The new 2023 ESC guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions.

In the ESC 2023 guidelines, cardiomyopathies are conservatively defined as 'myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormality'. They are morpho-functionally classified as hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy with the addition of the left ventricular non-dilated cardiomyopathy that describes intermediate phenotypes not fulfilling standard disease definitions despite the presence of myocardial disease on cardiac imaging or tissue analysis. The new ESC guidelines provide 'a guide to the diagnostic approach to cardiomyopathies, highlight general evaluation and management issues, and signpost the reader to the relevant evidence base for the recommendations'. The recommendations and suggestions included in the document provide the tools to build up pathways tailored to specific cardiomyopathy (phenotype and cause) and define therapeutic indications, including target therapies where possible. The impact is on clinical cardiology, where disease-specific care paths can be assisted by the guidelines, and on genetics, both clinics and testing, where deep phenotyping and participated multi-disciplinary evaluation provide a unique tool for validating the pathogenicity of variants. The role of endomyocardial biopsy remains underexploited and confined to particular forms of restrictive cardiomyopathy, myocarditis, and amyloidosis. New research and development will be needed to cover the gaps between science and clinics. Finally, the opening up to disciplines such as bioinformatics, bioengineering, mathematics, and physics will support clinical cardiologists in the best governance of the novel artificial intelligence-assisted resources.

First- Versus New-Generation Drug-Eluting Stents in Patients With Heart Transplant With Cardiac Allograft Vasculopathy.

Although several studies have previously reported on the efficacy of percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (DES) in heart transplant patients with cardiac allograft vasculopathy, few data regarding new-generation DES are currently available. We sought to compare the efficacy of new-generation versus first-generation DES in 90 consecutive patients with heart transplant (113 de novo coronary lesions) who underwent urgent or elective PCI with first-generation (28 patients) or new-generation (62 patients) DES. For each patient, the severity of cardiac allograft vasculopathy and postprocedural extent of revascularization were quantified calculating baseline and residual SYNTAX score, respectively. The primary end point was a composite of major adverse cardiac events-myocardial infarction, cardiovascular death, or target vessel revascularization-at 3 years. Overall, the median baseline SYNTAX score was 8 (5 to 15), and a total number of stents per patient of 1.6 ± 0.9 was implanted. Post-PCI residual SYNTAX score was 1.5 (0 to 4), with 13 patients having a score >8. At 3 years, the Kaplan-Meier estimate of freedom from major adverse cardiac events was 64%, with no differences between first-generation and new-generation DES groups (log-rank test p = 0.269). Nevertheless, patients treated with new-generation DES experienced a lower rate of target vessel revascularization (15% vs 31%, log-rank test p = 0.058). In the multivariate Cox regression analysis, a post-PCI residual SYNTAX score >8 (hazard ratio 2.37, confidence interval 0.98 to 5.73, p = 0.054) was identified as an independent predictor of the primary end point.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy in Heart Transplantation: New Strategies and Preliminary Results in Endomyocardial Biopsies.

Tacrolimus (TAC) is an immunosuppressant drug approved both in the US and in the EU, widely used for the prophylaxis of organ rejection after transplantation. This is a critical dose drug: low levels in whole blood can lead to low exposure and a high risk of acute rejection, whereas overexposure puts patients at risk for toxicity and infection. Both situations can occur at whole-blood concentrations considered to be within the narrow TAC therapeutic range. We assumed a poor correlation between TAC trough concentrations in whole blood and the incidence of acute rejection; therefore, we propose to study TAC concentrations in endomyocardial biopsies (EMBs). We analyzed 70 EMBs from 18 transplant recipients at five scheduled follow-up visits during the first year post-transplant when closer TAC monitoring is mandatory. We observed five episodes of acute rejection (grade 2R) in three patients (2 episodes at 0.5 months, 2 at 3 months, and 1 at 12 months), when TAC concentrations in EMBs were low (63; 62; 59; 31; 44 pg/mg, respectively), whereas concentrations in whole blood were correct. Our results are preliminary and further studies are needed to confirm the importance of this new strategy to prevent acute rejection episodes.

Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients.

The development and persistence of SARS-CoV-2-specific immune response in immunocompetent (IC) and immunocompromised patients is crucial for long-term protection. Immune response to SARS-CoV-2 infection was analysed in 57 IC and 15 solid organ transplanted (TX) patients. Antibody responses were determined by ELISA and neutralization assay. T-cell response was determined by stimulation with peptide pools of the Spike, Envelope, Membrane, and Nucleocapsid proteins with a 20-h Activation Induced Marker (AIM) and 7-day lymphoproliferative assays. Antibody response was detected at similar levels in IC and TX patients. Anti-Spike IgG, IgA and neutralizing antibodies persisted for at least one year, while anti-Nucleocapsid IgG declined earlier. Patients with pneumonia developed higher antibody levels than patients with mild symptoms. Similarly, both rapid and proliferative T-cell responses were detected within the first two months after infection at comparable levels in IC and TX patients, and were higher in patients with pneumonia. T-cell response persisted for at least one year in both IC and TX patients. Spike, Membrane, and Nucleocapsid proteins elicited the major CD4+ and CD8+ T-cell responses, whereas the T-cell response to Envelope protein was negligible. After SARS-CoV-2 infection, antibody and T-cell responses develop rapidly and persist over time in both immunocompetent and transplanted patients.

[Early diagnosis and management of cardiac allograft vasculopathy: is it time for a standardized approach?] / Individuazione precoce e gestione della coronaropatia nel cuore trapiantato: è tempo per una uniformità di approccio?

Cardiac allograft vasculopathy (CAV) still represents the main cause of long-term graft loss after heart transplantation. Its silent clinical presentation makes an early identification difficult, with relevant implications for a standardized follow-up. Although technological advances have provided sophisticated non-invasive techniques for CAV assessment, intravascular ultrasound in conjunction with coronary angiography is still the gold standard to detect rapidly progressive CAV and to provide prognostic information during follow-up. Current guidelines recommend annual coronary angiography during the first 5 years and every 2 years thereafter. Although commonly performed, coronary angiography has multiple limitations, especially in young patients and in case of chronic kidney disease. This article aims to review the literature about the monitoring of CAV and to propose an ideal and individualized pathway for early diagnosis of CAV in transplanted patients, based on their cardiovascular risk.

Calcineurin Inhibitor-Based Immunosuppression and COVID-19: Results from a Multidisciplinary Cohort of Patients in Northern Italy.

The role of immunosuppression in SARS-CoV-2-related disease (COVID-19) is a matter of debate. We here describe the course and the outcome of COVID-19 in a cohort of patients undergoing treatment with calcineurin inhibitors. In this monocentric cohort study, data were collected from the COVID-19 outbreak in Italy up to April 28th 2020. Patients were followed at our hospital for solid organ transplantation or systemic rheumatic disorders (RMDs) and were on calcineurin inhibitor (CNI)-based therapy. Selected patients were referred from the North of Italy. The aim of our study was to evaluate the clinical course of COVID-19 in this setting. We evaluated 385 consecutive patients (220 males, 57%; median age 61 years, IQR 48-69); 331 (86%) received solid organ transplantation and 54 (14%) had a RMD. CNIs were the only immunosuppressant administered in 47 patients (12%). We identified 14 (4%) COVID-19 patients, all transplanted, mainly presenting with fever (86%) and diarrhea (71%). Twelve patients were hospitalized and two of them died, both with severe comorbidities. No patients developed acute respiratory distress syndrome or infectious complications. The surviving 10 patients are now fully recovered. The clinical course of COVID-19 patients on CNIs is generally mild, and the risk of superinfection seems low.

Development and validation of a combined enzymatic-digestion/mass spectrometry assay for Tacrolimus quantitation in cardiac biopsies.

Recent studies report strategies for analysing immunosuppressive drugs in brain, liver and renal tissue, mostly in animals: we developed and validated a two steps combined enzymatic digestion/mass spectrometry assay to quantify Tacrolimus (TAC) in heart biopsies. Our aims were to avoid sample loss and sample contamination during the laboratory preparation, and to limit matrix effects in the electrospray ionization source (ESI) of the mass spectrometer. Enzymatic tissue digestion followed by a liquid-liquid drug extraction in the same vial of reaction allowed us to reach both our aims. The assay was assessed for selectivity, matrix effect, linearity, Lower Limit of Quantification (LLOQ) and Detection (LOD), accuracy and precision, according to the "Guideline on Bioanalytical Method Validation (EMA). A stable isotopically labelled (SIL) analogue (13CD2-TAC) was used as internal standard. The chromatographic separation of the analyte took 6 min. The observed linear range of quantification was 0.0162-0.520 ng in terms of TAC added to the biopsies (by 50 µL of the corresponding working solutions). The limit of detection and the lower limit of quantification (LLOQ) were 0.008 and 0.0162 ng, respectively. Both the mobile phases contained ammonium acetate and formic acid that promote the formation of ammoniated precursor ions that can be easily fragmented ([M + NH4]+, TAC m/z 821.3; 13CD2-TAC m/z 824.3). The calibration curves were generated by plotting analyte-to-internal standard peak area ratios versus TAC amount (ng) added to the biopsies, and using a weighted (1/x) linear regression. Curves were not forced to pass through the origin. Swine hearts were employed as blank matrix for all the analytical method validation procedures but, after approval by the ethics committee (by "Fondazione IRCCS Policlinico San Matteo": Protocol 20190032933), TAC was also quantified in endomyocardial biopsies from informed and consenting heart transplant patients. The study was funded by Fondazione IRCCS Policlinico San Matteo (RC08017617), as a part of the clinical studies on the maintenance of immunosuppressive therapy in cardiac transplant patients. Tacrolimus concentrations in patients biopsies were expressed as ratio between the detected amount of TAC (ng) in the tissue and the weight of the tissue itself (mg).

Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor-Related Nephrotoxicity.

BACKGROUND: There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. METHODS: Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. RESULTS: In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. CONCLUSIONS: A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.

Advanced native-kidney carcinoma in a heart- and kidney-transplanted patient: a case report.

Malignancies are one of the leading causes of death in long-term surviving transplant recipients. Dose and prolonged durations of immunosuppressive regimens are considered the main cause, through a direct oncogenic effect and a renowned interaction on physiological anti-viral and anti-oncogenic immune response. Specific neoplasms are known to occur with different frequencies according to the transplanted organ. As a consequence, imaging screenings have been implemented in many graft surveillance programs, although a wide consensus on the timing and modality has not been concurred. There are little data available in the literature regarding incidence of de-novo malignancies in multi-organ recipients. We report the case of a 66-year-old man who developed a renal mass 10 years after a combined heart-kidney transplant.

Minimally invasive heart-port assisted technique as standard first choice approach for left ventricle endoplasty: a ten-year single-center experience.

BACKGROUND: Although the port-access technique has been shown to be an effective and safe approach for cardiac surgery procedures it has never become routine practice, and it is still limited to few and selected centers. Furthermore, such technique has rarely been applied to treat left ventricle disease. In 1999 we introduced left ventricle aneurysm repair through a left minithoracotomy using the port-access technique. Here we present the results in terms of early and medium-term follow-up using such technique as a routine first choice approach for left ventricle endoplasty. METHODS: From 1999 to date, out of 38 patients undergoing left ventricle endoplasty (+/-associate procedures), mini-left thoracotomy and port-access techniques have been used in 32 patients (84%). All patients underwent endoventricular patch-repair with ventricular reshaping and associated procedures were performed in 8 patients. RESULTS: All patients survived the operation and were discharged from the hospital (30 days mortality 0%). Two patients (6.2%) experienced prolonged mechanical ventilations and 3 patients (9.3%) prolonged intensive care unit stay. Mean follow-up was 40+/-34 months (range, 2 to 105). One patient died during follow-up (cumulative mortality 3.3%). Follow-up revealed an improvement of hemodynamic performances (left ventricular ejection fraction 0.44+/-0.09 compared with 0.34+/-0.09 preoperatively, p=0.004) and improved clinical conditions (New York Heart Association class 1.4+/-0.5 compared with 2.3+/-1 preoperatively, p=0.003). CONCLUSIONS: The port-access technique can be safely applied to perform left ventricle endoplasty through a left minithoracotomy. Such approach allows optimal surgical view and therefore optimal surgical correction. Based on our satisfactory experience we support left minithoracotomy as a valuable alternative approach for left ventricle endoplasty in view of an extended use of minimally invasive techniques.

Port-access surgery as elective approach for mitral valve operation in re-do procedures.

BACKGROUND: Re-do mitral valve procedures performed through median sternotomy carry substantial mortality and morbidity. To avoid complications of sternal re-entry and to provide adequate mitral valve exposure, antero-lateral thoracotomy has been suggested by some authors. METHODS: From October 1997 to January 2007, 677 mitral valve operations have been performed in our centre using port-access video-assisted right mini-thoracotomy. Among these, 241 (35.6%) were performed on patients who had undergone one or more previous cardiac surgery procedures. RESULTS: Mean cardio-pulmonary bypass time and endo-clamp time were 117+/-46 min and 71+/-31 min, respectively. Arterial cannulation was performed either on the ascending aorta, with the endo-direct cannula (112 patients, 46.5%), or peripherally with a femoral artery approach (129 patients, 53.5%). Conversion to median sternotomy was necessary in only two patients (0.8%) due to aortic dissection (one case) and left ventricle free wall rupture (one case). Median intensive care unit stay was 24h, median mechanical ventilation time was 12h; median hospital stay was 8 days. Bleeding requiring surgical revision occurred in 12 patients (4.9%). Hospital mortality was 4.9% (12/241 patients). CONCLUSIONS: Port-access video-assisted right mini-thoracotomy allows good results in a difficult subset of patients; it allows minimal adhesion dissection, short ICU and hospital stay. In our practice, this technique has become the treatment of choice for mitral valve re-do surgery.

Port-access minimally invasive surgery for atrial septal defects: a 10-year single-center experience in 166 patients.

OBJECTIVE: We assessed the surgical results and the benefits to the patient of a minimally invasive surgical approach for atrial septal defects. METHODS: Between May 1998 and May 2008, 166 patients (median age, 44 years) had surgery for atrial septal defects in our institution. Of these patients, 118 (71%) had a patent foramen ovale (associated with atrial septal aneurysm in 48 cases), 33 (20%) had a wide ostium secundum defect, 6 (3.6%) had an ostium primum defect, 6 (3.6%) had a sinus venosus defect with abnormal pulmonary vein connection, and 1 (0.6%) had a coronary sinus defect. In 2 cases (1.2%) patients were referred to our department for surgical correction after failure of interventional occluder placement. All patients were operated on via a right minithoracotomy (mean incision, 5.5 + or - 1 cm) in the fourth intercostal space and under cardiopulmonary bypass. RESULTS: The HeartPort access system was used in 106 patients (64%), with an endoaortic clamp (central kit in 50 cases and peripheral kit in 56). In the remaining patients (36%), we preferred the Portaclamp system (37 cases) or the Chitwood clamp (23 cases). Average crossclamp time was 38.4 + or - 22.2 minutes with a mean cardiopulmonary bypass time of 64.9 + or - 34.5 minutes. There was no conversion in classic sternotomy. There were no early or late hospital deaths. Surgical revision was performed in 6 patients for bleeding from the thoracic wall. The mean hospital stay was 5.8 days. At 51 months mean follow-up, 4 patients died of non-cardiac-related causes. CONCLUSIONS: Port-access minimally invasive surgery for atrial septal defects is a safe, less-invasive, reproducible, and cosmetic operation, providing an excellent outcome and an effective correction, and could be now considered the standard approach for this type of patient.

Should we perform heart retransplantation in early graft failure?

Cardiac retransplantation represents the gold standard treatment for a failing cardiac graft but the decision to offer the patient a second chance is often made difficult by both lack of donors and the ethical issues involved. The aim of this study was to evaluate whether retransplantation is a reasonable option in case of early graft failure. Between November 1985 and June 2008, 922 patients underwent cardiac transplantation at our Institution. Of these, 37 patients (4%) underwent cardiac retransplantation for cardiac failure resulting from early graft failure (n = 11) or late graft failure (acute rejection: n = 2, transplant-related coronary artery disease: n = 24). Survival at 1, 5 and 10 years of patients with retransplantation was 59%, 50% and 40% respectively. An interval between the first and the second transplantation of less than (n = 11, all in early graft failure) or more than (n = 26) 1 month was associated with a 1-year survival of 27% and 73%, and a 5-year survival of 27% and 65% respectively (P = 0.01). The long-term outcome of cardiac retransplantation is comparable with that of primary transplantation only in patients with transplant-related coronary artery disease. Early graft failure is a significant risk factor for survival after cardiac retransplantation and should be considered as an exclusion criteria.

The axillary artery as an alternative site of cannulation for redo port access-assisted minimally invasive mitral valve surgery: early report of 2 cases.

The minimally invasive Heartport (HP)-assisted technique has become first choice option for mitral valve surgery in many centres.The pool of patients potentially treated using HP techniques, however, is still limited by the presence of peripheral vessel disease, expecially in the elderly population. Alternative approaches to using the HP technique safely in such a subset of patients, therefore, should be evaluated. Here, we present our preliminary experience using the axillary artery as an alternative site of cannulation for HP-assisted redo mitral valve surgery in patients with concomitant peripheral vessel disease.

Angiogenic growth factors and/or cellular therapy for myocardial regeneration: a comparative study.

BACKGROUND: Locally delivered angiogenic growth factors and cell implantation have been proposed for patients with myocardial infarcts without a possibility of percutaneous or surgical revascularization. The goal of this study was to compare the effects of these techniques in an experimental model of myocardial infarct. METHODS: Left ventricular myocardial infarction was created in 27 sheep by ligation of 2 coronary arteries. Three weeks after creation of the infarct, animals were randomized into 4 groups. In group 1, sheep received a culture medium injection to the infarct area (control group); group 2 underwent autologous myoblast implantation; group 3 received vascular endothelial growth factor; and group 4 received injection of both vascular endothelial growth factor and myoblasts. Evaluation included serum troponin IC levels, echocardiography (2-dimensional and color kinesis), and immunohistologic studies for quantitative analysis of capillaries (3 months after surgery). RESULTS: Four animals died of refractory ventricular fibrillation during myocardial infarction; 2 died after surgery because of stroke and 2 because of infections. Serum troponin increased to 45.6 +/- 4.7 ng/mL at postinfarction day 2. Echocardiography at 3 months showed a significant limitation of left ventricular dilation in the cell group (57 +/- 11.1 mL) and in the cell plus vascular endothelial growth factor group (58.6 +/- 6.6 mL: control group, 74.4 +/- 11.2 mL; vascular endothelial growth factor group, 68.1 +/- 3.4 mL). Color kinesis echography showed important improvements of regional fractional area change in the cell group (from 13.6% +/- 0.8% to 21.1% +/- 1.5%) and in the cell plus vascular endothelial growth factor group (from 12.8% +/- 0.9% to 18.7% +/- 2.3%). The number of capillaries increased in the peri-infarct region of the vascular endothelial growth factor group (1036 +/- 75: control group, 785 +/- 31; cell group, 830 +/- 75; cell plus vascular endothelial growth factor group, 831 +/- 83). CONCLUSIONS: In the cell therapy groups, regional ventricular contractility improved and heart dilatation was limited compared with either vascular endothelial growth factor or control; thus, postischemic remodeling was reduced. Angiogenesis was demonstrated in the vascular endothelial growth factor group, without improvement of ventricular function and remodeling. To improve local conditions for cell survival, further studies are warranted on prevascularization of myocardial scars with angiogenic therapy.

From dynamic to cellular cardiomyoplasty.

Dynamic Cardiomyoplasty. Latissimus dorsi dynamic cardiomyoplasty has been used in our institution for heart failure patients refractory to medical therapy; 113 cases were operated at Broussais and Pompidou Hospitals and 75 patients by our team abroad, in the scope of an international cooperative program. Cardiomyoplasty has been associated with better results due to technical improvements, the most significant mini-invasive techniques, the latest the use of growth factors to enhance muscle vascularization. Risk factors have been identified, resulting in more precise indications, a lower hospital mortality, and a wider use of this operation. There has been a new tendency to associate cardiomyoplasty with electrophysiological therapies: implantation of ventricular defibrillators and multisite cardiac pacing (for atrioventricular and interventricular resynchronization). Cellular Cardiomyoplasty. Adult myocardium cannot repair after infarction due to the absence of stem cells. Cell transplantation strategies for heart failure have been designed to replace damaged cells with cells that can perform cardiac work. Current possibilities in cell therapy for heart failure is the transplantation into the infarcted myocardium of autologous myoblasts (satellite cells originated from skeletal muscle), fetal cardiomyocytes, autologous heart cells, cells derived from bone marrow stem cells, and smooth muscle cells. Experimental studies demonstrated that cell transplantation into the myocardium was associated with the recovery of myocardial contractility and compliance, as well as the diastolic pressure-strain relationship in animal models (infarctlike myocardial lesions and dilated cardiomyopathy models). Healthy myoblasts and myotubes were observed 2 months after myocardial implantation. Clinical studies are now in progress.

Treatment of heart failure with autologous skeletal myoblasts.

BACKGROUND: The management of patients with heart failure is a daily challenge for cardiologists and cardiac surgeons. Pharmacotherapy, atrio-biventricular resynchronization, myocardial revascularization, valve repair techniques, latissimus dorsi cardiomyopathy, acorn cardiac support device, heart transplantation and mechanical assist devices do not cover all the needs. The recent progress in cellular and molecular biology allows the development of new therapies for heart failure. TRANSPLANTATION OF AUTOLOGOUS CELLS: One of the most innovative consists in the transplantation of autologous ex-vivo expanded cells into the myocardium for heart muscle regeneration. This approach is called "cellular cardiomyoblasty".