Novel Anti-Inflammatory Therapies in Coronary Artery Disease and Acute Coronary Syndromes.

Evidence suggests that inflammation plays an important role in atherosclerosis and the consequent clinical presentation, including stable coronary artery disease (CAD) and acute coronary syndromes (ACS). The most essential elements are cytokines, proteins with hormone-like properties that are produced by the immune cells, endothelial cells, platelets, fibroblasts, and some stromal cells. Interleukins (IL-1ß and IL-6), chemokines, interferon-γ (IFN-γ), and tumor necrosis factor-alpha (TNF-α) are the cytokines commonly associated with endothelial dysfunction, vascular inflammation, and atherosclerosis. These molecules can be targeted by commonly used therapeutic substances or selective molecules that exert targeted anti-inflammatory actions. The most significant anti-inflammatory therapies are aspirin, statins, colchicine, IL-1ß inhibitors, and IL-6 inhibitors, along with novel therapies such as TNF-α inhibitors and IL-1 receptor antagonists. Aspirin and statins are well-established therapies for atherosclerosis and CAD and their pleiotropic and anti-inflammatory actions contribute to their efficacy and favorable profile. Colchicine may also be considered in high-risk patients if recurrent ACS episodes occur when on optimal medical therapy according to the most recent guidelines. Recent randomized studies have also shown that therapies specifically targeting inflammatory interleukins and inflammation can reduce the risk for cardiovascular events, but these therapies are yet to be fully implemented in clinical practice. Preclinical research is also intense, targeting various inflammatory mediators that are believed to be implicated in CAD, namely repeated transfers of the soluble mutant of IFN-γ receptors, NLRP3 inflammasome inhibitors, IL-10 delivery by nanocarriers, chemokine modulatory treatments, and reacting oxygen species (ROS) targeting nanoparticles. Such approaches, although intriguing and promising, ought to be tested in clinical settings before safe conclusions can be drawn. Although the link between inflammation and atherosclerosis is significant, further studies are needed in order to elucidate this association and improve outcomes in patients with CAD.

Effects of Chemotherapy on Aortic 18-Fluorodeoxyglucose Uptake in Patients With Hodgkin and Non-Hodgkin Lymphoma.

Background: Despite advances in the treatment of oncology patients, therapy-related side effects may lead to premature morbidity. Inflammatory activation that has been linked to cardiovascular disease is crucial for the pathogenesis of both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Objectives: The purpose of this study was to assess the vascular effects of chemotherapy in patients with HL and NHL by positron emission tomography/computed tomography with 18-fluorodeoxyglucose (18-FDG PET/CT) and to investigate interactions with systemic inflammation as assessed by circulating inflammatory markers. Methods: Between July 2015 and July 2019, 65 consecutive patients (mean age 56 ± 17.78 years) with confirmed diagnosis of either HL (n = 33) or NHL (n = 32) were prospectively studied. PET/CT imaging was performed at baseline, at an interim phase, and after first-line treatment. Aortic FDG uptake was assessed by measuring global aortic target-to-background ratio (GLA-TBR). Serum biomarkers interleukin (IL)-6 and IL-1b were measured at each phase. Results: Patients with HL demonstrated significant reduction in aortic TBR after first-line treatment (median GLA-TBR baseline: 1.98, median GLA-TBR third scan: 1.75, median difference = -0.20, 95% CI: -0.07 to -0.33, P = 0.006), which remained significant after adjustment for confounders (adj. R2 of model = 0.53). In contrast, patients with NHL did not demonstrate a significant aortic inflammation response (P = 0.306). Furthermore, patients with HL demonstrated a significant reduction in IL-6 (P = 0.048) and IL-1b (P = 0.045), whereas patients with NHL did not demonstrate significant reduction in IL-6 (P = 0.085) and IL-1b levels (P = 0.476). Conclusions: Aortic inflammation, as assessed by 18-FDG PET/CT, is reduced in HL patients after first-line treatment but not in NHL patients. These findings imply that different pathophysiological pathways and different therapies might affect the arterial bed in different ways for patients with lymphoma.

Risk and protective factors for atrial fibrillation after cardiac surgery and valvular interventions: an umbrella review of meta-analyses.

OBJECTIVE: Postoperative atrial fibrillation (POAF) is a common complication affecting approximately one-third of patients after cardiac surgery and valvular interventions. This umbrella review systematically appraises the epidemiological credibility of published meta-analyses of both observational and randomised controlled trials (RCT) to assess the risk and protective factors of POAF. METHODS: Three databases were searched up to June 2021. According to established criteria, evidence of association was rated as convincing, highly suggestive, suggestive, weak or not significant concerning observational studies and as high, moderate, low or very low regarding RCTs. RESULTS: We identified 47 studies (reporting 61 associations), 13 referring to observational studies and 34 to RCTs. Only the transfemoral transcatheter aortic valve replacement (TAVR) approach was associated with the prevention of POAF and was supported by convincing evidence from meta-analyses of observational data. Two other associations provided highly suggestive evidence, including preoperative hypertension and neutrophil/lymphocyte ratio. Three associations between protective factors and POAF presented a high level of evidence in meta-analyses, including RCTs. These associations included atrial and biatrial pacing and performing a posterior pericardiotomy. Nineteen associations were supported by moderate evidence, including use of drugs such as amiodarone, b-blockers, glucocorticoids and statins and the performance of TAVR compared with surgical aortic valve replacement. CONCLUSIONS: Our study provides evidence confirming the protective role of amiodarone, b-blockers, atrial pacing and posterior pericardiotomy against POAF as well as highlights the risk of untreated hypertension. Further research is needed to assess the potential role of statins, glucocorticoids and colchicine in the prevention of POAF. PROSPERO REGISTRATION NUMBER: CRD42021268268.

Risk and Protective Factors for Sudden Cardiac Death: An Umbrella Review of Meta-Analyses.

Background: Sudden cardiac death (SCD) is a global public health issue, accounting for 10-20% of deaths in industrialized countries. Identification of modifiable risk factors may reduce SCD incidence. Methods: This umbrella review systematically evaluates published meta-analyses of observational and randomized controlled trials (RCT) for the association of modifiable risk and protective factors of SCD. Results: Fifty-five meta-analyses were included in the final analysis, of which 31 analyzed observational studies and 24 analyzed RCTs. Five associations of meta-analyses of observational studies presented convincing evidence, including three risk factors [diabetes mellitus (DM), smoking, and early repolarization pattern (ERP)] and two protective factors [implanted cardiac defibrillator (ICD) and physical activity]. Meta-analyses of RCTs identified five protective factors with a high level of evidence: ICDs, mineralocorticoid receptor antagonist (MRA), beta-blockers, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with HF. On the contrary, other established, significant protective agents [i.e., amiodarone and statins along with angiotensin-converting enzyme (ACE) inhibitors in heart failure (HF)], did not show credibility. Likewise, risk factors as left ventricular ejection fraction in HF, and left ventricular hypertrophy, non-sustain ventricular tachycardia, history of syncope or aborted SCD in pediatric patients with hypertrophic cardiomyopathy, presented weak or no evidence. Conclusions: Lifestyle risk factors (physical activity, smoking), comorbidities like DM, and electrocardiographic features like ERP constitute modifiable risk factors of SCD. Alternatively, the use of MRA, beta-blockers, SGLT-2 inhibitors, and ICD in patients with HF are credible protective factors. Further investigation targeted in specific populations will be important for reducing the burden of SCD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020216363, PROSPERO CRD42020216363.

The Fundamental Role of Stress Echo in Evaluating Coronary Artery Disease in Specific Patient Populations.

Stress echocardiography (SE) was initially used for assessing patients with known or suspected coronary heart disease by detecting and evaluating myocardial ischemia and viability. The implementation of SE has gradually been extended to several cardiovascular diseases beyond coronary artery disease, and SE protocols have been modified and adapted for the detection of coronary artery disease (CAD) or other cardiovascular diseases in specific patient populations. This review attempts to summarize current data concerning SE implementation and clinical value in these specific and diverse populations: patients with an intramural course of a coronary artery, known as a myocardial bridge, chronic severe or end-stage hepatic disease, chronic severe or end-stage kidney disease, cardiac allograft vasculopathy, patients scheduled for solid-organ transplantation and other intermediate and high-risk surgery and, finally, patients treated with anticancer drugs or radiotherapy.

Cardiac Masses: The Role of Cardiovascular Imaging in the Differential Diagnosis.

Cardiac masses are space occupying lesions within the cardiac cavities or adjacent to the pericardium. They include frequently diagnosed clinical entities such as clots and vegetations, common benign tumors such as myxomas and papillary fibroelastomas and uncommon benign or malignant primary or metastatic tumors. Given their diversity, there are no guidelines or consensus statements regarding the best diagnostic or therapeutic approach. In the past, diagnosis used to be made by the histological specimens after surgery or during the post-mortem examination. Nevertheless, evolution and increased availability of cardiovascular imaging modalities has enabled better characterization of the masses and the surrounding tissue. Transthoracic echocardiography using contrast agents can evaluate the location, the morphology and the perfusion of the mass as well as its hemodynamic effect. Transesophageal echocardiography has increased spatial and temporal resolution; hence it is superior in depicting small highly mobile masses. Cardiac magnetic resonance and cardiac computed tomography are complementary providing tissue characterization. The scope of this review is to present the role of cardiovascular imaging in the differential diagnosis of cardiac masses and to propose a step-wise diagnostic algorithm, taking into account the epidemiology and clinical presentation of the cardiac masses, as well as the availability and the incremental value of each imaging modality.

Twelve-lead and signal-averaged electrocardiographic parameters among beta-thalassemia major patients.

BACKGROUND: The majority of beta thalassemia major (ß-TM) patients suffer from cardiac disease, while a significant proportion of them die suddenly. Twelve-lead and signal-averaged electrocardiography (SAECG) are simple, inexpensive, readily available tools for identifying an unfavorable arrhythmiological substrate by detecting the presence of arrhythmias, conduction abnormalities, and late potentials (LPs) in these patients. METHODS: A total of 47 ß-TM patients and 30 healthy controls were submitted to 12-lead and signal-averaged electrocardiography. Basic electrocardiographic parameters and prevalence of LPs were recorded. Basic echocardiographic parameters were estimated by transthoracic echocardiography. T2* was calculated by cardiac magnetic resonance imaging wherever available. RESULTS: ß-TM patients demonstrated a more prolonged PR interval (167.74 msec vs 147.07 msec) (P = .043), a higher prevalence of PR prolongation (21.05% vs 0%) (P = .013), and a higher prevalence of LPs (18/47, 38.3% vs 2/30, 6.7%) (P = .002) compared with controls. The prevalence of atrial fibrillation among b-TM patients was estimated at 10.64%. Patients had also greater E/e' ratio (8.35, SD = 2.2 vs 7, SD = 2.07) (P = .012) and LAVI (30.7 mL/m2, SD = 8.76 vs 24.6 mL/m2, SD = 6.57) (P = .002) than controls. Regression analysis showed that QTc and LAVI could correctly predict the presence of LPs in the 80.9% of the patients. CONCLUSIONS: ß-TM patients have a higher prevalence of a prolonged PR interval, atrial fibrillation, and LPs. Twelve-lead and SAECG performance was feasible in all subjects and constitutes a readily available tool for assessing myocardial electrophysiological alterations in this patient group.

Lymphoma Severity and Type Are Associated With Aortic FDG Uptake by 18F-FDG PET/CT Imaging.

BACKGROUND: There is evidence that metabolic disease burden in lymphoma influences patient outcome. However, the impact of disease severity on the cardiovascular system is unknown. OBJECTIVES: The aim of this study was to examine whether lymphoma is associated with arterial inflammation by investigating the relationship between disease metabolic burden and arterial fluorodeoxyglucose (FDG) uptake. METHODS: Sixty-two chemotherapy-naïve patients with active Hodgkin's or non-Hodgkin's lymphoma were matched (2:1) to individual control groups of lymphoma patients previously treated and free of active disease. All groups underwent 18F-FDG position emission tomography-computed tomography imaging. Disease severity was quantified by metabolic tumor volume (MTV) and total lesion glycolysis corresponding to standardized uptake values (SUVs) ≥41% or ≥2.5 of the maximum SUV within lymphoma regions, and aortic FDG uptake was quantified through the target-to-background ratio (TBR). Inflammatory and disease severity biomarkers were also measured. RESULTS: MTV and total lesion glycolysis measurements were significantly correlated with inflammatory and disease biomarkers. Aortic TBR was higher in patients with active non-Hodgkin's lymphoma compared with control subjects (median difference 0.51; 95% confidence interval [CI]: 0.28 to 0.78; p < 0.001). Similarly, patients with active Hodgkin's lymphoma had higher values of aortic TBR compared with control subjects (median difference 0.31; 95% CI: 0.15 to 0.49; p < 0.001). In addition, aortic TBR was modestly increased in patients with stage III to IV disease compared with those with stage I to II disease (median aortic TBR: 2.23 [interquartile range: 2.01 to 2.54] vs. 2.06 [interquartile range: 1.83 to 2.27; p = 0.050). In multivariable analysis, aortic FDG uptake and MTV≥2.5 values were independently associated (ß = 0.425; 95% CI: 0.189 to 0.662; p = 0.001; R2 = 0.208), as were aortic FDG uptake and MTV≥41% (ß = 0.407; 95% CI: 0.167 to 0.649, p = 0.001; R2 = 0.191). CONCLUSIONS: Aortic wall FDG uptake is related with disease severity indicative of a possible vascular effect of lymphoma. This work highlights a new potential role of molecular imaging in cardio-oncology for evaluating disease severity and its consequences on the vasculature.

Transfemoral transcatheter aortic valve replacement in the presence of a mitral prosthesis.

PURPOSE: In the current case series, we present our experience with the self-expanding CoreValve or Evolut R (Medtronic Inc.) in patients with severe symptomatic aortic valve stenosis and concomitant mitral valve prosthesis. METHODS: Twelve patients with previous mitral valve prosthesis underwent transcatheter aortic valve replacement for severe symptomatic aortic valve stenosis and/or aortic valve regurgitation. All patients underwent evaluation with an echocardiogram, computed tomography and coronary angiogram. After the index intervention and before discharge all patients underwent transthoracic echocardiography. All outcomes were defined according to the Valve Academic Research Consortium-2 criteria. RESULTS: Eleven patients underwent transcatheter aortic valve replacement for severe symptomatic aortic valve stenosis and one patient for severe aortic valve regurgitation. There was immediate improvement of patients' hemodynamic status; no cases of procedural death, stroke, myocardial infarction, or urgent cardiac surgery occurred. There was no 30-day mortality and all patients improved, with 91.6% in functional New York Heart Association class I-II. CONCLUSION: The current study demonstrates that in patients with severe aortic valve stenosis or regurgitation and mitral valve prosthesis, the implantation of a self-expanding aortic valve via the transfemoral route is safe and feasible, with maintained long-term results.

Vascular inflammation and metabolic activity in hematopoietic organs and liver in familial combined hyperlipidemia and heterozygous familial hypercholesterolemia.

BACKGROUND: Familial dyslipidemias of either heterozygous (heFH) or combined (FCH) type lead to accelerated atherogenesis and increased cardiovascular risk. OBJECTIVE: The aim of this study was to investigate in statin-naïve adult patients with familial dyslipidemias whether inflammatory activation and liver, spleen and bone marrow metabolic activity differ compared with normolipidemic subjects and between dyslipidemic groups. METHODS: Fourteen patients with FCH, 14 with heFH, and 14 normolipidemic individuals were enrolled. Serum lipids, high-sensitivity C-reactive protein, and fibrinogen levels were measured, followed by 18F-fluorodeoxyglucose positron-emission tomography/computed tomography imaging. Radiotracer uptake in the aortic wall, spleen, bone marrow, and liver was quantified as tissue-to-background ratio (TBR). RESULTS: Patients with heFH had significantly higher low-density lipoprotein levels compared with those with FCH and controls (P < .001). However, aortic TBRs were higher in FCH compared with heFH patients and controls (P = .02 and P < .001, respectively). FCH patients exhibited higher FDG uptake in the spleen compared with controls (P = .05). In addition, FCH exhibited higher bone marrow FDG uptake compared with heFH patients and controls (P = .03 and P = .02, respectively). FCH had higher liver uptake compared with heFH patients and controls (P < .001 for both). Significant correlations were observed between inflammatory biomarkers and imaging indices as well as between aortic TBR and FDG uptake of hematopoietic organs and liver. CONCLUSIONS: Systemic, as well as vascular inflammation and spleen, bone marrow, and hepatic metabolic activity are increased in patients with FCH despite lower levels of low-density lipoprotein.

Effect of gender on the prognostic value of dobutamine stress myocardial contrast echocardiography.

BACKGROUND: Dobutamine stress contrast echo (DSCE) has a well-established prognostic value in the context of coronary artery disease (CAD). However, data regarding its prognostic capability separately in men and women are scarce. The aim of the current study was to assess gender-related differences in the prognostic performance of DSCE. METHODS: DSCE was performed in 2645 consecutive patients, who were classified into two groups depending on gender. Follow-up lasted 57.1±10.1 months. End points included all-cause mortality, cardiac death, late revascularization, and hospitalizations. Survival analysis was performed comparing men and women. RESULTS: Of the 2645 patients (59.3±8.7 years), 69.1% were men. DSCE was positive in 23.4% of male patients, while in females, the respective percentage was 14.3%. There was statistically significant difference between the two groups with regard to end point occurrence (11.6% vs. 6.1%, p<0.05). Multivariate analysis revealed that the DSCE response was the strongest predictor of adverse outcomes (Exp(B)=51.9, p<0.05) in both groups. The predictive model including DSCE results along with clinical data performed well without significant differences between males and females (C-index 0.93 vs. 0.87 respectively, p=NS). CONCLUSION: DSCE has a strong prognostic value for patients with known or suspected CAD, regardless of patient gender. This makes DSCE an attractive screening option for women in whom CAD assessment can be challenging.

Diagnosis and Treatment of Left-Sided Prosthetic Paravalvular Regurgitation.

Paravalvular leak (PVL) is a complication related to the surgical implantation of left-sided prosthetic valves. The prevalence of paravalvular regurgitation ranges between 5 and 20%. Left-sided prosthetic paravalvular regurgitation presents with a wide constellation of signs and symptoms ranging from asymptomatic murmur to heart failure, hemolysis and cardiac cachexia. Echocardiography plays a key role in imaging the PVL and can help in guiding the closure procedure with both transesophageal and intracardiac probes. Transcatheter closure of paravalvular regurgitations is an appealing prospect.

Cardiovascular disease and hepatitis C virus infection: an irrelevant statement or a hot relationship?

Hepatitis C virus (HCV) is well known for being the leading cause of hepatocellular carcinoma and cirrhosis, contributing to a devastating array of metabolic dysfunctions associated with hepatic failure. However, the cardiac manifestations of HCV and chronic hepatitis C (CHC) are being explored, thus illuminating the connection between HCV infection and cardiac disease. Although not all studies agree, the evidence in favor of CHC promoting major risk factors for cardiovascular disease such as hypertension, insulin resistance, diabetes mellitus, and atherosclerosis is compelling. Similarly, properly warranted attention is being guided towards CHC as an independent risk factor for the development of atherosclerotic heart disease and cardiomyopathy. This review provides a synopsis on the relationship between (HCV) infection and cardiac disease, emphasizing on some of the key possible mechanisms and population derived data.