubo syndrome, coronary dissection, MINOCA, and myocarditis have been increasingly recognized, characterized and their causes and mechanisms defined. The management of these novel forms of ACS is still not evidence-based, but significant progress has been made recently. Furthermore, disparities in the implementation of guideline-based therapies are increasingly addressed to the benefit of the patient population at large.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Acknowledgements

The authors would wish to thank Susanne Dedecke for her support.

Conflict of interest: A.B. is partially funded by the NHS NIHR Oxford Biomedical Research Centre and reports an Institutional Educational Grant from Boston Scientific and honoraria from Abbott, Boston Scientific, Medtronic, and Miracor. F.C. reports speaker fees by Amgen, BMS, Servier, Menarini, Novartis, Astra Zeneca, and TFL reports research grant or honoraria by Abbott, Amgen, Biotronik, Boston Scientific, Eli Lilly, Medtronic, and Sanofi-Regeneron.

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