Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies: JACC: CardioOncology State-of-the-Art Review.

Proteasome inhibitors (PIs) are the backbone of combination treatments for patients with multiple myeloma and AL amyloidosis, while also indicated in Waldenström's macroglobulinemia and other malignancies. PIs act on proteasome peptidases, causing proteome instability due to accumulating aggregated, unfolded, and/or damaged polypeptides; sustained proteome instability then induces cell cycle arrest and/or apoptosis. Carfilzomib, an intravenous irreversible PI, exhibits a more severe cardiovascular toxicity profile as compared with the orally administered ixazomib or intravenous reversible PI such as bortezomib. Cardiovascular toxicity includes heart failure, hypertension, arrhythmias, and acute coronary syndromes. Because PIs are critical components of the treatment of hematological malignancies and amyloidosis, managing their cardiovascular toxicity involves identifying patients at risk, diagnosing toxicity early at the preclinical level, and offering cardioprotection if needed. Future research is required to elucidate underlying mechanisms, improve risk stratification, define the optimal management strategy, and develop new PIs with safe cardiovascular profiles.

Safety of same-day discharge versus overnight stay strategy following cardiac device implantations: a high-volume single-centre experience.

BACKGROUND: The strategy of cardiac implantable electronic device (CIED) implantations performed as day-case admissions has gained a wider acceptance overtime; however, data on safety are still limited. This study aims to investigate the safety of a same-day discharge protocol introduced in our hospital for the postprocedural management of patients undergoing CIED implantation. METHODS: Α prospective, non-interventional, non-randomised study performed in a single high-volume implanting centre for a 16-month period (March 2020 to June 2021). At total of 821 of 965 (85.1%) patients scheduled for elective CIED implantation were considered to be eligible for inclusion in the Short-stay Device Management Protocol. These patients were compared with a historical group of 932 patients, meeting the same inclusion criteria. RESULTS: Procedure was successful in 812 patients (98.9%), committed to same-day discharge versus 921 of 932 patients (98.8%) admitted for overnight stay (p = 0.87). Overall, 90-day complication rate was comparable in both groups (4.14% vs 4.07%, p = 0.95), as was major (1.46% vs. 1.82%, p = 0.55) and minor (2.67% vs. 2.25%, p = 0.64) complication rates. The composite early post-procedural complication rates and late post-procedural complication rates were comparable among groups (0.97 vs 1.18%, p = 0.70 and 0.73% vs 0.64%, p = 0.83, respectively). Six hundred sixty-seven patients (84%) preferred the same-day discharge strategy. Finally, a reduction of 792 bed-days was recorded, resulting in possible financial Health System benefits. CONCLUSIONS: Same-day discharge is feasible and safe in the majority of patients referred for CIED implantation. Additionally, same-day discharge is preferred by patients and may reduce procedure-related costs due to significant bed-day reductions.

Beta-Secretase-1 Antisense RNA Is Associated with Vascular Ageing and Atherosclerotic Cardiovascular Disease.

BACKGROUND: The noncoding antisense transcript for ß-secretase-1 (BACE1-AS) is a long noncoding RNA with a pivotal role in the regulation of amyloid-ß (Aß). We aimed to explore the clinical value of BACE1-AS expression in atherosclerotic cardiovascular disease (ASCVD). METHODS: Expression of BACE1-AS and its target, ß-secretase 1 (BACE1) mRNA, was measured in peripheral blood mononuclear cells derived from 434 individuals (259 without established ASCVD [non-CVD], 90 with stable coronary artery disease [CAD], and 85 with acute coronary syndrome). Intima-media thickness and atheromatous plaques evaluated by ultrasonography, as well as arterial wave reflections and pulse wave velocity, were measured as markers of subclinical ASCVD. Patients were followed for a median of 52 months for major adverse cardiovascular events (MACE). RESULTS: In the cross-sectional arm, BACE1-AS expression correlated with BACE1 expression (r = 0.396, p < 0.001) and marginally with Aß1-40 levels in plasma (r = 0.141, p = 0.008). Higher BACE1-AS was associated with higher estimated CVD risk assessed by HeartScore for non-CVD subjects and by European Society of Cardiology clinical criteria for the total population (p < 0.05 for both). BACE1-AS was associated with higher prevalence of CAD (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.37-2.5), multivessel CAD (OR = 1.36, 95% CI: 1.06-1.75), and with higher number of diseased vascular beds (OR = 1.31, 95% CI: 1.07-1.61, for multiple diseased vascular beds) after multivariable adjustment for traditional cardiovascular risk factors. In the prospective arm, BACE1-AS was an independent predictor of MACE in high cardiovascular risk patients (adjusted hazard ratio = 1.86 per ascending tertile, 95% CI: 1.011-3.43, p = 0.046). CONCLUSION: BACE1-AS is associated with the incidence and severity of ASCVD.

Buprenorphine withdrawal induced takotsubo cardiomyopathy: A series of unfortunate events.

This case report describes a 64-year-old female with history of previous intravenous drug abuse on opioid substitution treatment with buprenorphine, who presented to the emergency department with angina and electrocardiographic findings suggestive of acute coronary syndrome. Echocardiography and left ventriculography were indicative of takotsubo cardiomyopathy, probably attributed to abrupt discontinuation of buprenorphine. Opioid withdrawal leads to sympathetic hyperactivity and increased catecholamine release, which in our case triggered takotsubo cardiomyopathy presentation. .

QT interval extracted from 30-minute short resting Holter ECG recordings predicts mortality in heart failure.

BACKGROUND: Prolonged repolarization duration is a significant total mortality (TM) predictor in post-myocardial infarction patients. AIM: We examined the clinical significance of QT interval that was extracted from a Short Resting Holter ECG (SRH ECG - 30-min duration) as a TM predictor in heart failure (HF) patients. METHODS: One hundred forty-five HF patients (male = 84%, mean age = 64 ± 12 years, mean LVEF = 33 ± 10%) underwent an SRH ECG recording for 30 min. These high-resolution ECG signals were analyzed and the QT interval was calculated and corrected according to the Fridericia formula. After 42.1 months, 26 patients died. RESULTS: Univariate analysis for Deceased and Living groups: QTc:455 ± 33 ms vs 441 ± 32 ms (p = 0.04), LVEF:32 ± 10% vs 34 ± 9% (p < 0.5), Mean Heart Rate: 73 ± 11 bpm vs 69 ± 12 bpm (p = 0.2), SDNN/HRV: 45 ± 42 ms vs 41 ± 29 ms (p = 0.4), QRS: 123 ± 26 ms vs 119 ± 29 ms (p = 0.5). Multivariate Cox regression analysis with model adjusted for QTc, Mean Heart Rate, LVEF, QRS, revealed that QTc-Fridericia interval was an independent TM predictor (H.R.:1.017, 95% C.I.: 1.003-1.030, p = 0.01). The cut-off point of 490 ms (90th percentile) in the same model presented HR: 2.9 for TM (95%C.I.: 1.066-7.882, p = 0.03). Kaplan Meier curves depicted a clear difference in survival between the two patients' groups (QTc Group≥490 ms vs QTc Group <490 ms). The curve diverge was important (log-rank, p = 0.02). CONCLUSION: A fast risk stratification approach with SRH ECG recording is an efficient method for flash evaluation of mortality risk in HF patients.

Permanent pacemaker implantation in unexplained syncope patients with electrophysiology study-proven atrioventricular node disease.

OBJECTIVE: Syncope, whose cause is unknown after an initial assessment, has an uncertain prognosis. It is critical to identify patients at the highest risk who may require a pacemaker and to identify the cause of recurrent syncope to prescribe proper therapy. The aim of this study was to evaluate the effect of permanent pacing on the incidence of syncope in patients with unexplained syncope and electrophysiology study (EPS)-proven atrioventricular (AV) node disease. METHODS: This was an observational study based on a prospective registry of 236 consecutive patients (60.20 ± 18.66 years, 63.1% male, 60.04 ± 9.50 bpm) presenting with recurrent unexplained syncope attacks admitted to our hospital for invasive EPS. The decision to implant a permanent pacemaker was made in all cases by the attending physicians according to the results of the EPS. A total of 135 patients received the antibradycardia pacemaker (ABP), while 101 patients were declined. RESULTS: The mean of reported syncope episodes was 1.97 ± 1.10 (or presyncope 2.17 ± 1.50) before they were referred for a combined EP-guided diagnostic and therapeutic approach. Over a mean follow-up of approximately 4 years (49.19 ± 29.58 months), the primary outcome event (syncope) occurred in 31 of 236 patients (13.1%), and 6 of 135 (4.4%) patients in the ABP group as compared to 25 of 101 (24.8%) in the no pacemaker group (p < 0.001). CONCLUSION: Among patients with a history of unexplained syncope, a set of positivity criteria for the presence of EPS-defined AV node disease identifies a subset of patients who will benefit from permanent pacing.

His bundle pacing: A promising alternative strategy for anti-bradycardic pacing - report of a single-center experience.

His bundle pacing (HBP) is proven to be a safe and effective alternative pacing modality that, in addition, avoids pacemaker-induced cardiomyopathy (PICM) by achieving a "physiological" ventricular stimulation, via the native conduction system. Indications include various causes of bradycardia requiring anti-bradycardic pacing, inadequately controlled atrial fibrillation requiring AV node ablation and established PICM. In addition, HBP may also be used as an alternative therapy for patients with heart failure (HF) and an indication for cardiac resynchronization therapy (CRT). Available data show several advantages of HBP with regard to preservation or restoration of intra- and inter-ventricular synchronization; improvement in left ventricular ejection fraction, functional status and quality of life; decrease in atrial fibrillation incidence and improvement in HF hospitalization rates, compared with conventional pacing. Nevertheless, superiority in terms of mortality rates has not been consistently demonstrated, and the long-term efficacy and safety of HBP remain to be proven. In the present manuscript, we review the status of HBP and present our current experience with this novel pacing modality.

Daratumumab May Attenuate Cardiac Dysfunction Related to Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma: A Prospective Study.

Carfilzomib has improved survival in patients with relapsed/refractory multiple myeloma (RRMM), but it may exert cardiovascular adverse events (CVAEs). The aim of this study was to assess whether treatment with daratumumab may ameliorate carfilzomib-related toxicity. We prospectively evaluated 25 patients with RRMM who received either daratumumab in combination with carfilzomib and dexamethasone (DaraKd) (n = 14) or Kd (n = 11). Cardiac ultrasound was performed before treatment initiation and C6D16 or at the time of treatment interruption. Patients were followed for a median of 10 months for CVAEs. The mean (± SD) age was 67.8 ± 7.6 years and 60% were men. The two treatment groups did not significantly differ in baseline demographic characteristics (p > 0.1 for all). In the DaraKd group, we did not observe any significant change in markers of ventricular systolic function. However, these markers deteriorated in the Kd group; left ventricular (LV) ejection fraction, LV global longitudinal strain, tricuspid annular plane systolic excursion and RV free wall longitudinal strain significantly decreased from baseline to second visit (p < 0.05). A significant group interaction (p < 0.05) was observed for the abovementioned changes. CVAEs occurred more frequently in the Kd than the DaraKd group (45% vs. 28.6%). DaraKd was associated with preserved post-treatment cardiac systolic function and lower CVAE rate compared with Kd. The clinical significance and the underlying mechanisms merit further investigation.

Syncope associated with supraventricular tachycardia: Diagnostic role of implantable loop recorders.

Syncope represents a relatively uncommon symptom of supraventricular tachycardia (SVT). It is likely that an impaired autonomic vasomotor response to the hemodynamic stress of tachycardia is the determinant of hemodynamic changes leading to cerebral hypoperfusion and syncope. In this regard, tilt-table test may detect abnormalities in the autonomic nervous function and predict the occurrence of syncope during SVT. Electrophysiology studies may reproduce the SVT, distinguish it from other life-threatening ventricular tachyarrhythmias, and exclude other causes of syncope. Not infrequently mixed syncope mechanisms are revealed during the above diagnostic workup raising doubts about the operating mechanism in the clinical setting. In such cases of uncertainty, an implantable loop recorder, providing long-term cardiac monitoring, may play a pivotal role in the establishment of the diagnosis, confirming the association of an arrhythmic event with the symptom. Herein, we present four such cases with recurrent unexplained syncope finally attributed to paroxysmal SVT guiding them to a potentially radical treatment through radiofrequency catheter ablation.

Additive contribution of microRNA-34a/b/c to human arterial ageing and atherosclerosis.

BACKGROUND AND AIMS: Preclinical data suggest that the ageing-induced miR-34a regulates vascular senescence. Herein we sought to assess whether the miR-34 family members miR-34a, miR-34b and miR-34c are involved in human arterial disease. METHODS: Expression levels of miR-34a/b/c were quantified by TaqMan assay in peripheral blood mononuclear cells (PBMCs) derived from a consecutive cohort of 221 subjects who underwent cardiovascular risk assessment and thorough vascular examination for aortic stiffness and extent of arterial atherosclerosis. RESULTS: High miR-34a was independently associated with the presence of CAD [OR (95%C.I.): 3.87 (1.56-9.56); p = 0.003] and high miR-34c with the number of diseased arterial beds [OR (95%C.I.): 1.88 (1.034-3.41); p = 0.038], while concurrent high expression of miR-34-a/c or all three miR-34a/b/c was associated with aortic stiffening (miR-34a/c: p = 0.022; miR-34a/b/c: p = 0.041) and with the extent of atherosclerosis [OR (95%C.I.) for number of coronary arteries [miR-34a/c: 3.29 (1.085-9.95); miR-34a/b/c: 6.06 (1.74-21.2)] and number of diseased arterial beds [miR-34a/c: 3.51 (1.45-8.52); miR-34a/b/c: 2.89 (1.05-7.92)] after controlling for possible confounders (p < 0.05 for all). Mechanistically, the increased levels of miR-34a or miR-34c were inversely associated with expression of SIRT1 or JAG1, NOTCH2, CTNNB1 and ATF1, respectively. The association of miR-34a/c or miR-34a/b/c with CAD was mainly mediated through SIRT1 and to a lesser extent through JAG1 as revealed by generalized structural equation modeling. Leukocyte-specific ablation of miR-34a/b/c ameliorates atherosclerotic plaque development and increases Sirt1 and Jag1 expression in an atherosclerosis mouse model confirming the human findings. CONCLUSIONS: The present study reveals the clinical significance of the additive role of miR-34a/b/c in vascular ageing and atherosclerotic vascular disease.

Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study.

Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m2 and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p < 0.01) and FMD decreased at cycles 3 and 6 compared to baseline (p ≤ 0.05). FMD changes were associated with CFZ-induced PrA changes (p < 0.05) and lower PrA recovery during first cycle was associated with more prominent FMD decrease (p = 0.034 for group interaction). During treatment, 25 patients developed Grade ≥3 CVAEs. Low baseline FMD (HR 2.57 lowest vs. higher tertiles, 95% CI 1.081-6.1) was an independent predictor of CVAEs. During treatment, an acute FMD decrease >40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29-11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.

The effect of treatment response on endothelial function and arterial stiffness in depression. A prospective study.

BACKGROUND: Major depression is associated with endothelial dysfunction and arterial stiffening, which may mediate development of hypertension and increased cardiovascular risk. The effect of response to antidepressant treatment on these vascular parameters has not been elucidated. AIMS: We aimed to assess the net effect of antidepressant therapy on endothelial function and arterial stiffness in patients with psychotic depression. METHOD: Thirty-seven patients with major psychotic depression, according to DSM-IV-TR, were treated with titrated citalopram 20-60 mg and risperidone 0.5-1 mg and were followed for 6 months. Twelve additional patients who denied treatment, or were non-compliant, were also followed for the same time period. Vascular function was assessed by flow-mediated dilatation (FMD), carotid-femoral pulse wave velocity (PWV) and augmentation index (AI), at baseline and at the end of follow-up. RESULTS: Aortic and peripheral blood pressure (BP), PWV, FMD and AI (p < 0.05 for all) were significantly improved in the group that received treatment. Overall, only responders to treatment (n = 24) presented significant improvements in all hemodynamic and vascular parameters (p < 0.05 for all), irrespectively of traditional cardiovascular risk factors (TRFs), vasoactive medication and BP lowering. In a secondary analysis, patients with psychotic depression presented worse endothelial function as compared to controls matched for TRFs. LIMITATIONS: Non-randomized study. CONCLUSIONS: Patients who respond to therapy for major psychotic depression present sustained improvement in vascular function. Given that depressed patients are considered to be at high cardiovascular risk and are often non-compliant with treatment, further research to assess cardiovascular benefits of vigilant monitoring of antidepressant therapy is warranted.

Age-dependent association of pulse wave velocity with coronary artery disease and myocardial aging in high-risk patients.

AIMS: Progressive arterial stiffening, as a marker of arterial aging, may reach a plateau in elderly patients and may thus lose its clinical utility. This phenomenon may be more prominent in high-risk patients. We aimed to investigate if carotid-to-femoral pulse wave velocity (cf-PWV) is related to coronary artery disease (CAD) and diastolic dysfunction in elderly high-risk patients as compared to a control group of younger individuals. METHODS: One-hundred and ninety-two high-risk stable patients who underwent coronary artery angiography and assessment of cf-PWV were consecutively recruited. Indices of diastolic dysfunction were also measured by echocardiography, including the volume of the left atrium and the ratio of early transmitral peak velocity (E) to the mitral annular early diastolic velocity (E'). RESULTS: Increased cf-PWV was associated with the presence of CAD [odds ratio (OR) 1.34, P = 0.02], number of diseased coronary vessels (OR 1.17, P = 0.029) and CAD severity (P = 0.023) as assessed by Gensini score, in patients less than 65 years old after adjustment for traditional risk factors. Moreover, cf-PWV correlated with E/E' (P = 0.019) and increased the odds by 16% (OR 1.16, P = 0.048) for more severe diastolic dysfunction in patients aged below 65 years old. None of these outcomes correlated with cf-PWV in the elderly. CONCLUSION: In high cardiovascular risk patients, an age-dependent association of cf-PWV with CAD and diastolic dysfunction was evinced. In contrast to younger patients, these results suggest that measuring arterial stiffness in elderly high-risk patients may lack clinical value.

Abdominal Fat Tissue Echogenicity: A Marker of Morbid Obesity.

Purpose: Menopause-related changes may affect regional but also morphological characteristics of adipose tissue. We sought to assess the clinical value of echogenicity of subcutaneous adipose tissue (SAT) and preperitoneal adipose tissue (pPAT) in postmenopausal women without cardiovascular disease. Methods: In 244 consecutively recruited postmenopausal women, subclinical atherosclerosis was assessed in the femoral and carotid arteries by intima-media thickness (IMT) and atheromatous plaques using high-resolution ultrasonography. In 41 women with a second visit (median follow-up 41.5 months), carotid atherosclerosis was re-evaluated. Images of SAT and pPAT were ultrasonographically acquired, and their echogenicity was evaluated by grayscale mean (GSMn) using a dedicated software. A control group of 20 healthy premenopausal women was used for comparisons in fat echogenicity. Results: SAT GSMn but not pPAT was higher in postmenopausal as compared with healthy premenopausal women and was independently associated with metabolic markers of adiposity including body mass index (BMI) and waist circumference (WC). SAT GSMn was associated with carotid IMT and the presence and number of atheromatous plaques [adjusted OR 2.44 and 2.32 per 1-SD increase in GSMn (95% CIs 1.55 to 3.93 and 1.55 to 3.45), respectively]. SAT GSMn conferred incremental value over traditional risk factors, insulin resistance, BMI, and WC for the detection of subclinical atherosclerosis. Increased baseline SAT GSMn was associated with increased rate of progression in carotid IMT. Conclusions: SAT echogenicity may serve as a qualitative marker of adiposity, conferring incremental clinical value over BMI and WC in postmenopausal women. Further investigation is warranted to assess the utility of ultrasonography-derived fat echogenicity as a screening method for morbid obesity.

RNA Therapeutics in Cardiovascular Precision Medicine.

Since our knowledge on structure and function of messenger RNA (mRNA) has expanded from merely being an intermediate molecule between DNA and proteins to the notion that RNA is a dynamic gene regulator that can be modified and edited, RNA has become a focus of interest into developing novel therapeutic schemes. Therapeutic modulation of RNA molecules by DNA- and RNA-based therapies has broadened the scope of therapeutic targets in infectious diseases, cancer, neurodegenerative diseases and most recently in cardiovascular diseases as well. Currently, antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), and microRNAs are the most widely applied therapeutic strategies to target RNA molecules and regulate gene expression and protein production. However, a number of barriers have to be overcome including instability, inadequate binding affinity and delivery to the tissues, immunogenicity, and off-target toxicity in order for these agents to evolve into efficient drugs. As cardiovascular diseases remain the leading cause of mortality worldwide, a large number of clinical trials are under development investigating the safety and efficacy of RNA therapeutics in clinical conditions such as familial hypercholesterolemia, diabetes mellitus, hypertriglyceridemia, cardiac amyloidosis, and atrial fibrillation. In this review, we summarize the clinical trials of RNA-targeting therapies in cardiovascular disease and critically discuss the advances, the outcomes, the limitations and the future directions of RNA therapeutics in precision transcriptomic medicine.