Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment-Part 1 Pharmacological Differences in Women and Men; How Relevant Are They?

BACKGROUND: Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine. AREA OF UNCERTAINTY: The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice. DATA SOURCES: A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases. RESULTS: Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most "sex-dependent" differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported. CONCLUSIONS: Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

The portrait of a stranger: the hypereosinophilic syndrome with cardiac involvement.

INTRODUCTION: Hypereosinophilic syndrome is a rare clinical condition, and cardiac involvement confers a poor prognosis. Hypereosinophilic myocarditis is a medical emergency and targeted treatment should be started promptly even before a definitive diagnosis could be made. CASE PRESENTATION: A 27-year-old female patient is hospitalized for exertional dyspnea, chest pain, and fatigue for the past 2 weeks. She also describes left leg paresthesias. Clinical examination was in normal limits. ECG showed sinus tachycardia, QS pattern in V1-V4, and diffuse flattened T waves. Laboratory tests revealed increased inflammatory markers, hypereosinophilia, elevated cardiac enzymes, high NT-proBNP. Echocardiography revealed LV dysfunction (EF 31%), while cardiac MRI showed diffuse delayed enhancement with predominant subendocardial disposition. The electromyogram was suggestive of left tibial nerve neuropathy. We interpreted the case as eosinophilic myocarditis with an urgent requirement of therapy and initiated high-dose glucocorticoid therapy and the GDMT 4-pillar heart failure treatment. We excluded common infectious, myeloproliferative syndromes, and frequent associated autoimmune diseases. With prednisone, the eosinophil count rapidly normalized and we gradually tapered the dose by 5 mg per week, however continuing with heart failure therapy. At monthly follow-up visits, there was a significant clinical improvement, with normalization of the eosinophilic count, and a near-normalization of myocardial function. The only symptom that persisted was paresthesias linked to left tibial neuropathy. CONCLUSION: The surprisingly rapid and favorable course of the disease offers a high index of suspicion for a toxic or a reactive transitory etiology, however still unidentified. In our case, the cause of eosinophilia remained unknown, although we managed to narrow down the possible etiologies. A surprisingly good clinical response was obtained with non-specific treatment targeting mainly hyperosinophilic myocarditis.

Acute rate control in atrial fibrillation: an urgent need for the clinician.

Rate and rhythm control are still considered equivalent strategies for symptom control using the Atrial Fibrillation Better Care algorithm recommended by the recent atrial fibrillation guideline. In acute situations or critically ill patients, a personalized approach should be used for rapid rhythm or rate control. Even though electrical cardioversion is generally indicated in haemodynamically unstable patients or for rapid effective rhythm control in critically ill patients, this is not always possible due to the high percentage of failure or relapses in such patients. Rate control remains the background therapy for all these patients, and often rapid rate control is mandatory. Short and rapid-onset-acting beta-blockers are the most suitable drugs for acute rate control. Esmolol was the classical example; however, landiolol a newer very selective beta-blocker, recently included in the European atrial fibrillation guideline, has a more favourable pharmacokinetic and pharmacodynamic profile with less haemodynamic interference and is better appropriate for critically ill patients.

Stroke risk scores for prediction of mortality and hemorrhages in atrial fibrillation patients.

Background: Atrial fibrillation (AF) is an emerging epidemic worldwide, responsible for a twofold increase in mortality, independent of other risk factors. Stroke prevention is the cornerstone of AF management. However, oral anticoagulation imposes an increased risk of bleeding. Several risk scores have been developed for estimating both the thromboembolic and the bleeding risks. The aim of the study was to determine the usefulness of different stroke risk scores as predictors of mortality and hemorrhagic events in AF patients. Methods: We retrospectively enrolled 211 AF patients hospitalized in the Cardiology Ward of our tertiary hospital. The primary endpoints were mortality and non-minor bleeding events. The mean follow-up period was 378 days for bleeding events and 5 years and 1 month for mortality. For each patient, we evaluated the following stroke risk scores: CHADS2, CHA2DS2-VASc, R2CHADS2, ABC, ATRIA, GARFIELD. Results: The mean age in our cohort is 66, with a slight predominance of women (52.2%). For a CHA2DS2-VASc ≥ 4 as well as for a score of 2-3, 5-year survival was worse than for patients with a score of 0-1(chi-squared=8.13; p=0.01). Similarly, all subgroups of patients with an ABC <2%, had a worse 5-year survival when compared with an ABC score of ≥2% (chi-squared=12.85; p=0.005). C-statistics show a modest predictive value for mortality, for all stroke scores except Garfield, with similar AUCs, the highest being for CHA2DS2-VASc (AUC 0.656; p=0.0001). CHA2DS2-VASc also correlates with bleeding events, having a good predictive ability (AUC 0.723; 95%CI 0.658-0.782, p=0.001), mildly superior to HAS-BLED (AUC 0.674; 95% CI 0.523-0.825; p = 0.04) and very close to Garfield-bleeding (0.765; 95%CI 0.702-0.80; p=0.0001). Conclusions: CHA2DS2-VASc is comparable to HAS-BLED and Garfield-bleeding in predicting bleeding events in AF patients. CHA2DS2-VASc and ABC correlate directly and consistently with mortality rate. For CHA2DS2-VASc, the AUCs for our endpoints are similar to the ones for stroke prediction, highlighting the potential of extending its applicability to various outcomes.

Stroke Risk Scores as Predictors of Severe Outcomes in Atrial Fibrillation: A Comprehensive Review.

BACKGROUND: Atrial fibrillation (AF) is the most frequent sustained arrhythmia. It increases the risk of stroke, heart failure, death, hospitalizations, and costs. AREA OF UNCERTAINTY: Several scores were introduced to stratify the stroke risk and need for anticoagulation in patients (pts) with AF . CHA2DS2-VASc, the most frequently used score, as well as other stroke risk scores have been additionally applied to estimate outcomes for different other conditions, with inhomogeneous results. To date, there has been no consensus regarding the usefulness of these scores to estimate outcomes outside of thromboembolic risk assessment, and their value in estimating different end-point outcomes is still a subject of debate. We conducted this review to investigate whether the stroke risk scores' utility can be extended for the prediction of other severe outcomes in pts with AF. DATA SOURCES: We searched PubMed database and included studies that stratified the outcome of pts with AF by different stroke risk scores. We also included studies with a separate analysis of the pts with AF subpopulation. RESULTS: Mortality rates increased with higher CHADS2 [from 2.28% (2.00%-2.58%) to 13.2% (8.24%-20.8%) per year] and CHA2DS2-VASc scores [risk ratio 1.26 (1.21-1.32), P < 0.0001 for score ≥3]. CHADS2 and CHA2DS2-VASc predicted poor outcome in stroke [odds ratio (OR) ranging 1.42-6 for CHADS2 and 1.3-7.3 for CHA2DS2-VASc]. Acute myocardial infarction rates increased with higher CHADS2 [OR 2.120 (1.942-2.315) P < 0.001] and CHA2DS2-VASc [OR 1.63 (1.53-1.75), P < 0.001]. Limited data were reported for ABC( Age, Biomarkers, Clinical histoty) and R2CHADS2. No statistically significant correlation was found for major bleeding. CONCLUSIONS: CHADS2 and CHA2DS2-VASc are useful tools in identifying pts with AF at higher risk for all-cause death, regardless of other pathologies. Both scores correlated with the development of acute myocardial infarction, cardiovascular hospitalization, outcome in stroke, major adverse cardiovascular events, and major adverse cardiovascular and cerebral events, but not with serious bleeding.

Stroke risk scores to predict hospitalization for acute decompensated heart failure in atrial fibrillation patients.

Introduction. Atrial fibrillation (AF) is the most frequent hospitalized arrhythmia. It associates increased risk of death, stroke and heart failure (HF). Stroke risk scores, especially CHA2DS2-VASc, have been applied also for populations with different diseases. There is, however, limited data focusing on the ability of these scores to predict HF decompensation.Methods. We conducted a retrospective observational study on a cohort of 204 patients admitted for cardiovascular pathology to the Cardiology Ward of our tertiary University Hospital. We aimed to determine whether the stroke risk scores could predict hospitalisations for acute decompensated HF in AF patients.Results. C-statistics for CHADS2 and R2CHADS2 showed a modest predictive ability for hospitalisation with decompensated HF (CHADS2: AUC 0.631 p = 0.003; 95%CI 0.560-0.697. R2CHADS2: AUC 0.619; 95%CI 0.548-0.686; p = 0.004), a marginal correlation for CHA2DS2-VASc (AUC 0.572 95%CI 0.501-0.641 with a p value of only 0.09, while the other scores failed to show a correlation. A CHADS2 ≥ 2 showed a RR = 2.96, p<0.0001 for decompensated HF compared to a score <2. For R2CHADS2 ≥ 2, RR = 2.41, p = 0.001 compared to a score <2. For CHA2DS2-VASc ≥ 2 RR = 2.18 p = 0.1, compared to CHA2DS2-VASc <2. The correlation coefficients showed a weak correlation for CHADS2 (r = 0.216; p = 0.001) and even weaker for R2CHADS2 (r = 0.197; p = 0.0047 and CHA2DS2-VASc (r = 0.14; p = 0.035).Conclusions. Among AF patients, CHADS2, CHA2DS2-VASc and R2CHADS2 were associated with the risk of hospitalisation for decompensated HF while ABC and ATRIA failed to show an association. However, predictive accuracy was modest and the clinical utility for this outcome remains to be determined.