Italian Association of Hospital Cardiologists Position Paper 'Gender discrepancy: time to implement gender-based clinical management'.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women's diseases.

Novelties in Therapy of Chronic Heart Failure.

In recent decades, considerable advances have been made in the treatment of heart failure. The main target of heart failure therapy is the inhibition of the sympathetic nervous system and renin-angiotensin-aldosterone system. The angiotensin receptor blockers represent a breakthrough in the treatment of heart failure with a demonstrated effect on reduction of cardiovascular events. However, new perspectives derive from latest drugs developed for diabetes, iron deficiency, and hyperkalemia. New frontiers are also opened to the development of neurohormonal therapies, antagonists of inflammatory mediators, inotropic agents, and cell-based treatments.

[Proposal to improve the patient journey for women's cardiovascular prevention]. / Proposta di miglioramento del percorso di prevenzione cardiovascolare della donna.

The relevance of gender medicine in cardiovascular prevention is still underestimated, and there is a lack of viable women-specific preventive, diagnostic, and therapeutic strategies. To ensure women have equal access to cardiovascular prevention, cardiovascular disease risk stratification needs to consider gender-specific factors related to women reproductive cycle phases together with the different impact that traditional risk factors have on men and women. The aim of this document is to improve the patient journey for cardiovascular risk prevention in women, enhancing the importance of a multidisciplinary approach and the role of the various professional figures involved, starting with the general practitioner, as the main actor of the first risk stratification. The goal of the proposed patient journey is to ensure effective risk assessment of cardiovascular disease in women, by raising attention on the risk factors related to different hormonal phases and to bridge the sex and gender gap in cardiovascular prevention. We hope that this journey can be implemented as uniformly as possible in clinical practice throughout Italy.

[Gender cardiology: focus on clinical and pathophysiological peculiarities in women with long COVID syndrome]. / Cardiologia di genere: il punto su peculiarità cliniche e fisiopatologiche nelle donne nel long COVID.

Long COVID is a clinical syndrome characterized by the persistence or development of symptoms due to COVID-19 at least 12 weeks after initial infection. More than 200 different symptoms have been ascribed to long COVID, the most common being fatigue, shortness of breath, and muscle weakness. Women have a three-fold higher risk of being diagnosed with long COVID, and the symptoms more often described are persistent weakness, chest pain, altered smell and taste, palpitations or muscle pain, as well as neurological, gastrointestinal and rheumatologic symptoms. Long COVID features are influenced by immune function, endothelial dysfunction and sex hormones. Moreover, it leads to systemic dysfunction, so various therapeutic strategies have been explored and still different trials are ongoing, mainly regarding anticoagulation and immuno-modulators. Nowadays the most quoted interventions are focused rehabilitation programs and pharmacological selected treatments in specifical cases. The aim of this review will be focusing the clinical and pathophysiological sex-related peculiarities to understand the different long COVID phenotypes and possibly address a better tailored approach and treatment.

Sex differences in patients presenting with acute coronary syndrome: a state-of-the-art review.

Cardiovascular conditions in the spectrum of acute coronary syndromes are characterized by sex differences with regard to pathophysiology, risk factors, clinical presentation, invasive and pharmacologic treatment, and outcomes. This review delves into these differences, including specific subsets like myocardial infarction with non-obstructed coronary arteries or Spontaneous Coronary Artery Dissection, and alternative diagnoses like Takotsubo cardiomyopathy or myocarditis. Moreover, practical considerations are enclosed, on how a sex-specific approach should be integrated in clinical practice: in fact, personal history should focus on female-specific risk factors, and hormonal status and hormonal therapy should be assessed. Moreover, physical and psychological stressors should be investigated, particularly in the event of Spontaneous Coronary Artery Dissection or Takotsubo cardiomyopathy.

[Gender discrepancy: time to implement gender-based clinical management]. / Position paper ANMCO: Differenze di genere nell'approccio farmacologico cardiovascolare.

It is well established that gender strongly influences cardiovascular risk factors, playing a crucial role in cardiovascular prevention, clinical pathways, diagnostic approach and treatment. Beyond the sex, which is a biological factor, gender entails a socio-cultural condition that impacts access and quality of care due to structural and institutional barriers. However, despite its great importance, this issue has not been adequately covered. Indeed sex and gender differences scarcely impact the clinical approach, creating a lot of disparities in care and outcomes of patients. Therefore, it becomes essential to increase the awareness of the importance of sex and gender influences on cardiovascular diseases. Moreover, new strategies for reducing disparities should be developed. Importantly, these differences should be taken into account in guideline recommendations. In this regard, it is crucial to include a greater number of women in clinical trials, since they are currently underrepresented. Furthermore, more women should be involved as member of international boards in order to develop recommendations and guidelines with more attention to this important topic.The aim of this ANMCO position paper is to shed light on gender differences concerning many cardiovascular drugs in order to encourage a more personalized therapeutic approach.

Lights and Shadows of Clinical Applications of Cardiac Scintigraphy with Bone Tracers in Suspected Amyloidosis.

Radionuclide bone scintigraphy is the cornerstone of an imaging-based algorithm for accurate non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA). In patients with heart failure and suggestive echocardiographic and/or cardiac magnetic resonance imaging findings, the positive predictive value of Perugini grade 2 or 3 myocardial uptake on a radionuclide bone scan approaches 100% for the diagnosis of ATTR-CA as long as there is no biochemical evidence of a clonal dyscrasia. The technetium-labelled tracers that are currently validated for non-invasive diagnosis of ATTR-CA include pyrophosphate (99mTc-PYP); hydroxymethylene diphosphonate (99mTc-HMDP); and 3,3-diphosphono-1,2-propanodicarboxylate (99mTc-DPD). Although nuclear scintigraphy has transformed the contemporary diagnostic approach to ATTR-CA, a number of grey areas remains, including the mechanism for binding tracers to the infiltrated heart, differences in the kinetics and distribution of these radiotracers, differences in protocols of image acquisition worldwide, the clinical significance of extra-cardiac uptake, and the use of this technique for prognostic stratification, monitoring disease progression and assessing the response to disease-modifying treatments. This review will deal with the most relevant unmet needs and clinical questions concerning scintigraphy with bone tracers in ATTR-CA, providing expert opinions on possible future developments in the clinical application of these radiotracers in order to offer practical information for the interpretation of nuclear images by physicians involved in the care of patients with this ATTR-CA.

Women at heart: Introducing gender cardio-oncology.

As cardio-oncology imposed itself as the reference specialty for a comprehensive cardiovascular approach to all patients with cancer, a more specific and careful cardiac evaluation of women entering their journey into cancer care is needed. Gender medicine refers to the study of how sex-based biological and gender-based socioeconomic and cultural differences influence people's health. Gender-related aspects could account for differences in the development, progression, and clinical signs of diseases as well as in the treatment of adverse events. Gender also accounts for major differences in access to healthcare. As for medicine and healthcare in general, gender-related characteristics have gained significance in cardio-oncology and should no longer be neglected in both clinical practice and research. We aimed to review the most relevant cardiovascular issues in women related to the cardio-oncology approach to offer a specific gender-related point of view for clinicians involved in the care process for both cancer and cardiovascular disease.

The impact of COVID-19 on myocardial infarctions, strokes and out-of-hospital cardiopulmonary arrests: an observational retrospective study on time-sensitive disorders in the Friuli Venezia Giulia region (Italy).

The COVID-19 global pandemic has changed considerably the way time-sensitive disorders are treated. Home isolation, people's fear of contracting the virus and hospital reorganisation have led to a significant decrease in contacts between citizens and the healthcare system, with an expected decrease in calls to the Emergency Medical Services (EMS) of the Friuli-Venezia Giulia (FVG) region. However, mortality in clinical emergencies like acute ST-elevation myocardial infarction (STEMI), stroke and out-of-hospital cardiopulmonary arrest (OHCA) remained high. An observational retrospective cross-sectional study was carried out in FVG, taking into account the period between March 1, 2020, and May 31, 2020, the first wave of the COVID-19 pandemic, and comparing it with the same period in 2019. The flow of calls to the EMS was analysed and COVID-19 impact on time-sensitive disorders (STEMIs, ischemic strokes and OHCPAs) was measured in terms of hospitalisation, treatment and mortality. Despite a -8.01% decrease (p value ˂0.001) in emergency response, a 10.89% increase in calls to the EMS was observed. A lower number of advanced cardiopulmonary resuscitations (CPR) (75.8 vs 45.2%, p=0.000021 in April) and ROSC (39.1 vs 11.6%, p=0.0001 in April) was remarked, and survival rate dropped from 8.5 to 5%. There were less strokes (-27.5%, p value=0.002) despite a more severe onset of symptoms at hospitalisation with NHISS˃10 in 38.47% of cases. Acute myocardial infarctions decreased as well (-20%, p value=0.05), but statistical significances were not determined in the variables considered and in mortality. Despite a lower number of emergency responses, the number of calls to the EMS was considerably higher. The number of cardiac arrests treated with advanced CPR (ALS) was lower, but mortality was higher. The number of strokes decreased as well, but at the time of hospitalisation the clinical picture of the patient was more severe, thus affecting the outcome when the patient was discharged. Finally, STEMI patients decreased; however, no critical issues were observed in the variables taken into account, neither in terms of response times nor in terms of treatment times.

[ANMCO Position paper: Cardiovascular disease in women - prevention, diagnosis, treatment and organization of care]. / Position paper ANMCO: Malattie cardiovascolari nella donna ­ prevenzione, diagnosi, terapia e organizzazione delle cure.

Cardiovascular diseases are still the main cause of death among women despite the improvements in treatment and prognosis achieved in the last 30 years of research. The determinant factors and causes have not been completely identified but the role of "gender" is now recognized. It is well known that women tend to develop cardiovascular disease at an older age than men, and have a high probability of manifesting atypical symptoms not often recognized. Other factors may also co-exist in women, which may favor the onset of specific cardiac diseases such as those with a sex-specific etiology (differential effects of estrogens, pregnancy pathologies, etc.) and those with a different gender expression of specific and prevalent risk factors, inflammatory and autoimmune diseases and cancer. Whether the gender differences observed in cardiovascular outcomes are influenced by real biological differences remains a matter of debate.This ANMCO position paper aims at providing the state of the research on this topic, with particular attention to the diagnostic aspects and to care organization.

Effect of hydroxymethylglutaryl coenzyme-a reductase inhibitors on the long-term progression of rheumatic mitral valve disease.

BACKGROUND: At present, no medical therapy is known to affect the progression of rheumatic mitral stenosis (MS). We sought to assess the effect of statin treatment on long-term progression of MS in a large population. METHODS AND RESULTS: From our 20-year database, we identified all patients with rheumatic MS with > or =2 echocardiographies > or =1 year apart. Exclusion criteria were previous intervention on the mitral valve, more than moderate aortic regurgitation, or symptoms at first examination. The study sample included 315 patients (mean age, 61+/-12 years; 224 women); 35 patients (11.1%) were treated with statins, and 280 (88.9%) were not. Mean follow-up period was 6.1+/-4.0 years (range, 1 to 20). The rate of decrease in mitral valve area was significantly lower in the statin group compared with the untreated group (0.027+/-0.056 versus 0.067+/-0.082 cm(2)/y; P=0.005). The annualized change in mean transmitral gradient was lower in statin-treated patients (0.20+/-0.59 versus 0.58+/-0.96 mm Hg/y; P=0.023). The prevalence of fast MS progression (annual change in mitral valve area >0.08 cm(2)) was significantly lower in the statin group (P=0.008). An increase in systolic pulmonary artery pressure of >10 mm Hg was found in 17% of patients in the statin group versus 40% of untreated patients (P=0.045). CONCLUSIONS: Our study shows a significantly slower progression of rheumatic MS in patients treated with statins. These findings could have an important impact in the early medical therapy of patients with rheumatic heart disease.

Analysis of beta1 and beta2-adrenergic receptors polymorphism in patients with apical ballooning cardiomyopathy.

OBJECTIVE: The aim of our study was to analyse the frequency of beta1 and/or beta2 adrenergic receptor polymorphisms in patients with takotsubo cardiomyopathy (TTC). METHODS AND RESULTS: beta1 and/or beta2 adrenergic receptor polymorphisms in 61 patients with TTC were compared with 109 controls. The beta1 adrenoreceptor (amino acid position 389) genotype frequencies were significantly different in the two groups; assuming a recessive model for the allelic variant coding for Arg on this position, the odds ratio was 3.14, 95% Cl 1.55-6.37 (P = 0.0015). The beta2 adrenoreceptor amino acid position 27 genotype was significantly different and assuming a recessive model for the allelic variant coding for Gln on this position, the odds ratio was 0.29, 95% Cl 0.12-0.74 (P = 0.009). CONCLUSIONS: This study showed for the first time an association between TTC phenotype and beta1 adrenoreceptor gene polymorphisms. Beta adrenoreceptors gene polymorphisms are probably disease modifiers, and any risk estimate should be based on a combination of genotypes and on interactions with other genes and environmental features.

Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Although oral P2Y12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined. OBJECTIVES: The purpose of this study was to compare downstream and upstream oral P2Y12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment. METHODS: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit). RESULTS: We randomized 1,449 patients to downstream or upstream oral P2Y12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment). CONCLUSIONS: Downstream and upstream oral P2Y12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).

Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist's point of view.

The assessment of arterial stiffness, a common feature of ageing, exacerbated by many common disorders such as hypertension, diabetes mellitus, or renal diseases, has become an attractive tool for identifying structural and functional abnormalities of the arteries in the preclinical stages of the atherosclerotic disease. Arterial stiffness has been recognized as an important pathophysiological determinant of systolic blood pressure and pulse pressure increases and therefore the cause of cardiovascular complications, demonstrating also an independent predictive value for cardiovascular events. Although there are many techniques and indices currently available, their large clinical application is limited by a lack of standardization, with important difficulties when one try effectively to measure, quantify, and compare. Moreover, information on the 'heart-vessel coupling disease', in which combined stiffness of both heart and arteries interact to limit cardiovascular performance and its possible implications in different clinical conditions, is still not well known. We overviewed main methods and indices used to estimate arterial stiffness and aimed to provide an insight into the knowledge of the ventricular-arterial coupling from the cardiologist's point of view.

Tako-tsubo syndrome and hypovolemia.

Tako-tsubo syndrome (TTS) is a rare disorder characterized by reversible apical left ventricular ballooning usually triggered by an emotional and/or physical stress and often mimicking an acute myocardial infarction. We describe a case of 78 year old woman with TTS associated with hypovolemia and hyponatraemia. The hypovolemic state could have activated the sympathetic system and in turn catecolamine overload with consequent myocardial stunning.

Stage-related effect of statin treatment on the progression of aortic valve sclerosis and stenosis.

It has been suggested that statins could slow the progression of aortic stenosis (AS), but this hypothesis is still debated and has not been validated in large series of patients by long-term follow-up studies. Moreover, information about the role of statins in patients with different degrees of severity of AS is scarce. From our 1988 to 2007 echocardiographic database, we retrospectively identified all asymptomatic patients with aortic valve sclerosis (abnormal irregular thickening of the aortic valve with a peak aortic velocity [Vmax] > or =1.5 and <2 m/s), mild AS (Vmax > or =2 and <3 m/s), and moderate AS (Vmax > or =3 and <4 m/s), age > or =50 years, and with > or =2 echocardiographic studies > or =2 years apart. Exclusion criteria were moderate/severe aortic regurgitation, bicuspid aortic valve, rheumatic valve disease, and ejection fraction <40%. The final study population consisted of 1,046 patients (mean age 70 +/- 8 years, 587 men); 309 were treated with statins. Mean follow-up duration was 5.6 +/- 3.2 years (range 2 to 19). Progression of AS was slower in patients receiving statins compared with untreated patients in aortic sclerosis (0.04 +/- 0.09 vs 0.07 +/- 0.10 m/s/year, p = 0.01) and mild AS (0.09 +/- 0.15 vs 0.15 +/- 0.15 m/s/year, p = 0.001), but not in moderate AS (0.21 +/- 0.18 vs 0.22 +/- 0.15 m/s/year, p = 0.70). In multivariate analysis only statin therapy, initial Vmax, and dialysis were independently related to progression of aortic valve disease. In conclusion, in a large series of patients with long-term follow-up, statins were effective in slowing the progression of aortic valve disease in aortic sclerosis and mild AS, but not in moderate AS. These results suggest that statin therapy should be taken into consideration in the early stages of this common disease.

Heterogeneity of clinical presentation in Tako-Tsubo syndromes: the prevalence of normal segmental wall motion and normal ECG pattern.

AIM: The aim of this study is to report the heterogeneity of clinical presentation in Tako-Tsubo syndrome (TTS), including a significant prevalence of normal ECG and echocardiographic patterns in a series of consecutive patients from a single center. METHODS AND RESULTS: From our database we selected a total of 168 cases of TTS. A total of 140 of these (Group A); 14 men (10%), mean age 60.3 years, range 39-87; 126 women (90%), mean age 66.1 years, range 43-93; matched the following reported criteria: typical stenocardic pain immediately following an emotional acute stress, or acute medical or surgical event within the preceding 12 h; acute rise and fall of troponin release; absence of significant coronary disease at coronary angiography. ECG findings at presentation ranged from T wave abnormalities (41 cases, 29.3%) to ST elevation (52 cases, 37.1%) and ST depression (11 cases, 7.9%), whereas in 36 cases (25.7%) the ECG was normal. Echocardiography at presentation showed akinesia of the total apical or medium-apical segments in 74 patients (53%), whereas it showed akinesia of left ventricular wall segments in other locations in 30 patients (21%) and even normal regional wall motion and thickening in 36 patients (26%). We described also a series of 13 female patients (mean age 70.2 years; age range 45-85 years) (Group B) who did not complain of chest pain at presentation, but showed a classical Tako-Tsubo evolution of wall motion abnormalities at echocardiography. Finally we selected 15 female patients (mean age 69.3 years; age range 49-89 years) (Group C) who formally did not report acute stress immediately preceding their presentation to the hospital for chest pain. They showed a classical Tako-Tsubo evolution of wall motion abnormalities at echocardiography and only one case of normal ECG pattern at presentation. CONCLUSION: In this series of acute TTS, a wide variability of ECG and echocardiographic patterns are observed, ranging from ST elevation with coexisting segmental wall motion abnormalities of the typical TTS to a clinical presentation characterized by normal ECG and normal segmental wall motion pattern.

Cardiac imaging in patients with arterial hypertension.

Hypertension is considered the major modifiable risk factor for cardiovascular disease. Conventional echocardiography is the most common and used imaging technique and can detect anatomical and functional changes easily in a real-time, quick, noninvasive and relatively inexpensive manner. Other imaging techniques, such as magnetic resonance imaging and 3-D echocardiography gained an increasing role in selected patients, as well as the study of arterial stiffness, also using ultrasonographic echo-tracking methods. This review analyzes the role of echocardiography and other imaging techniques in the evaluation of the cardiovascular effects of hypertension.

Progression of aortic valve sclerosis and aortic valve stenosis: what is the role of statin treatment?

BACKGROUND: It has recently been suggested that statins could slow the progression of aortic stenosis, but this hypothesis has not been validated in large series. Moreover, there is little information about the role of statin treatment in patients with aortic valve sclerosis. METHODS: From our database 1988--2002, we retrospectively identified 1136 consecutive patients with aortic valve sclerosis (peak aortic velocity [Vmax] > 1.5 and < 2 m/s), or mild to moderate aortic stenosis (Vmax 2.0-3.9 m/s) and with > or = 2 echocardiographic studies > or = 6 months apart; 121 (11 %) were treated with statins. As a control group we randomly selected 121 age-gender-matched patients not treated with statins, with similar initial Vmax. RESULTS: The mean follow-up duration was 54+/-34 months in the statin group, and 50+/-33 months in controls (p = 0.35). There were no differences between statin-treated patients and controls with respect to age, gender, and prevalence of hypertension. More patients in the statin group had documented hypercholesterolemia, diabetes, or had proven coronary artery disease. Overall, the rate of change of Vmax was not different between statin-treated patients and controls (0.13+/-0.24 vs 0.14+/-0.19 m/s/year, p = 0.72). However, in the subgroup of patients with aortic valve sclerosis (n = 52, 26 statin-treated, 26 controls), the rate of change of Vmax was significantly lower in statin-treated patients (0.04+/-0.04 vs 0.08+/-0.06 m/s/year, p = 0.007). CONCLUSIONS: The results of our retrospective study show that statins could be beneficial in retarding the progression of valvular aortic sclerosis to aortic stenosis. This suggests that statins retard the progression of aortic valve lesion in its early stage, a finding that may have important implications in the management of this very common disease.