Recent highlights on acute myocardial infarction and takotsubo syndrome from the International Journal of Cardiology: Heart & Vasculature

1. Acute myocardial infarction

Worldwide, ischemic heart disease is the single most common cause of death, and its frequency is increasing. Although most prevalent in the elderly, myocardial infarction (MI) also affects younger adults. In this population, both traditional risk factors, including cigarette smoking, obesity, hyperlipidemia, and a family history of coronary artery disease, along with non-traditional risk factors such as human immunodeficiency virus, systemic lupus erythematosus, and obstructive sleep apnea are associated with a higher risk of MI [1]. Compared with older patients, younger are more likely to receive guideline-proven therapies and have reduced in-hospital and post-discharge mortality [2]. Having an ST-segment elevation MI (STEMI) after entering the seventh decade of life was described to quadruple the risk of future death or re-hospitalization for heart failure [HF] [3]. Regardless of patient age, Baechli et al. [4] reported for patients with MI a stepwise increase in risk for adverse clinical outcomes with each additional comorbidity, including diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, cerebrovascular disease, and peripheral artery disease. STEMI diagnosis cannot be separated from a 12-lead electrocardiogram (ECG) execution. However, several reports questioned the diagnostic accuracy of traditional STEMI criteria for acute coronary occlusion [ACO] [5], [6]. Interestingly, a new diagnostic electrocardiographic paradigm named occlusion ACO-MI/non-ACO-MI was demonstrated to be superior to STEMI criteria for the ECG diagnosis of ACO-MI in two retrospective blinded interpretations [7], [8]. In case of suspected acute MI, it is recommended to record an ECG, with its interpretation being made within 10 min of ambulance arrival. Nevertheless, concerns about the feasibility and gender equality of obtaining a pre-hospital ECG were raised by Murbeckh et al. [9], who reported that women have longer delay times to the acquisition of a pre-hospital ECG than men. Being financially limited, older, illiterate, and living in a rural area were also reported as risk factors associated with longer treatment delays [10]. Once a STEMI diagnosis is obtained, reperfusion therapy t be initiated as soon as possible. Unfortunately, during the COVID-19 pandemic, patients considerably delayed their calls to emergency service, which caused substantial prolongation of the time to coronary reperfusion, seriously affecting the extension of myocardial damage [11], [12]. Primary percutaneous coronary intervention (PCI) has significantly improved the outcomes in patients with acute MI and is now considered the preferred reperfusion strategy in patients with STEMI within 12 h of symptom onset [13]. Coronary stenting is the technique of choice during primary PCI. New-generation drug-eluting stent (DES) has shown superior safety and preserved or even improved efficacy compared with first-generation DES [14]. Among these, amphilimus-eluting stent, a novel polymer-free DES that combines sirolimus with fatty acid as an antiproliferative drug, was found to be effective with a low incidence of major adverse cardiovascular events (MACE) in a population with a high rate of diabetes mellitus [15]. Further interesting results were obtained with a new thin-strut cobalt chromium biolimus-eluting stent, whose use was associated with a low incidence of MACE, cardiac death, and MI, in line with contemporary studies of other latest-generation DES [16]. Despite the ability of primary PCI to restore epicardial perfusion in approximately 90% of patients, infarct size is often substantial, thus leading to an increased risk of heart failure and mortality. Notably, pressure-controlled intermittent coronary sinus occlusion (PiCSO), a mechanical catheter-based device placed into the coronary sinus after initial primary PCI, which intermittently increases mean coronary sinus pressure and coronary sinus pulse pressure, was associated with significantly smaller infarct size at 5 days than historical controls who underwent primary PCI alone [17].

Approximately half of STEMI patients have a multivessel disease (MVD), which carries worse clinical outcomes after primary PCI those with single-vessel coronary disease. Whether treatment of non-culprit lesions might result in better outcomes in STEMI has been a matter of debate and research over the last decade. A recent meta-analysis suggested that in patients with STEMI and MVD, complete revascularization is superior to culprit-only PCI in reducing the risk of MACE and cardiovascular mortality without increasing the risk of adverse safety outcomes [18]. Furthermore, Gupta et al. present a subgroup analysis of early vs delayed complete revascularization showing similar MACE rates for either strategy [19]. Thus, the optimal timing of revascularization completion between staged PCI before hospital discharge (early) and staged PCI after discharge (delayed) remains unclear [20].

Other technical aspects of PCI have been demonstrated to significantly affect patient outcomes. The radial approach has emerged as the default access site in acute coronary syndrome (ACS) patients undergoing primary PCI, in whom a lower rate of mortality and bleeding was described compared to femoral access PCI [21]. According to European Cardiology Society (ESC) guidelines on STEMI management [13], routine thrombus aspiration is not recommended. However, the use of this technique in the real world could be associated with the intracoronary thrombotic burden. In their retrospective study, Del Portillo et al. reported that a high thrombus burden, as classified by the TIMI scale, was significantly associated with the use of manual thrombus aspiration, which was not related to any major cardiovascular events [22]. Once patients undergo primary PCI, they should receive dual antiplatelet therapy (DAPT), a combination of aspirin and a P2Y12 inhibitor. Antiplatelet therapy encompassing P2Y12 adenosine diphosphate receptor antagonists is a cornerstone of secondary prevention in patients after MI. Among these drugs, ticagrelor provides a faster, greater, and more consistent platelet inhibition than clopidogrel and was demonstrated to be superior in terms of preventing MI, stroke, and cardiovascular death in patients with ACS [23]. However, it is questionable if the more potent antiplatelet action of ticagrelor comes at the cost of increased bleeding, which is itself associated with higher mortality in MI survivors. Although the PLATO trial clearly showed no difference in adverse bleeding, a recent observational study conducted on a cohort of patients representing the typical elderly, multimorbid survivor of STEMI demonstrated that ticagrelor-based DAPT strategy was associated with significantly more bleeding complications, without any significant change in death, MI, or stroke [24]. Thus, a careful assessment of the balance between the individual bleeding risk and the requirement for stringent platelet inhibition should guide the best antiplatelet approach in an individual patient [25]. To facilitate this evaluation, the ‘predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT)’ score was developed to predict the bleeding risk in patients treated with DAPT after PCI [26]. Particularly, a score of ≥25 indicates that the DAPT period should be shorter 3–6 months, than that in patients with a score of <25. Furthermore, Ando et al. reported that a PRECISE-DAPT score ≥25 was associated with higher long-term all-cause mortality in patients with MI, suggesting that it could be useful not only for the risk stratification of bleeding but also for predicting all-cause mortality in patients with acute MI (AMI) [27]. Nevertheless, a premature or inappropriate suspension of DAPT could hesitate in early stent thrombosis, which is particularly feared because of the associated high mortality rates. Tariq et al. reported stent thrombosis as relatively frequent in patients undergoing primary PCI, where diabetic and hypertensive patients were found at increased risk of its occurrence [28]. Fibrinolysis is a revascularization strategy for the management of STEMI when primary PCI cannot be performed timely. However, coronary angiography and PCI, if indicated, need to be performed between 2 and 24 h after fibrinolysis, and emergent PCI termed rescue PCI is recommended for failed fibrinolysis [13]. Interestingly, Fernando et al. demonstrated that short-term ischemic outcomes and long-term mortality in this setting are similar to those in patients undergoing primary PCI, even if the rate of hemorrhagic stroke was higher in the rescue PCI group [29]. All acute MI patients should participate in an exercise-based cardiac rehabilitation program [13]. The absence of a capillary network between the hospital and community healthcare represents the main limit to applying systematic referral to cardiac rehabilitation, which has been shown to significantly improve the participation rate of patients with subsequent improvement in clinical outcomes [30].

2. Takotsubo Syndrome

Takotsubo Syndrome (TTS), also known as stress cardiomyopathy, is a disorder characterized by acute and transient wall motion abnormalities with left ventricular systolic [and diastolic] dysfunction, often associated with a stressful, emotional, or physical event [31]. Although initially thought to be a benign condition, it is increasingly recognized as a potentially life-threatening condition that could be associated with severe complications such as ventricular arrhythmias and cardiogenic shock [32]. Females in their seventh or eighth decade of life are more prone to TTS. The predominance of TTS in women has been related to the absence of cardioprotective effects of androgens [32]. The race might contribute to the incidence and prognosis of TTS [33]. For example, small-sampled research has demonstrated an increased in-hospital mortality rate among patients of Afro-American patients [34]. Patients with TTS usually present with chest pain and ECG changes, which are very similar to those observed in patients with AMI. TTS presenting with ST elevation (STE-TTS) is especially challenging in the differential diagnosis against STEMI, and none of the proposed methods can clearly distinguish TTS from STEMI to reliably prevent coronary angiography. Zeijlon et al. reported a comparative analysis between electrocardiographic characteristics of STE-TTS and STEMI patients and demonstrated that admission ECG in STE-TTS was similar to left anterior descending artery STEMI, but reciprocal ST depression was less common in STE-TTS compared with STEMI overall [35].

While the role of left bundle branch block (LBBB) as an independent predictor of MACE in patients with AMI is well established, little is known regarding the effects of LBBB in TTS. Notably, a recently published retrospective study showed that the presence of LBBB was associated with ventricular arrhythmias occurring in patients with TTS, thus suggesting a possible value of LBBB in the prognosis of this population [36]. In addition to the low sensitivity of ECG, there is a lack of diagnostic biomarkers that can discriminate patients with TTS from those with AMI, thereby allowing clinical monitoring and providing prognostic information in the long term [37]. In contrast, echocardiography is essential in visualizing wall motion abnormalities extending beyond the territory of the involved coronary artery, which is the main feature of TTS. Most patients show the typical apical contraction abnormality pattern, although atypical contraction patterns [midventricular, basal, or focal contraction abnormalities] may also be present [31]. The relationship between wall motion abnormalities distribution and the long-term outcome has been investigated by Gaede et al., who demonstrated that contraction pattern had no influence on overall long-term morality despite the higher level of cardiac enzymes found in the typical apical pattern group [38]. Even if echocardiography can provide first-line imaging and valuable information in patients with acute TTS or AMI, the traditional echocardiographic exam can frequently be insufficient to differentiate between the two pathologies, especially in the early phase. Interestingly, the left ventricular sphericity index, a marker of left ventricular remodeling and reflective of geometric changes in the left ventricle, has been suggested as a rapid and reproducible diagnostic tool to discriminate between TTS and AMI in the acute phase [39]. Although an important characteristic of TTS is rapid and often complete recovery of left ventricular function once the acute phase of the syndrome has ended, the long-term clinical outcome remains uncertain [40]. In a large retrospective analysis, male sex and the presence of ventricular arrhythmias were demonstrated to constitute strong predictors of mortality in patients hospitalized with TTS, while atrial arrhythmias were associated with increased mortality in women [41].

During the COVID-19 pandemic, a variety of extrapulmonary manifestations have been reported in the literature, including TTS [42]. It was hypothesized that exaggerated inflammatory response and direct viral cytotoxicity might be the mechanisms of TTS development in COVID-19 patients [43]. However, the spread of SARS-CoV-2 in family clusters could represent an additional factor capable of significantly increasing the levels of emotional stress, thus leading to a state of central sympathetic hyper-activation determining TTS [44]. TTS occurrence was also reported in patients receiving COVID-19 vaccines, particularly messenger RNA (mRNA) vaccines. Among these patients, chest pain should be considered an alarming symptom, especially in those who received a second dose of the vaccine in the previous three days [45]. Since robust evidence has demonstrated that psychological factors can impair the immune system’s response to vaccines, the stress of an ongoing pandemic and the uncertainties related to COVID-19 vaccination may therefore have contributed, in a susceptible patient, to TTS occurrence [46]. All the cases had fully recovered without any obvious irreversible cardiomyopathy changes [45].

3. Outlook

The International Journal of Cardiology: Heart & Vasculature has published many papers related to TTS and is expecting to continue to advance our understanding of the diagnosis and treatment of TTS. We are hoping to further serve as a publishing platform for the dissemination of new knowledge related to TTS.

Sources of funding

National Institutes of Health [R01-HL131517, R01-HL136389, R01-HL089598, and R01HL163277 to D.D.], European Union [large-scale integrative project MAESTRIA, No. 965286 to D.D.], and Italian Ministry of Health [GR-2019-12368506, to E.A.].

Disclosures

E.A. is a consultant for Kiniksa Pharmaceutical and Cytokinetics. Other authors have nothing to disclose.

Conflict of Interest

The authors report no relationships that could be construed as a conflict of interest.