Atrial Natriuretic Peptides as a Bridge between Atrial Fibrillation, Heart Failure, and Amyloidosis of the Atria.

ANP is mainly synthesized by the atria, and upon excretion, it serves two primary purposes: vasodilation and increasing the renal excretion of sodium and water. The understanding of ANP's role in cardiac systems has improved considerably in recent decades. This review focuses on several studies demonstrating the importance of analyzing the regulations between the endocrine and mechanical function of the heart and emphasizes the effect of ANP, as the primary hormone of the atria, on atrial fibrillation (AF) and related diseases. The review first discusses the available data on the diagnostic and therapeutic applications of ANP and then explains effect of ANP on heart failure (HF) and atrial fibrillation (AF) and vice versa, where tracking ANP levels could lead to understanding the pathophysiological mechanisms operating in these diseases. Second, it focuses on conventional treatments for AF, such as cardioversion and catheter ablation, and their effects on cardiac endocrine and mechanical function. Finally, it provides a point of view about the delayed recovery of cardiac mechanical and endocrine function after cardioversion, which can contribute to the occurrence of acute heart failure, and the potential impact of restoration of the sinus rhythm by extensive ablation or surgery in losing ANP-producing sites. Overall, ANP plays a key role in heart failure through its effects on vasodilation and natriuresis, leading to a decrease in the activity of the renin-angiotensin-aldosterone system, but it is crucial to understand the intimate role of ANP in HF and AF to improve their diagnosis and personalizing the patients' treatment.

Effect of a Fourth Dose of mRNA Vaccine and of Immunosuppression in Preventing SARS-CoV-2 Breakthrough Infections in Heart Transplant Patients.

Patients with heart transplantation (HT) have an increased risk of COVID-19 disease and the efficacy of vaccines on antibody induction is lower, even after three or four doses. The aim of our study was to assess the efficacy of four doses on infections and their interplay with immunosuppression. We included in this retrospective study all adult HT patients (12/21-11/22) without prior infection receiving a third or fourth dose of mRNA vaccine. The endpoints were infections and the combined incidence of ICU hospitalizations/death after the last dose (6-month survival rate). Among 268 patients, 62 had an infection, and 27.3% received four doses. Following multivariate analysis, three vs. four doses, mycophenolate (MMF) therapy, and HT < 5 years were associated with an increased risk of infection. MMF ≥ 2000 mg/day independently predicted infection, together with the other variables, and was associated with ICU hospitalization/death. Patients on MMF had lower levels of anti-RBD antibodies, and a positive antibody response after the third dose was associated with a lower probability of infection. In HT patients, a fourth dose of vaccine against SARS-CoV-2 reduces the risk of infection at six months. Mycophenolate, particularly at high doses, reduces the clinical effectiveness of the fourth dose and the antibody response to the vaccine.

Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction.

INTRODUCTION: Sacubitril/valsartan is the first-in-class angiotensin-receptor neprilysin inhibitor approved in 2015 for the treatment of heart failure with reduced ejection fraction (HFrEF). On 16 February 2021, the Food and Drug Administration acknowledged that "Benefits are most clearly evident in patients with left ventricular ejection fraction below normal," thus potentially extending the use in subjects with heart failure and preserved ejection fraction (HFpEF). AREAS COVERED: The authors outline the regulatory history, pharmacokinetics, pharmacodynamics, and risk-benefit profile of sacubitril/valsartan in HFrEF and HFpEF. A critical cross-trial comparison is presented, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), together with an insight into the latest European Society of Cardiology guidelines, where the new category of heart failure with mildly reduced ejection fraction is introduced. EXPERT OPINION: Sacubitril/valsartan is a foundation of the pharmacological armamentarium in HFrEF to counteract the neuro-hormonal changes and reverse cardiac remodeling, together with beta-blockers, SGLT2i and mineralocorticoid receptor antagonists. The optimal sequence algorithm is an evolving issue, and the authors provide the reader with their personal perspective. A multidisciplinary management is encouraged to minimize the therapeutic inertia and manage tolerability issues, thus supporting adherence. Pragmatic trials, pharmacovigilance, and high-quality real-world evidence are crucial toward personalized safe prescribing of sacubitril/valsartan.

Pretransplant Right Ventricular Dysfunction Is Associated With Increased Mortality After Heart Transplantation: A Hard Inheritance to Overcome.

BACKGROUND: Right ventricular dysfunction (RVD) is a major issue in patients with advanced heart failure because it precludes the implantation of left ventricular assist device, usually leaving heart transplantation (HTx) as the only available treatment option. The pulmonary artery pulsatility index (PAPi) is a hemodynamic parameter integrating information of right ventricular function and of pulmonary circulation. Our aim is to evaluate the association of preoperative RVD, hemodynamically defined as a low PAPi, with post-HTx survival. METHODS AND RESULTS: Consecutive adult HTx recipient at 2 Italian transplant centers between 2000 and 2018 with available data on pre-HTx right heart catheterization were included retrospectively. RVD was defined as a value of PAPi lower than the 25th percentile of the study population. The association of RVD with the 1-year post-HTx mortality and other secondary end points were evaluated. Multivariate logistic regression was used to adjust for clinical and hemodynamic variables. Analyses stratified by pulmonary vascular resistance (PVR) status (≥3 Woods units vs <3 Woods units) were also performed. Among 657 HTx recipients (female 31.1%, age 53 ± 11 years), patients with pre-HTx RVD (PAPi of <1.68) had significantly lower 1-year survival rates (77.8% vs 87.1%, P = .005), also after adjusting for estimated glomerular filtration rate, total bilirubin, PVR, serum sodium, inotropes, and mechanical circulatory support at HTx (hazard ratio 2.0, 95% confidence interval, 1.3-3.1). RVD was also associated with post-HTx renal replacement therapy (hazard ratio 2.0, 95% confidence interval 1.05-3.30) and primary graft dysfunction (hazard ratio 1.7, , 95% confidence interval 1.02-3.30). When stratifying patients by estimated PVR status, RVD was associated with worse 1-year survival among patients with normal PVR (76.9% vs 88.3%, P = .003), but not in those with increased PVR (78.6% vs 83.2%, P = .49). CONCLUSIONS: Preoperative RVD, evaluated through PAPi, is associated with mortality and morbidity after HTx, providing incremental prognostic value over traditional clinical and hemodynamic parameters.

Clinical profile and in-hospital outcome of patients supported by intra-aortic balloon pump in the clinical setting of cardiogenic shock.

Background: Despite controversial evidences, intra-aortic balloon pump (IABP) is still the most widely used temporary mechanical support device in cardiogenic shock (CS), as a bridge to recovery or to more invasive mechanical supports/heart transplantation. Methods: We analyzed retrospectively data of all patients receiving IABP for CS from 2009 to 2018 in a referral centre for advanced heart failure and heart transplantation; we included CS following acute coronary syndrome (ACS) and other CS etiologies different from ACS. We excluded patients in which IABP was implanted as a support following cardiac surgery, non-cardiac surgery in patients with severe chronic heart failure, or in elective high risk or complicated Cath Lab procedures.We focused on in-hospital outcomes (including death, recovery, heart transplantation, LVAD) and IABP complications. Results: 403 patients received IABP, 303 (75.2%) following ACS and 100 (24.8%) in non-ACS CS. Non-ACS patients were younger (59 ± 18.3 vs 73.1 ± 12.6 years, p < 0.001), had lower median left ventricular ejection fraction (LVEF) (25% [18-35] vs 38% [25-45], p < 0.001). In patients with non-ACS etiologies IABP was more frequently a bridge to heart transplantation [20% (n = 20) vs 0.3% (n = 1), P < 0.001] or LVAD [4% (n = 4) vs 0.6% (n = 2), P = 0.055], while ACS patients were more frequently discharged without transplantation/LVAD [65.7% (n = 199) vs 33% (n = 33), P < 0.001]. Non-ACS patients showed higher in-hospital mortality [46% (n = 46) vs 33.9% (n = 103), P = 0.042]. Post-transplant/LVAD outcome in non-ACS subgroup was favorable (21 out of 24 patients were discharged). Serious IABP-related adverse events occurred in 21 patients (5.2%). Ischemic/hemorrhagic complications, infections and thrombocytopenia were more frequent with longer IABP stay. Conclusions: Despite therapy including percutaneous circulatory support, mortality in CS is still high. In our experience, in the clinical setting of refractory CS an IABP support represents a relatively safe circulatory support, associated with a low rate of serious complications in complex clinical scenarios.

miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy.

Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.

The pharmaceutical management of cardiac allograft vasculopathy after heart transplantation.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival after heart transplantation. Its peculiar pathophysiology involves multifactorial pathways including immune-mediated and metabolic risk factors, which are associated with the development of specific pathological lesions. The often diffuse and chronic nature of the disease reduces the effectiveness of revascularization procedures, and pharmacological prevention of the disease is the sole therapeutic approach with some proven efficacy. AREAS COVERED: In this article, after briefly outlining the risk factors for CAV, the authors revise the potential pharmacological approaches that may reduce the burden of CAV. While several therapies have shown convincing efficacy in terms of CAV prevention diagnosed by coronary imaging, very few have been reported to improve prognosis with any meaningful level of evidence. EXPERT OPINION: The authors believe that a customizable approach is necessary for clinical practice given the currently available evidence. Furthermore, it is important, in the future, to address the glaring therapeutic gap of an effective treatment against donor-specific antibodies, whose effect on endothelial injury is currently one of the major mechanisms of CAV development and for which no pharmacological treatment is currently available.

Does the antibody mediated rejection grading scale have prognostic prediction? Yes, but the picture is still blurry.

PURPOSE OF REVIEW: Antibody-mediated rejection (ABMR) is a condition difficult to diagnose and treat, which may significantly impair the outcome of heart transplant recipients. In clinical practice, diagnosis is based on immunopathology grading of endomyocardial biopsies (EMB). Despite its value, the current diagnostic system has several pitfalls that have been addressed in recent literature. RECENT FINDINGS: Pathology grading of ABMR (pAMR) has a relevant prognostic factor. However, it does not capture several nuances, such as chronic vs. acute ABMR, mixed rejection or microvascular inflammation. Molecular biology-based assays are shedding new light on the mechanisms of ABMR, which could improve the precision of ABMR diagnosis. SUMMARY: These new findings have the potential to rearrange EMB grading system and to guide more precisely decision-making, but studies validating the therapeutic management based on molecular-pathology coupling are still missing.

Clinical outcomes with percutaneous coronary revascularization vs coronary artery bypass grafting surgery in patients with unprotected left main coronary artery disease: A meta-analysis of 6 randomized trials and 4,686 patients.

Some but not all randomized controlled trials (RCT) have suggested that percutaneous coronary intervention (PCI) with drug-eluting stents may be an acceptable alternative to coronary artery bypass grafting (CABG) surgery for the treatment of unprotected left main coronary artery disease (ULMCAD). We therefore aimed to compare the risk of all-cause mortality between PCI and CABG in patients with ULMCAD in a pairwise meta-analysis of RCT. METHODS: Randomized controlled trials comparing PCI vs CABG for the treatment of ULMCAD were searched through MEDLINE, EMBASE, Cochrane databases, and proceedings of international meetings. RESULTS: Six trials including 4,686 randomized patients were identified. After a median follow-up of 39 months, there were no significant differences between PCI vs CABG in the risk of all-cause mortality (hazard ratio [HR] 0.99, 95% CI 0.76-1.30) or cardiac mortality. However, a significant interaction for cardiac mortality (Pinteraction= .03) was apparent between randomization arm and SYNTAX score, such that the relative risk for mortality tended to be lower with PCI compared with CABG among patients in the lower SYNTAX score tertile, similar in the intermediate tertile, and higher in the upper SYNTAX score tertile. Percutaneous coronary intervention compared with CABG was associated with a similar long-term composite risk of death, myocardial infarction, or stroke (HR 1.06, 95% CI 0.82-1.37), with fewer events within 30 days after PCI offset by fewer events after 30 days with CABG (Pinteraction < .0001). Percutaneous coronary intervention was associated with greater rates of unplanned revascularization compared with CABG (HR 1.74, 95% CI 1.47-2.07). CONCLUSIONS: In patients undergoing revascularization for ULMCAD, PCI was associated with similar rates of mortality compared with CABG at a median follow-up of 39 months, but with an interaction effect suggesting relatively lower mortality with PCI in patients with low SYNTAX score and relatively lower mortality with CABG in patients with high SYNTAX score. Both procedures resulted in similar long-term composite rates of death, myocardial infarction, or stroke, with PCI offering an early safety advantage and CABG demonstrating greater durability.

Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: Epidemiology, risk factors, and outcomes.

BACKGROUND: Primary graft dysfunction (P-GD) is the leading cause of early mortality after heart transplantation (HT). In this 2-center study we analyze outcomes and risk factors of P-GD according to the recent consensus conference classification endorsed by International Society for Heart and Lung Transplantation. METHODS: We included all adult HTs performed between 1999 and 2013. P-GD was graded as mild, moderate, and severe, according to International Society for Heart and Lung Transplantation recommendations, and analyzed separately from secondary GD. The primary end point was the combined occurrence of in-hospital death or emergency retransplantation. RESULTS: Early GD was found in 118 of 518 patients (23%), and 72 (13.9%) met the criteria for P-GD. Of these, 4 (5%) were mild, 33 (46%) moderate, and 35 (49%) severe and mostly characterized by biventricular involvement (78%). The end point occurred in 53 patients (10.2%). Overall, GD was a strong predictor of death-graft loss (odds ratio, 15.9; 95% confidence interval, 7.9-33.5; p < 0.01), with non-significant worse outcomes in P-GD (37%) vs secondary GD (27%) patients (p = 0.2). The study end point was more frequent in severe P-GD patients (65%) than in moderate (12%) or mild (0%; p < 0.01). Several known risk factors influenced the risk for P-GD, and the combination of specific donor and recipient risk factors accounted for approximately 22-times increased odds for P-GD. Donor age, recipient diabetes, ischemic time, and post-operative dialysis predicted non-recovery from P-GD. CONCLUSIONS: Consensus-defined P-GD identifies patients at major risk for early death and graft loss after HT, although the "mild" grade appeared under-represented and clinically irrelevant. The amplified negative effect of donor and recipient factors on P-GD risk underscores the need for appropriate donor-recipient match.

Heart allograft preservation: an arduous journey from the donor to the recipient.

PURPOSE OF REVIEW: The discrepancy between needs and availability of organs for heart transplantation may be partially reduced by improving the utilization of organs currently deemed unsuitable. Strategies to achieve this goal need optimization of the entire process of organ procurement, transportation, and functional recovery after transplant. RECENT FINDINGS: In the latest years, several studies reported improvements in organ utilization after appropriate donor management, and management of heart transportation is approaching a new era. In particular, apart from perfecting of traditional cold static preservation techniques, novel technologies now allow continuous heart perfusion prolonging out-of-body times, and prompted to the 'resuscitation' of hearts injured by the warm ischemia of circulatory death donors. The accomplishment of the journey needs appropriate protection of the graft during and after the transplant surgery. This concept is driven by adequate donor-recipient matching and aided by the assist devices that, mimicking organ perfusion machines, may allow graft reconditioning while maintaining recipient's peripheral organ function. SUMMARY: The researches reviewed in this article support a significant improvement of the heart preservation during the multifaceted process of procurement, transport, and transplant. Future challenges will be to develop healing of currently unsuitable organs, while keeping the cost of technology within the borders of affordability for healthcare systems.

Role of Intra-Aortic Balloon Pump and Extracorporeal Membrane Oxygenation in Early Graft Failure After Cardiac Transplantation.

Early graft failure (EGF) is a major risk factor for death after heart transplantation (Htx). We investigated the predictive risk factors for moderate-to-severe EGF requiring an intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) circulatory support as treatment after Htx. Between January 2000 and December 2014, 412 consecutive adult patients underwent isolated Htx at our institution. Moderate and severe EGF were defined as the need for IABP and ECMO support, respectively, within 24 h after Htx. All available recipient and donor variables were analyzed to assess the risk of EGF occurrence. Overall, moderate-to-severe EGF occurred in 46 (11.1%) patients. Twenty-nine (63.04%) patients required peripheral or central ECMO support in the treatment of severe EGF and 17 (36.9%) patients required IABP support for the treatment of moderate EGF. The predictive risk factors for moderate-to-severe EGF in recipients, as assessed by logistic regression analysis, were a preoperative transpulmonary gradient > 12 mm Hg (odds ratio [OR] 5.2; P = 0.023), a preoperative inotropic score > 10 (OR 8.5; P = 0.0001), and preoperative ECMO support (OR 4.2; P = 0.012). For donors, the predictive risk factor was a donor score ≥ 17 (OR 8.3; P = 0.006). The absence of EGF was correlated with improved long-term survival: 94% at 1 year and 81% at 5 years without EGF versus 76% and 36% at 1 year (P < 0.001), and 70% and 28% at 5 years (P < 0.001) with EGF requiring IABP and ECMO support, respectively. In-hospital weaned and survived patients after IABP or ECMO treatment for moderate-to-severe EGF had a similar 5-year conditional survival rate as transplant patients who had not suffered EGF: 88% without EGF versus 84% with EGF treated with mechanical circulatory support devices (P = 0.08). The occurrence of EGF is a multifactorial deleterious event that depends on donor and recipient profiles. IABP and ECMO support are reliable treatment strategies, depending on the grade of EGF. Furthermore, surviving patients treated with IABP or ECMO have the same long-term conditional survival rate as patients who have not suffered EGF.

Interplay of coronary angiography and intravascular ultrasound in predicting long-term outcomes after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the major cause of late graft-related death after heart transplantation (HT). Identification of patients at risk of cardiovascular events has relevant implications in appropriately guiding resources and intensity of follow-up. In this context, the prognostic relevance of serial coronary imaging long-term after HT is unexplored. METHODS: Recipients with intravascular ultrasound (IVUS) and coronary angiography performed 1 and 5 years after HT were monitored for subsequent 1 to 10 years to analyze the association of serial coronary imaging with cardiovascular death and major cardiovascular events (MACEs). RESULTS: Included were 131 patients. The MACE incidence was 31.8 per 1,000 patient-years, and cardiovascular mortality was 17.4 per 1,000 patient-years. Progression of coronary lesions detected by angiography and changes in IVUS-defined parameters, including an increase in maximal intimal thickness (MIT) ≥0.35 mm and vascular remodeling, predicted MACE occurrence. However, only MIT change ≥0.35 mm also predicted cardiovascular mortality. Among patients with normal or stable angiography, an MIT change ≥0.35 mm identified those with a significantly higher MACE rate (80 vs 13 events/1,000 patient-years). Worsening metabolic parameters appeared associated with the increasing severity of CAV development. CONCLUSIONS: Combined imaging analysis of progression of angiographic lesions and IVUS-detected MIT between 1 and 5 years post-HT allows discriminating patients at high, intermediate, and low risk for adverse long-term cardiovascular outcomes. The metabolic syndrome milieu is confirmed as a key risk factor for long-term CAV progression and adverse prognosis.