The role and application of current pharmacological management in patients with advanced heart failure.

In the last decades, several classifications and definitions have been proposed for advanced heart failure (ADVHF) patients, including clinical, functional, hemodynamic, imaging, and electrocardiographic features. Despite different inclusion criteria, ADVHF is characterized by some common items, such as drug intolerance, low arterial pressure, multiple organ dysfunction, chronic kidney disease, and diuretic use dependency. Additional features include fatigue, hypotension, hyponatremia, and unintentional weight loss associated with a specific laboratory profile reflecting systemic multiorgan dysfunction. Notably, studies evaluating guideline-directed medical therapy recently endorsed by guidelines in stable HF, including the 4 drug classes all together (i.e., betablocker, mineral corticoid antagonist, renin angiotensin inhibitors/neprilysin inhibitors, and sodium glucose transporter inhibitors), remain scarcely analyzed in ADVHF and New York Heart Association (NYHA) Class IV. Additionally, due to the common conditions associated with advanced stages, the balance between drug tolerance and potential benefits of the contemporary use of all agents is questioned. Therefore, less hard endpoints, such as exercise tolerance, quality of life (QoL) and self-competency, are not clearly demonstrated. Specific analyses evaluating outcome and rehospitalization of each drug provided conflicting results and are often limited to subjects with stable conditions and less advanced NYHA class. Current European Society of Cardiology/American Heart Association (ESC/AHA) Guidelines do not indicate the type of treatment, dosage, and administration modalities, and they do not suggest specific indications for ADVHF patients. Due to these concerns, there is an impelling need to understand what drugs may be used as the first line, what management leads to the better outcome, and what is the best treatment algorithm in this setting. In this paper, we summarize the most common pitfalls and limitations for the use of the traditional agents, and we propose a personalized approach aiming at preserve drug tolerance and maintaining adverse event protection and satisfactory QoL.

Novel Therapeutic Insights Into the Treatment of Pericarditis: Targeting the Innate Immune System.

ABSTRACT: Acute pericarditis is characterized by pericardial inflammation that can be treated with anti-inflammatory drugs. A considerable percentage of patients develops recurrent pericarditis with several relapses. In developed countries, the idiopathic form is the most frequent and has a high risk of recurrences. Two pathophysiological mechanisms have been described for idiopathic recurrent pericarditis: autoimmune and autoinflammatory. The autoimmune mechanism is more frequently encountered in patients with rheumatologic disorders, especially systemic lupus erythematosus. The innate immune system plays a central role in the pathophysiology of pericarditis, especially in the autoinflammatory phenotype. Current evidence highlights the central role played by interleukin 1 and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) in idiopathic recurrent pericarditis. Accordingly, interleukin 1 blockers have been approved for the treatment of this condition. Neutrophils are likely to be important in such setting; however, their role has only been partially investigated. In the present review, we have collected the current knowledge on the role of innate immune system in pericarditis pathophysiology and how this can be used to provide targeted treatments for patients with recurrent pericarditis.

An Overview of Cannabidiol as a Multifunctional Drug: Pharmacokinetics and Cellular Effects.

Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound's pharmacological profile. CBD's role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound's anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa's use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD's emergence as a pivotal phytocannabinoid. As research continues, CBD's integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility.

Novel Pathophysiological, Diagnostic and Therapeutic Concepts in Acute and Recurrent Pericarditis.

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models. More recently, following seminal clinical trials with colchicine and interleukin-1 (IL-1) blockers and a novel murine model of acute pericarditis using zymosan A, it has become clear that the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome/IL-1 ß axis plays a central role in driving acute pericardial inflammation and in sustaining this process during recurrences. Diagnostic management of pericarditis has been implemented with multimodality imaging including echocardiography, cardiac computed tomography, and cardiac magnetic resonance. These imaging modalities provide essential diagnostic and pathogenetic information, and are able to characterize pericardial inflammation, allowing to refine risk stratification and personalize treatment. Recent acquisitions yield relevant implications with regard to the therapeutic management of acute and recurrent pericarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are cornerstone therapies either for acute and recurrent pericarditis. However, the benefits of targeted agents, such as anakinra - a recombinant human IL-1 receptor antagonist - and rilonacept - an IL-1 α /IL-1 ß trap, are being increasingly recognized. To this end, phenotyping patients with pericarditis and addressing such therapies to those presenting with auto-inflammatory features (elevated C-reactive protein, sustained pericardial and systemic inflammation, multiple recurrences) is of utmost importance to identify patients who might be more likely to benefit from NLRP3 inflammasome/IL-1 ß pathway blockade.

Therapeutic potential of cannabidiol (CBD) in the treatment of cardiovascular diseases.

INTRODUCTION: Cannabidiol (CBD) is the primary non-psychoactive chemical derived from Cannabis Sativa, and its growing popularity is due to its potential therapeutic properties while avoiding the psychotropic effects of other phytocannabinoids, such as tetrahydrocannabinol (THC). Numerous pre-clinical studies in cellular and animal models and human clinical trials have demonstrated a positive impact of CBD on physiological and pathological processes. Recently, the FDA approved its use for the treatment of seizures, and clinical trials to test the efficacy of CBD in myocarditis and pericarditis are ongoing. AREAS COVERED: We herein reviewed the current literature on the reported effects of CBD in the cardiovascular system, highlighting the physiological effects and the outcomes of using CBD as a therapeutic tool in pathological conditions to address this significant global health concern. EXPERT OPINION: The comprehensive examination of the literature emphasizes the potential of CBD as a therapeutic option for treating cardiovascular diseases through its anti-inflammatory, vasodilatory, anti-fibrotic, and antioxidant properties in different conditions such as diabetic cardiomyopathy, myocarditis, doxorubicin-induced cardiotoxicity, and ischemia-reperfusion injury.

Cardiac rupture as a life-threatening outcome of Takotsubo syndrome: A systematic review.

BACKGROUND: Takotsubo syndrome (TS) is a reversible cause of heart failure; however, a minority of patients can develop serious complications, including cardiac rupture (CR). OBJECTIVES: Analyze case reports of CR related to TS, detailing patient characteristics to uncover risk factors and prognosis for this severe complication. METHODS: We conducted a systematic search of MEDLINE and Embase databases to identify case reports of patients with TS complicated by CR, from inception to October 2023. RESULTS: We included 44 subjects (40 females; 4 males) with a median age of 75 (IQR 71-82) years, of White/Caucasian (61%) or East Asian/Japanese (39%) ethnicity. An emotional trigger was present in 15 (34%) subjects and an apical ballooning pattern was observed in all cases (100%). ST-segment elevation was reported in 39 (93%) of 42 cases, with the anterior myocardial segments (37 [88%]) being the most compromised, followed by lateral (26 [62%]) and inferior (14 [33%]) segments. The median time to cardiac rupture was 48 (5-120) hours since admission, with the left ventricular free wall (25 [57%]) being the most frequent site of perforation. Surgery was attempted in 16 (36%) cases, and 28 (64%) patients did not survive. CONCLUSIONS: CR related to TS is a rare complication associated with high mortality and affecting elderly females, specially from White/Caucasian or East Asian/Japanese descent, presenting with anterior or lateral ST-segment elevation, and an apical ballooning pattern. Although data is limited and additional prospective studies are needed, the awareness of this life-threatening complication is crucial to early identify high-risk patients. CONDENSED ABSTRACT: Cardiac rupture is a rare complication of Takotsubo syndrome. We conducted a systematic review of cases complicated by cardiac rupture, and we identified 44 subjects (40 females and 4 males) with a median age of 75 (IQR 71-82) years, of White/Caucasian (61%) or East Asian/Japanese (39%) ethnicity, all with an apical ballooning pattern (100%). The median time to cardiac rupture was 48 (5-120) hours since admission, with the left ventricular free wall (25 [57%]) being the most frequent site of perforation. Surgery treatment was attempted in 16 (36%) cases, and 28 (64%) patients did not survive.

Innate and adaptive immunity in acute myocarditis.

Acute myocarditis is an acute inflammatory cardiomyopathy associated with cardiac damage triggered by a virus or a pathological immune activation. It may present with a wide range of clinical presentations, ranging from mild symptoms to severe forms like fulminant myocarditis, characterized by hemodynamic compromise and cardiogenic shock. The immune system plays a central role in the pathogenesis of myocarditis. In fact, while its function is primarily protective, aberrant responses can be detrimental. In this context, both innate and adaptive immunity play pivotal roles; notably, the innate system offers a non-specific and immediate defense, while the adaptive provides specialized protection with immunological memory. However, dysregulation in these systems can misidentify cardiac tissue, triggering autoimmune reactions and possibly leading to significant cardiac tissue damage. This review highlights the importance of innate and adaptive immune responses in the progression and treatment of acute myocarditis.

Early reduction in cardiorespiratory fitness and diastolic reserve following radiation therapy for lung cancer.

BACKGROUND: Contemporary radiotherapy for the treatment of lung cancer is effective in targeting tumor tissue while limiting heart exposure, yet cardiac toxicity still occurs, often becoming clinically apparent years later. Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular, cancer-related, and overall mortality and may serve as a sensitive measure of subclinical cardiac toxicity following anti-cancer treatments. Prior work has demonstrated a significant relationship between reduced CRF and impaired left-ventricular (LV) diastolic reserve in cancer survivors following thoracic radiotherapy. The purpose of this study was to assess early longitudinal changes in CRF and cardiac function in patients with lung cancer following radiotherapy. METHODS: Ten patients (69 [61-76] years, 70% female) with lung cancer without known cardiovascular disease scheduled to receive radiotherapy involving a clinically-relevant heart dose (≥ 5 Gy to > 10% of heart volume) were evaluated prior to and following treatment. Changes in CRF (peak oxygen consumption [VO2peak], oxygen uptake efficiency slope [OUES]), cardiac function (LV ejection fraction [LVEF], rest and exercise diastolic function [diastolic functional reserve index (DFRI)]), cardiac biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein [hsCRP]), and health-related quality of life (HRQOL; Functional Assessment of Cancer Therapy-General-7 [FACT-G7]) were measured. RESULTS: The VO2peak was reduced at baseline (1.245 [0.882-1.605] L·min- 1; 70 [62-86] %-predicted) and significantly declined (1.095 [0.810-1.448] L·min- 1, P = 0.047; 62 [56-76] %-predicted, P = 0.005) at 6.0 [3.0-6.0] months post-radiotherapy. Similarly, a significant decline in the OUES was observed (1.63 [1.27-1.88] to 1.57 [1.12-1.75], P = 0.032). Systolic cardiac function was normal at baseline and did not change following radiotherapy (LVEF; 62 [56-65]% to 66 [57-68]%, P = 0.475). The DFRI significantly declined following radiotherapy (34.9 [22.7-41.6] vs. 12.8 [3.1-35.9]). The hsCRP increased significantly from 4.4 [1.4-5.8] to 6.1 [3.7-20.7] g/L, P = 0.047 with a trend towards higher levels of NT-proBNP (65 [49-125] to 121 [88-191] pg/mL, P = 0.110). Health-related quality of life significantly decreased (FACT-G7; 21.5 [18.8-25] to 15.5 [11.5-20]; P = 0.021) post-radiotherapy. CONCLUSIONS: Patients with lung cancer receiving radiotherapy with a clinically-significant heart dose experience reductions in CRF (VO2peak, OUES) as early as six months following treatment with concurrent reductions in diastolic reserve (DFRI), HRQOL, and increases in cardiac biomarkers (NT-proBNP, hsCRP).

Efficacy of colchicine in addition to anakinra in patients with recurrent pericarditis.

AIM: Anakinra, an anti IL-1 agent targeting IL-1 alfa and beta, is available for the treatment of recurrent pericarditis in cases with corticosteroid dependence and colchicine resistance after failure of conventional therapies. However, it is unclear if the combination with colchicine, a non-specific inhibitor of the inflammasome targeting the same inflammatory pathway of IL-1, could provide additional benefit to prevent further recurrences. The aim of the present observational study is to assess whether the addition of colchicine on top of anakinra could prolong the time to first recurrence and prevent recurrences better than anakinra alone. METHODS: International, all-comers, multicentre, retrospective observational cohort study analysing all consecutive patients treated with anakinra for corticosteroid-dependent and colchicine-resistant recurrent pericarditis. The efficacy endpoint was recurrence rate and the time to the first recurrence. RESULTS: A total of 256 patients (mean age 45.0±15.4 years, 65.6% females, 80.9% with idiopathic/viral aetiology) were included. 64 (25.0%) were treated with anakinra as monotherapy while 192 (75.0%) with both anakinra and colchicine. After a follow-up of 12 months, 56 (21.9%) patients had recurrences. Patients treated with colchicine added to anakinra had a lower incidence of recurrences (respectively, 18.8% vs 31.3%; p=0.036) and a longer event-free survival (p=0.025). In multivariable analysis, colchicine use prevented recurrences (HR 0.52, 95% CI 0.29 to 0.91; p=0.021). CONCLUSIONS: The addition of colchicine on top of anakinra treatment could be helpful to reduce recurrences and prolong the recurrence-free survival.

Cardiac Involvement in Patients With Multisystem Inflammatory Syndrome in Adults.

Multisystemic inflammatory syndrome in adults is a hyperinflammatory condition following (within 4-12 weeks) SARS-CoV-2 infection. Here, the dysregulation of the immune system leads to a multiorgan involvement often affecting the heart. Cardiac involvement in multisystemic inflammatory syndrome in adults has been described mainly in young men without other comorbidities and may present with different clinical scenarios, including acute heart failure, life-threatening arrhythmias, pericarditis, and myocarditis, with a nonnegligible risk of mortality (up to 7% of all cases). The heterogeneity of its clinical features and the absence of a clear case definition make the differential diagnosis with other postinfectious (eg, infective myocarditis) and hyperinflammatory diseases (eg, adult Still disease and macrophage activation syndrome) challenging. Moreover, the evidence on the efficacy of specific treatments targeting the hyperinflammatory response underlying this clinical condition (eg, glucocorticoids, immunoglobulins, and other immunomodulatory agents) is sparse and not supported by randomized clinical trials. In this review article, we aim to provide an overview of the clinical features and the diagnostic workup of multisystemic inflammatory syndrome in adults with cardiac involvement, highlighting the possible pathogenetic mechanisms and the therapeutic management, along with remaining knowledge gaps in this field.

Life-Threatening Arrhythmias in Patients With Takotsubo Syndrome: Insights Into Pathophysiology and Treatment Innovations.

Takotsubo syndrome (TTS) is a reversible form of acute myocardial injury due to a neurocardiogenic mechanism associated with a relevant risk for life-threatening ventricular arrhythmias, occurring in up to 25% of all patients and including both ventricular arrhythmias (especially) in the context of QT prolongation and atrial tachy- or bradyarrhythmias. The pathogenetic mechanisms of TTS-related arrhythmic complications are not completely understood, and there are no randomized clinical trials addressing the pharmacologic and nonpharmacologic management in this specific setting. In this narrative review, the authors provide an overview of the pathogenesis and the therapeutic management of arrhythmic complications in patients with TTS, along with the future perspectives and the remaining knowledge gaps in this field.

Sustained Pericarditis Recurrence Risk Reduction With Long-Term Rilonacept.

BACKGROUND: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment. METHODS AND RESULTS: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P<0.0001). CONCLUSIONS: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Pericardial Diseases: International Position Statement on New Concepts and Advances in Multimodality Cardiac Imaging.

Pericardial diseases have gained renewed clinical interest, leading to a renaissance in the field. There have been many recent advances in pericardial diseases in both multimodality cardiac imaging of diagnoses, such as recurrent, transient constrictive and effusive-constrictive pericarditis, and targeted therapeutics, especially anti-interleukin (IL)-1 agents that affect the inflammasome as part of autoinflammatory pathophysiology. There remains a large educational gap for clinicians, leading to variability in evaluation and management of these patients. The latest pericardial imaging (American Society of Echocardiography, European Association of Cardiovascular Imaging) and clinical guidelines (European Society of Cardiology) are >8-10 years of age and may not reflect current practice. Recent clinical trials involving anti-IL-1 agents in recurrent pericarditis, including anakinra (AIRTRIP), rilonacept (RHAPSODY), and goflikicept have demonstrated their efficacy. The present document represents an international position statement from world leaders in the pericardial field, focusing on novel concepts and emphasizing the role of multimodality cardiac imaging as well as new therapeutics in pericardial diseases.

Pericardial late gadolinium enhancement and time to recurrence: a substudy from RHAPSODY, a phase 3 clinical trial of rilonacept in recurrent pericarditis.

Aims: In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence. Methods and results: RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE (n = 9), patients with moderate or severe pericardial LGE (n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence. Conclusions: Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered. ClinicalTrialsgov Identifier: NCT03737110.

Patients with recurrent pericarditis (RP) can suffer from debilitating pain and a poor quality of life. Rilonacept blocks interleukin 1 (IL-1), the major inflammatory driver of RP, and is highly effective at treating active episodes of RP and preventing recurrence. In pericarditis, there is the recruitment of blood vessels to the pericardium, and the extent of these new blood vessels tracks with the degree of inflammation. Cardiac magnetic resonance imaging (CMR) readily images this blood supply and can therefore assess inflammation by the magnitude of pericardial late gadolinium enhancement (LGE). In this study of RP patients with CMR, no patients who continued rilonacept had a recurrence compared to 10/14 (71.4%) patients who stopped rilonacept and received a placebo. In the patients who received a placebo, the rate of eventual recurrence was similar among patients with trace or mild pericardial LGE at baseline (5/7) compared to patients with moderate or severe pericardial LGE at baseline (5/7). However, patients who demonstrated moderate or severe pericardial LGE had a faster recurrence (∼4 weeks after stopping rilonacept) compared to patients with trace or mild pericardial LGE (∼11 weeks after stopping rilonacept). These results suggest that pericardial LGE can serve as an imaging biomarker to assess the severity of RP and raise the possibility that CMR could be studied in future clinical trials to determine appropriate therapy and treatment duration in patients with RP.