AIM:The primary objective of this study was to assess the impact of attending a phase 3 cardiac rehabilitation (CR) program on all-cause mortality. METHODS:We conducted a systematic review using database searches (MEDLINE and Cochrane Central Register of Controlled Trials) up to December 2022 to identify studies that compared adult patients undergoing phase 3 of CR with those receiving usual care. RESULTS:Out of a total of 1867 identified articles, eight met the eligibility criteria (two randomized controlled trials (RCT) and six non-RCT) and were included (n=60939 patients; 82% male, average age of 62±11 years). Phase 3 of a CR program showed a significant association with reduced mortality rates, with a hazard ratio (HR) of 0.56 (95% CI 0.49-0.65), with minimal evidence of statistical heterogeneity. The studies presented a range of differently structured CR programs. They varied in duration, training methods, and components. CONCLUSION:This systematic review demonstrates that attending a phase 3 CR program has the beneficial effect of reducing mortality among patients with cardiovascular disease, in particular those with coronary artery disease. These findings highlight the importance of CR participation on a long-term basis and reinforce the value of increasing the number of specialized worldwide and optimizing patient referrals to participate in a long-term phase 3 CR program.
INTRODUCTION AND OBJECTIVES:Cardiovascular disease (CVD) is the leading cause of mortality in Portugal. Dyslipidemia, particularly elevated LDL-C, is a key modifiable risk factor. European guidelines recommend LDL-C targets based on cardiovascular (CV) risk, yet treatment gaps persist. This study aimed to evaluate LDL-C control and management in primary care patients with dyslipidemia in the Algarve, according to the 2019/2021 ESC/EAS guidelines. METHODS:A cross-sectional study was conducted using electronic health records from nine Family Health Units in the Algarve. Adults aged ≥40 years with a diagnosis of dyslipidemia (ICPC-2 code T93) were included. CV risk was assessed using SCORE2/OP for patients in primary prevention; LDL-C levels and treatment strategies were analyzed. RESULTS:Among 2904 patients (mean age 66.4 years; 54.5% female), 79% were classified as being high or very high risk. Only 15.7% achieved LDL-C targets. Among high/very high-risk patients, 88% were above recommended LDL-C thresholds. 29.9% of patients received no pharmacological treatment, and 47% were on low/moderate-intensity statins. High-intensity statins alone or in combination therapy were used in only 14.4% of cases. CONCLUSIONS:LDL-C target achievement remains suboptimal in Portuguese primary care, particularly in high-risk patients. The underuse of intensive treatment highlights opportunities for improving CV prevention, especially through updated risk assessment tools like SCORE2/OP.
INTRODUCTION AND OBJECTIVES:Current guidelines recommend a stepwise, low-density lipoprotein cholesterol (LDL-C) guided lipid-lowering therapy (LLT) approach for patients after acute coronary syndrome (ACS). This study aimed to assess whether an early intensive "strike early, strike strong" strategy with upfront combination LLT improves LDL-C goal attainment. METHODS:This single-center retrospective study included 211 consecutive ACS patients admitted between January and October 2020, with a median follow-up of six months. Metabolic profiles were assessed during hospitalization and at follow-up. Patients were grouped by follow-up LDL-C levels (<55 mg/dL and ≥55 mg/dL). Discharge medication, adherence, and LDL-C reduction were compared. RESULTS:A total of 211 patients were included in the analysis, with a mean age of 65±12 years; 74% were male. LDL-C on target (<55 mg/dL) was achieved in 36% of patients during a median follow-up of six months. This group was more commonly medicated with combination therapy [high-intensity statin (HI-statin) plus ezetimibe] at discharge (46% vs. 31%, p=0.040), had higher adherence rates (94% vs. 81%, p<0.001) and had significantly greater LDL-C reduction (80±48 mg/dL vs. 49±53 mg/dL, p<0.001). The combination therapy was the only independent predictor for LDL-C on target during follow-up (OR=2.054, 95% CI: 1.063-3.969, p=0.032). CONCLUSION(S):Low-density lipoprotein target attainment was suboptimal at median follow-up of six months. The LDL-C target group was associated with combination therapy with HI-statins plus ezetimibe upfront, better adherence and greater LDL-C reduction. These findings support the "strike early, strike strong" approach in very high-risk patients.
INTRODUCTION AND OBJECTIVES:Sodium-glucose cotransporter 2 inhibitors (SGLT2) were initially developed as antihyperglycemic agents for the management of type 2 diabetes mellitus (T2DM). This study sought to evaluate the impact of sodium-glucose cotransporter 2 inhibitors on blood glucose levels in patients with HFrEF without diabetes. METHODS:This randomized controlled trial included 130 patients with HF classified as NYHA class II to IV and without diabetes, with an ejection fraction (EF) below 40% as determined by echocardiography within the preceding three months. Baseline assessments included serum creatinine, random and fasting blood glucose, 2-hour postprandial glucose, HbA1c, urine acetone, BMI, blood pressure, and serum electrolytes (sodium, potassium, magnesium, ionized calcium, and phosphorus). After three months of treatment, all these clinical and laboratory parameters were reassessed in both groups. RESULTS:Treatment led to significant improvements in cardiac function, including reductions in left ventricular diameters and volumes, and increases in ejection fraction, tricuspid annular plane systolic excursion, and right ventricular fractional area change (p<0.05). Glycemic control also improved, with significant decreases in fasting, postprandial, HbA1c, and random blood glucose (p<0.001). Serum creatinine, magnesium, and phosphorus levels increased significantly (p<0.001). Adverse events were minimal, with only one patient showing urine acetone positivity (1.5%, p=0.99), and no symptomatic hypoglycemia, ketoacidosis, or significant hypotension occurred. CONCLUSIONS:SGLT2 inhibitors safely reduce blood glucose in patients with HFrEF without diabetes without causing hypoglycemia, highlighting their potential cardiovascular and metabolic benefits and supporting their use in this population.
INTRODUCTION AND OBJECTIVES:Aortic valve stenosis (AVS) is a growing healthcare burden and a paradigmatic example of sexual dimorphism in cardiovascular disease. Degenerative AVS results from valve fibrosis and calcification, affecting mainly women and men, respectively. Despite >20 years of clinical trials testing drugs such as statins, actaciguat, or vitamin K, aortic valve replacement (AVR) remains the only effective treatment. Evidence points to the relevance of protein ubiquitination in AVS progression, yet a holistic characterization of the ubiquitinome using mass spectrometry (MS) is lacking. Such an approach could uncover new targets for proteolysis-targeting chimeras (PROTACs), which remain underexplored in cardiovascular disease. RUBITAV aims to characterize the ubiquitinome landscape associated with fibrotic and calcific transformation of the valve and unveil sex-specific therapeutic targets. RUBITAV also aims to test the effect of modulating ubiquitinated proteins with PROTACs to mitigate fibrosis and calcification. METHODS:Aortic valves will be collected from a sex-balanced and comorbidities-matched AVS cohort and dissected into morphologically normal, fibrotic, and calcified sections. Following protein extraction, ubiquitinated proteins will be enriched and quantified by MS. Putative sex-specific targets identified using bioinformatics will be modulated in vitro with PROTACs using valve interstitial cells maintained under pro-fibrotic or pro-calcific conditions. The primary outcome is defined as the % reduction in fibrosis (females) and calcification (males). RESULTS:Not applicable. CONCLUSION:RUBITAV is expected to advance our understanding of the role of protein ubiquitination in AVS, identify new sex-specific therapeutic targets, and pave the way for the application of PROTACs in the treatment of AVS.
INTRODUCTION AND OBJECTIVES:To assess long-term outcomes of acute myocarditis (AM). METHODS:Prospective, single-center observational study including patients admitted with AM between 2007 and 2022, followed at a tertiary cardiology center. Follow-up (FUP) included annual clinical evaluations, treadmill testing, Holter and echocardiography. Statistical analysis was performed using chi-square test and Cox regression. RESULTS:We included 158 patients, 12.7% female, with a mean age of 32±12 years. Most presented with chest pain (94.3%). Severe complications, including cardiogenic shock or arrhythmic storm, occurred in 3.6%. Upon admission, the mean left ventricle ejection fraction (LVEF) was 57%. Out of the 140 patients who underwent cardiac magnetic resonance imaging (CMR), myocardial oedema and late gadolinium enhancement (LGE) were present in 47.8% and 88.5%, respectively. During a mean FUP time of 6±4.3 years, 13.3% patients were readmitted, 80.9% of them due to recurrent myocarditis. Only one patient with LVEF <50% at admission did not recover at FUP. No patients exhibited significant arrhythmias during Holter monitoring or treadmill stress tests. Six patients died at FUP. Three patients had experienced fulminant myocarditis (FM) at index admission; two of them died due to CV causes. There was a statistically significant association between death and fulminant presentation during index admission (p<0.001). CONCLUSION:AM in adults typically followed a benign course with favorable short- and long-term outcomes. In contrast, a small but significant subset with FM had a markedly poorer prognosis, with severe recurrences frequently proving fatal. Clinical presentation was the sole determinant of prognosis, prompting consideration of whether patients with milder cases truly require extended FUP.
INTRODUCTION AND OBJECTIVES:The gap junction alpha-4 (GJA4) gene, which encodes connexin37, regulates endothelial function and influences inflammation, platelet adhesion, and thrombus formation in vascular endothelial cells, which may favour atherosclerosis and cardiovascular (CV) events. The main objective was to assess whether the GJA4 rs618675 T>C variant is a risk factor for the onset of CV events in an asymptomatic Portuguese population. METHODS:One thousand four hundred twenty-one individuals without CV disease (52.2±8.3 years, 73.6% male) were followed up during a mean of 7.3±6.0 years, and CV events were recorded. GJA4 rs618675 T>C was genotyped by real-time PCR (TaqMan), and four genetic models were created. We analyzed traditional, biochemical and clinical risk factors. We performed bivariate analysis and adjusted logistic regression with respective OR. Kaplan-Meier estimated event-free survival and Cox regression, adjusted for confounding, evaluated the association between four genetic models and CV events (HR). RESULTS:Wild TT genotype, TC, and CC were 50.6%, 39.2%, and 10.1% in the CV events group and 66.2%, 30.4% and 3.4% in the non-events group (p=0.001). After logistic regression, the codominant model (CCvsTT and CTvsTT) showed an OR of 3.9 (p=0.002). Kaplan-Meier showed 87.6% event-free time for TT and 64.8% for CC (p=0.005). Adjusted Cox regression identified the codominant model as the best predictor (HR=2.8; p=0.008), together with male gender (HR=2.1; p=0.020), age (HR=1.1; p=0.001), hypertension (HR=1.9; p=0.014), smoking (HR=1.9; p=0.010), and leukocytosis (HR=1.2; p=0.003). CONCLUSION:We have demonstrated that the CC variant of GJA4 is significantly associated with CV events. Further investigations into this biomarker may improve CV risk prediction, leading to better primary prevention.
Digitalis glycosides are among the oldest therapies for heart failure (HF) with reduced ejection fraction, yet their contemporary role remains debated. Clinical data now indicate that the predominant clinical benefits of digitalis appear to derive from autonomic and neurohormonal modulation (enhanced vagal activity, attenuation of sympathetic drive, and suppression of renin-angiotensin-aldosterone activation) rather than from classical positive inotropy. At low serum concentrations, these effects translate into improved rate control, reduced congestion, and fewer decompensations with a lower risk of toxicity, whereas higher "inotropic" levels are associated with proarrhythmia and excess mortality. This review summarises the mechanistic and pharmacokinetic differences between digoxin and digitoxin, appraises evidence from PROVED, RADIANCE and DIG, and integrates emerging outcome data from DIGIT-HF, which showed that low-dose digitoxin added to contemporary guideline-directed therapy reduces the composite of death or HF hospitalisation. Finally, this review also provides valuable insights from a 2025 survey of Portuguese HF specialists into real-world clinical practice regarding digitalis use. With 55 experts responding, the survey highlights a predominant, selective application of digitalis glycosides, primarily after optimization of foundational HF therapies, consistent with guideline recommendations. Perceived benefits focus on rate control and symptom relief, while concerns about toxicity, the need for monitoring, and gaps in modern trial evidence continue to restrict broader adoption. Together, current data support a repositioning of digitalis as a low-dose, concentration-guided, neurohormonal modulator and rate-control agent for carefully selected patients with HF with reduced ejection fraction, an approach that ongoing and future trials should further refine.
