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.

[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.

[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.

Management of Transcatheter Aortic Valve Implantation and Complex Aorta Anatomy: The Importance of Pre-Procedural Planning.

Aortic stenosis is the most common primary valve lesion requiring surgery or, especially for older patients, transcatheter intervention (TAVI). We showcase a successful transfemoral TAVI procedure in a very high-risk patient and an extremely tortuous S-shaped descending aorta, characterized by heavy calcifications and multiple strong resistance points. We demonstrated that transfemoral TAVI using the "buddy stiff guidewire" technique could be a feasible, simple, quick, and easy procedure able to straighten an extremely abdominal aorta tortuosity. With all techniques available and careful pre-procedural planning, and thanks to the flexibility of new generation TAVI delivery systems, it is possible to safely perform the procedure even in the most challenging patients.

[Transcatheter approach in patients with severe aortic stenosis and concomitant severe mitral regurgitation]. / Gestione dei pazienti affetti da stenosi aortica severa e concomitante insufficienza mitralica severa.

Patients with severe aortic valve stenosis who are candidates for transcatheter aortic valve replacement represent a high-risk population for the presence of frequent comorbidities (reduced left ventricular ejection fraction, associated valve insufficiency, right ventricular dysfunction and/or pulmonary hypertension). Aortic valve stenosis can be associated with any other valve defects but among these mitral regurgitation is the most commonly associated valve disease. The simultaneous presence of severe mitral regurgitation in patients with aortic stenosis is a negative prognostic factor, resulting in increased mortality and a high diagnostic complexity, in particular in the accuracy of the evaluation of the two valve defects and therapeutic management which, at present, are not supported by strong scientific evidence.

Long-term results of the randomized comparison of everolimus-eluting stents and sirolimus-eluting stent in patients with ST elevation myocardial infarction (RACES-MI trial).

BACKGROUND: Several concerns have emerged about the higher risk of very late stent thrombosis (ST) with first generation drug-eluting stent (DES), especially in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). New generation DES have demonstrated reduction in ST at mid-term follow-up, however no data are available on long-term follow-up. Therefore, the aim of this study was to report long-term results of the RACES-MI trial conducted to compare Everolimus-Eluting Stent (EES) vs Sirolimus-Eluting Stent (SES) in patients undergoing primary PCI. METHODS: The RACES-MI trial enrolled consecutive STEMI patients admitted within 12h of symptom onset, undergoing primary PCI with stent implantation at a tertiary center with 24-hour primary PCI capability, who were randomly assigned to SES or EES. Primary endpoint of this analysis is major adverse cardiac events (MACE) at long-term follow-up. Secondary endpoints are 1) death; 2) reinfarction; 3) definite or probable ST; 4) target-vessel revascularization (TVR) at long-term follow-up. RESULTS: From April 2007 to May 2009 500 patients with STEMI were randomized to EES (n=250) or SES (n=250). No difference was observed between the groups either in baseline clinical characteristics, in the number of implanted stent or total stent length per patient. However, a larger reference diameter was observed with SES (3.35±0.51 mm vs 3.25±0.51 mm, p=0.001), whereas patients randomized to EES received Gp IIb-IIIa inhibitors more often (54.4% vs 42.4%, p=0.006). At long-term follow-up (2132±528 days), EES was associated with a significant reduction in MACE (23.8 vs 34.1%, adjusted p=0.028), ST (2.5% vs 7.7%, adjusted p=0.009), without any difference in death (8.7% vs 11.4%, adjusted p=0.47), reMI (9.3% vs 13.1%; adjusted p=0.18) and TVR (8.6% vs 12.3%, adjusted p=0.31). CONCLUSIONS: This study shows that among STEMI patients undergoing primary PCI EES, as compared to SES, is associated with significant reduction in MACE and ST at long-term follow-up.

Impact of diabetes on the benefits from everolimus-eluting stent as compared to first-generation drug-eluting stent in patients with ST elevation myocardial infarction.

BACKGROUND: Drug-eluting stent has been shown to reduce the risk of repeated revascularization. However, as shown for first-generation drug-eluting stent, they may be counterbalanced by a potential higher risk of stent thrombosis, especially among ST-segment elevation myocardial infarction patients. In addition, diabetes has been shown to be an independent predictor of poor survival and repeated target vessel revascularization. No data have been reported so far on the long-term benefits and safety of new-generation drug-eluting stent in ST-segment elevation myocardial infarction according to diabetes. Therefore, the aim of this study was to evaluate whether diabetes may impact on the benefits from everolimus-eluting stent versus first-generation drug-eluting stent in patients undergoing primary angioplasty. METHODS: We combined data from two randomized trials (PaclitAxel or Sirolimus-Eluting Stent vs Bare-Metal Stent in Primary Angioplasty and randomized comparison of everolimus-eluting stents and sirolimus-eluting stents in patients with ST elevation myocardial infarction) including consecutive ST-segment elevation myocardial infarction patients admitted within 12 h of symptom onset undergoing primary angioplasty and stent implantation at a tertiary centre with 24-h primary percutaneous coronary intervention capability. Primary endpoint of this study was major adverse cardiac events at 3-year follow-up. Secondary endpoints were as follows: (1) death, (2) reinfarction, (3) definite or probable ST and (4) target vessel revascularization at 3-year follow-up. No patient was lost to follow-up. RESULTS: Our population is represented by 680 ST-segment elevation myocardial infarction patients treated with drug-eluting stent (180 enrolled in the PaclitAxel or Sirolimus-Eluting Stent vs Bare-Metal Stent in Primary Angioplasty trial, treated with first-generation drug-eluting stent, and 500 patients in the randomized comparison of everolimus-eluting stents and sirolimus-eluting stents in patients with ST elevation myocardial infarction, randomized to everolimus-eluting stent or sirolimus-eluting stent). Diabetes was observed in a total of 178 patients (26.1%) and associated with higher major adverse cardiac events, mortality, reinfarction, stent thrombosis and target vessel revascularization. Similar outcome was observed in terms of overall major adverse cardiac events, mortality, recurrent myocardial infarction, target vessel revascularization, with everolimus-eluting stent as compared to first-generation drug-eluting stent in both diabetic and non-diabetic patients, whereas everolimus-eluting stent was associated with a significantly lower rate of stent thrombosis only in diabetic patients (1.6% vs 9.6%, hazard ratio (95% confidence interval) = 0.15 (0.02-0.98), p = 0.04) whereas no difference was observed in non-diabetic patients. CONCLUSION: This study shows that among ST-segment elevation myocardial infarction patients undergoing primary angioplasty, diabetes is associated with a significantly worse outcome at 3-year follow-up. A similar outcome was observed between everolimus-eluting stent and first-generation drug-eluting stent in non-diabetic patients, whereas among diabetic patients everolimus-eluting stent was associated with a significant reduction in stent thrombosis.

Randomized comparison of everolimus-eluting stents and sirolimus-eluting stents in patients with ST elevation myocardial infarction: RACES-MI trial.

OBJECTIVES: The aim of the current study was to compare everolimus-eluting stents (EES) with sirolimus-eluting stents (SES) in patients undergoing primary angioplasty. BACKGROUND: Drug-eluting stents may offer benefits in terms of repeat revascularization. However, as shown for first-generation drug-eluting stents, they may be counterbalanced by a potential higher risk of stent thrombosis, especially among patients with ST-segment elevation myocardial infarction (STEMI). No data have been reported so far on the long-term benefits and safety of the new generation of drug-eluting stents in STEMI. METHODS: Consecutive STEMI patients admitted within 12 h of symptom onset and undergoing primary angioplasty and stent implantation at a tertiary center with 24-h primary percutaneous coronary intervention capability were randomly assigned to SES or EES. The primary endpoint was a major adverse cardiac event at 3-year follow-up. The secondary endpoints were death, reinfarction, definite or probable stent thrombosis, and target vessel revascularization at 3-year follow-up. No patient was lost to follow-up. RESULTS: From April 2007 to May 2009, 500 patients with STEMI were randomized to EES (n = 250) or SES (n = 250). No difference was observed in terms of baseline demographic and clinical characteristics between the groups. No difference was observed between the groups in terms of number of implanted stents per patient or total stent length. However, a larger reference diameter was observed with SES (3.35 ± 0.51 mm vs. 3.25 ± 0.51 mm, p = 0.001), whereas patients randomized to EES more often received glycoprotein IIb/IIIa inhibitors (54.4% vs. 42.4%, p = 0.006). Follow-up data were available in all patients (1,095 ± 159 days). No significant difference was observed between EES and SES in major adverse cardiac events (16% vs. 20.8%, adjusted hazard ratio [HR]: 0.75 [95% confidence interval (CI): 0.5 to 1.13], p = 0.17), cardiac death (4.4% vs. 5.6%, adjusted HR: 0.77 [95% CI: 0.35 to 1.71], p = 0.53), recurrent MI (6.4% vs. 10%, adjusted HR: 0.62 [95% CI: 0.33 to 1.16], p = 0.13), and target vessel revascularization (4.8% vs. 4.8%, adjusted HR: 1.00 [95% CI: 0.45 to 2.32], p = 0.99). However, EES was associated with a significant reduction in stent thrombosis (1.6% vs. 5.2%, adjusted HR: 0.3 [95% CI: 0.1 to 0.92], p = 0.035). CONCLUSIONS: This study shows that among STEMI patients undergoing primary angioplasty, EES has similar efficacy as SES, but is associated with a significant reduction in stent thrombosis. (Randomized Comparison of Everolimus Eluting Stents and Sirolimus Eluting Stent in Patients With ST Elevation Myocardial Infarction [RACES-MI]; NCT01684982).

Atypical response of class IC atrial flutter to adenosine.

We report the case of a 67-year-old female with a wide QRS complex tachycardia at 180 bpm. A diagnosis of class IC atrial flutter with aberrant ventricular conduction caused by flecainide therapy was formulated. Intravenous adenosine administration resulted in adequate slowing of the ventricular rate and normalization of QRS complexes. Restoration of sinus rhythm was achieved with intravenous amiodarone. The response to adenosine confirmed the diagnosis of supraventricular tachycardia with aberrant conduction, but the transition from arrhythmia onset to restoration of sinus rhythm showed interesting peculiarities.

The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients.

OBJECTIVE: The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa Pl(A1/A2) polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients. METHODS: We studied two populations. In loco, we genotyped 140 hypertensive control individuals and 28 hypertensive patients with ischemic stroke. Furthermore, we performed an analysis of previously published data of 451 Sardinian hypertensive patients, already characterized and genotyped. RESULTS: Association analysis revealed that the Pl(A2) distribution was similar between hypertensive patients with and without stroke, but when considering a more homogeneous population of high-risk hypertensive patients, defined according to ESH/ESC 2003 guidelines, we observed that the frequency of the Pl(A2) allele was higher among stroke versus nonstroke patients (stroke, 46.4%; nonstroke, 22.6%; P = 0.01). The multiple regression analysis taking into account this polymorphism among other factors known to contribute to ischemic stroke confirmed the Pl(A2) allele as an additive risk factor for stroke (B = 0.986, Wald = 4.943, P < 0.03), increasing the risk of stroke by 2.9 (95% confidence interval = 1.23-6.85, P < 0.02). Similar results were obtained in the Sardinian population: in hypertensive patients with three or more risk factors, Pl(A2) increases the risk (odds ratio = 2.8, 95% confidence interval = 1.3-6.0, P < 0.001) and is an additive risk factor for stroke (B = 1.073, Wald = 6.920, P < 0.01). CONCLUSIONS: Our data suggest that the Pl(A2) polymorphism is a genetic determinant of ischemic stroke in a selected high-risk hypertensive population.

Beta2-adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension.

OBJECTIVES: Although blood pressure is considered the major determinant of left ventricular hypertrophy in hypertension, genetic variability is increasingly being considered among the factors influencing this complication. beta(2)-Adrenergic receptors (beta(2)ARs) are up-regulated in hypertension and largely polymorphic within the human population. Recently, we have shown that the Glu27 beta(2)AR variant is strongly associated with cardiac hypertrophy in hypertension. The objective of this study is to verify whether this polymorphism also affects hypertrophy regression in response to antihypertensive therapy. METHODS: In a prospective follow-up study we screened 970 hypertensive patients of Caucasian descent for the Gly16Arg, Gln27Glu, and Thr164Ile beta(2)AR polymorphisms and left ventricular echocardiographic hypertrophy and assigned selected patients to enalapril or atenolol to assess left ventricular hypertrophy regression after 2-year follow-up. Results were stratified according to treatment and the Glu27Gln polymorphism of the beta(2)AR. In cells with stable overexpression of the Glu27 or Gln27 variant of beta(2)AR, we also explored the implications of this polymorphism on hypertrophy-related intracellular signal transduction. RESULTS: Among hypertensive patients, the Gly16 allele was found in 63% of patients and the Glu27 allele was found in 40.6%. Both polymorphisms were in linkage disequilibrium, as expected. Four hundred forty-one hypertrophic hypertensive patients completed the 2-year follow-up. At baseline, patients carrying at least 1 allele of the Glu27 variant presented with a larger cardiac size despite similar blood pressure levels (142.9 +/- 22.5 g/m(2) in Glu27 carriers versus 138.2 +/- 18.4 g/m(2) in Gln27 carriers, P < .02). Blood pressure normalization was achieved by both drugs. At follow-up, compared with the Gln27 patients, the Glu27 patients showed a larger reduction in hypertrophy when treated with enalapril (percent change in left ventricular mass, -6.3% +/- 7.7% in Glu27 carriers versus -2.18% +/- 7.9% in Gln27 carriers; P < .05) but not with atenolol therapy (-2.8% +/- 8.9% in Glu27 carriers versus -2.4% +/- 8.8% in Gln27 carriers, P = not significant). In in vitro studies the activation of p38 and extracellular signal-regulated kinase (ERK-) 1/2 (data not shown) and the activity of the atrial natriuretic factor (ANF) promoter after isoproterenol (INN, isoprenaline) stimulation were larger in Glu27 beta(2)AR overexpressing cells than in Gln27 beta(2)AR overexpressing cells (fold difference compared with unstimulated cells, 9.7 +/- 2.9 for Glu27 beta(2)AR versus 4.2 +/- 0.3 for Gln27 beta(2)AR; P < .05). CONCLUSIONS: The Glu27 variant of beta(2)AR enhances hypertension-induced left ventricular hypertrophy. In these patients angiotensin-converting enzyme inhibitors are more efficient than beta-blockers in reducing cardiac size.

The use of a telematic connection for the follow-up of hypertensive patients improves the cardiovascular prognosis.

BACKGROUND: Inadequate blood pressure (BP) control could be due to incorrect management of hypertensives caused by the lack of interaction between general practitioners (GP) and hypertension specialists. OBJECTIVES: To test the effectiveness on BP and total cardiovascular risk (TCVR) control of an internet-based digital network connecting specialists and GPs. METHODS: We created a network among the Hypertension Clinic, Federico II University (Naples, Italy), 23 hospital-based hypertension clinics and 60 GPs from the area (CampaniaSalute Network, CS). Randomized GPs enrolled in CS could update online records of patients (n = 1979). As a control, we included 2045 patients referred to the specialist clinics by GPs from outside the network. All patients completed a 2-year follow-up. RESULTS: CS provided a larger reduction in BP [systolic/diastolic BP (SBP/DBP): 7.3 +/- 0.4/5.4 +/- 0.3 versus 4.1 +/- 0.4/3.1 +/- 0.26 mmHg, CS versus control; P < 0.001 for both] and percentage of patients with BP < 140/90 mmHg (CS versus control: baseline, 33 versus 34%, NS; end of follow-up, 51 versus 47%, chi = 13.371; P < 0.001). A European Society of Hypertension-European Society of Cardiology (ESH/ESC) TCVR score was calculated [from 1 (average) to 5 (very high TCVR)]. The CS group showed a reduction in the mean TCVR score (CS: from 3.5 +/- 0.02 to 3.2 +/- 0, P < 0.01, ANOVA; control group: 3.5 +/- 0.03 to 3.4 +/- 0.03, NS) and, accordingly, fatal and non-fatal major cardiovascular events (MACE) were less frequent (2.9 versus 4.3%; chi = 5.047, P < 0.02). CS predicts fewer MACE in multiple binary regression analysis (beta:-7.27, P < 0.008) reducing the risk for MACE compared to control [odds ratio (OR): 0.838; 95% confidence interval (CI): 0.73-0.96]. CONCLUSION: Our results support the idea that telemedicine can achieve better control of BP and TCVR.

The Glu27 allele of the beta2 adrenergic receptor increases the risk of cardiac hypertrophy in hypertension.

OBJECTIVE: Cardiac and vascular remodeling occur in response to hypertension. Genetic background appears to modify the development of target organ damage (TOD). We evaluated the impact on hypertension-associated TOD of a highly polymorphic gene with elevated significance for the regulation of the cardiovascular system, the beta2AR gene. METHODS: We recruited 775 hypertensives (mean +/- SE: age 53.5 +/- 0.5, from 20 to 84 years; female 32.7%; systolic (SBP)/diastolic (DBP) blood pressure: 159 +/- 1.2/101 +/- 0.6 mmHg) referred to the departmental outpatient clinic and screened them for the Arg16Gly, Gln27Glu, and Ile164Thr variants of beta2AR gene. We performed association analyses on clinical, anamnesis, anthropometrical and biochemical parameters as well as cardiac and vascular ultrasound. RESULTS: We found that the three polymorphisms did not affect blood pressure levels. Cardiac TOD appeared to be related to the Glu27 variant. In fact, the Glu27 allele associates with a 1.4-fold higher risk of developing cardiac hypertrophy, and directly correlated with larger systolic and diastolic left ventricle internal diameters. Vascular TOD was not affected by the three polymorphisms. Ancillary to our finding we observed that the Glu27 variant is associated with a higher incidence of dyslipidemia. CONCLUSIONS: Our data indicate that beta2AR gene polymorphisms participate in the determination of cardiac TOD associated with hypertension.