**4. Discussion**

To the best of our knowledge, this is the first report to evaluate FCV-19S in patients with STEMI. This is particularly important, as many data have reported a marked reduction in AMI hospitalizations during the first wave of the worldwide pandemic [2,12–15]. Common international lockdown measures, contradictory and ambiguous information, and inaccurate communications from the media may have fueled fear of possible in-hospital contagion, which may have contributed to the decline in access to the CCU [2]. Clearly, other determinants may have played a role, such as the healthcare focus on COVID patients and the reduction in resources available for other acute emergencies because all efforts directed towards COVID-19, or the decrease in air pollution with the establishment of lockdown measures and consequently its diminished role as potential trigger of acute coronary artery disease, and others [2]. In any case, it is important to consider that STEMI care is strictly time-dependent; thus, any delay in reaching coronary emergency units can increase morbidity and mortality. In fact, the earlier the diagnosis and treatment, the more effective the STEMI treatment, in terms of infarct size and AMI-related complications.

In this context, these are the first data to estimate psychological distress using FCV-19S in CV patients. The values reported for CV outpatients, both in the first wave and in the following period, and in STEMI patients were higher for item 4 ("I am afraid of losing my life because of the coronavirus") and item 3 ("My hands become clammy when I think about the coronavirus"), compared to those observed in an Italian general population subjected to FCV-19S during the first pandemic wave (corresponding to the values of 2 and 1.5, respectively), indicating a greater emotional and symptomatic fear expression in all CV patients [8]. Certainly, in these types of studies, it must be considered that patients with acute or stable coronary artery disease may have high underlying rates of anxiety and depression that may influence the FCV-19S if compared to the general population [16,17]. However, based on our results when comparing patients in the different time periods (see Table 2), the differences in the FCV-19S response seem more related to the characteristics of the lockdown periods (e.g., information from the media, level of constraints imposed) than to the type of patients (acute *versus* stable), with adverse repercussions for all patients (e.g., lack of checks for stable CV patients, and delays in hospital admission in case of AMI).

For this reason, the analysis of data related to the so-called "Total ischemic time" (a term coined to indicate the time from the onset of chest pain to the first medical contact, arrival at the hospital, and balloon inflation during primary percutaneous coronary intervention) is essential in the interpretation of the present results. Indeed, the uncertainty in recognizing the severity of the symptoms and in reaching the emergency department introduces a "COVID-19-related delay" in the "Total ischemic time". This is especially true for the "symptom-onset-to-first-medical-contact time" that was significantly longer during the pandemic period than in the pre-pandemic period, as other researchers and we observed in the CCU [2,3,18]. This finding suggests patients' reluctance to promptly contact healthcare personnel who may intervene with the first treatment, go to the hospital or even not seek care at all, even though this attitude could have a detrimental impact on their outcomes. Noteworthy, "Door-to-hospital-arrival-time" and "Hospital-arrival-toinsufflation-time" did not vary significantly in the pre-COVID or during the pre-pandemic and pandemic periods in all evaluated clinical settings [2,3,18] suggesting a good functioning of the healthcare system, and also giving a major role to the patient's fear and reluctance for the reduction in AMI.

Regarding gender, we did not find any significant difference in the level of fear, although female patients presented slightly higher values for each item. This result is absolutely preliminary and limited by the low number of women in our cohort (13%) and certainly needs further deepening. In the literature, other data suggested that higher rates of fear among women can be associated with different emotional distress vulnerabilities depending on gender. Women seem more prone to stress, as well as to an increased risk of developing post-traumatic stress disorders [19]. A 2020 WHO report highlighted that women represent a population with specific concerns, as a significantly higher percentage

of women reported being stressed than men during the COVID-19 outbreak, evidencing a greater vulnerability of women to the negative impact of the COVID-19 in terms of mental health and wellbeing [20]. Interestingly, data on FCV-19S in different general ethnic populations (Bangladeshi, British, Brazilian, Taiwanese, Italian, New Zealander, Iranian, Cuban, Pakistani, Japanese, and French) showed that females had a greater fear of COVID-19 than males [21].

In addition, a study specifically designed to evaluate gender differences in fear of COVID-19 suggested greater psychological vulnerability in Cuban women during the pandemic, and that gender significantly predicted COVID-19 fear [22].

Accordingly, in the cardiovascular setting where FCV-19S evaluation had not still been performed, a greater reduction in STEMI admissions was observed comparing women *versus* men (41.2%; *p* = 0.011, and 17.8%; *p* = 0.191, respectively) during the COVID-19 pandemic, which may reflect increased fear in female patients [12].

Since COVID-19 and the highest mortality and complication rate were found in elderly subjects during the outbreak, it is not surprising that older CV patients are more likely to be psychologically affected, as reported in several general populations [23–27]. However, some studies reported lower levels of COVID-19 fear in older subjects than in young to middle-aged adults [21].

Nonetheless, patients with CV disease and comorbidities may feel more vulnerable to death and disability due to COVID-19 than their younger counterparts, likely thinking that the treatments for COVID-19 are somewhat limited and become more fearful of being infected from the virus [28,29].

Notably, "fear" may be a physiological and functional response, which represents a positive reaction towards more adaptive functions aimed at keeping oneself safe from risky situations [30]. However, many of the items in the FCV-19S scale are related to anxiety, a negative emotional state with adverse repercussions [30]. Moreover, loneliness is a strong determinant for all-cause mortality in aged people [31].

It is also noteworthy that CV outpatients examined in the period of November 2020– May 2021 showed significantly lower values for item 6 ("I cannot sleep because I'm worrying about getting the coronavirus") and 7 ("My heart races or palpitates when I think about getting the coronavirus") than those tested with FCV-19S in the first wave, indicating some kind of addiction to stressful conditions.

Indeed, as it is known in the field of stress neurobiology, a stress, always of the same nature, which repeatedly manifests over time (homotypic stress), typically leads to the habituation of stress-sensitive systems, including those affecting the hypothalamic– pituitary–adrenal axis, and unlike a heterotypic unpredictable and variable stress [32,33].

In fact, if biological responses give our body the strength to facilitate survival and face immediate danger, long-lasting stress can cause problems, potentially compromising the functions of the whole organism [34,35]. Therefore, homotypic stress addiction can reduce the overall burden. Further studies are warranted to understand whether biological responses to COVID-19 also fit into this context, as well as to clarify whether these biological responses can influence psychosocial behaviors.
