The Pharmacological Approach to Oncologic Patients with Acute Coronary Syndrome.

Among acute coronary syndrome (ACS) patients, 15% have concomitant cancer, especially in the first 6 months after their diagnosis, as well as in advanced metastatic stages. Lung, gastric, and pancreatic cancers are the most frequent malignancies associated with ACS. Chemotherapy and radiotherapy exert prothrombotic, vasospastic, and proinflammatory actions. The management of cancer patients with ACS is quite challenging: percutaneous revascularization is often underused, and antiplatelet and anticoagulant pharmacological therapy should be individually tailored to the thrombotic risk and to the bleeding complications. Sometimes oncological patients also show different degrees of thrombocytopenia, which further complicates the pharmacological strategies. The aim of this review is to summarize the current evidence regarding the treatment of ACS in cancer patients and to suggest the optimal management and therapy to reduce the risk of adverse coronary events after ACS in this high-risk population.

The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy.

Mutations in LMNA, which encodes the nuclear proteins Lamin A/C, can cause cardiomyopathy and conduction disorders. Here, we employ induced pluripotent stem cells (iPSCs) generated from human cells carrying heterozygous K219T mutation on LMNA to develop a disease model. Cardiomyocytes differentiated from these iPSCs, and which thus carry K219T-LMNA, have altered action potential, reduced peak sodium current and diminished conduction velocity. Moreover, they have significantly downregulated Nav1.5 channel expression and increased binding of Lamin A/C to the promoter of SCN5A, the channel's gene. Coherently, binding of the Polycomb Repressive Complex 2 (PRC2) protein SUZ12 and deposition of the repressive histone mark H3K27me3 are increased at SCN5A. CRISPR/Cas9-mediated correction of the mutation re-establishes sodium current density and SCN5A expression. Thus, K219T-LMNA cooperates with PRC2 in downregulating SCN5A, leading to decreased sodium current density and slower conduction velocity. This mechanism may underlie the conduction abnormalities associated with LMNA-cardiomyopathy.

Echocardiography in Athletes in Primary Prevention of Sudden Death.

Echocardiography is a noninvasive imaging technique useful to provide clinical data regarding physiological adaptations of athlete's heart. Echocardiographic characteristics may be helpful for the clinicians to identify structural cardiac disease, responsible of sudden death during sport activities. The application of echocardiography in preparticipation screening might be essential: it shows high sensitivity and specificity for identification of structural cardiac disease and it is the first-line imagining technique for primary prevention of SCD in athletes. Moreover, new echocardiographic techniques distinguish extreme sport cardiac remodeling from beginning state of cardiomyopathy, as hypertrophic or dilated cardiomyopathy and arrhythmogenic right ventricle dysplasia. The aim of this paper is to review the scientific literature and the clinical knowledge about athlete's heart and main structural heart disease and to describe the rule of echocardiography in primary prevention of SCD in athletes.

Effectiveness and Safety of Transcatheter Aortic Valve Implantation in Patients With Pure Aortic Regurgitation and Advanced Heart Failure.

Results of transcatheter aortic valve implantation (TAVI) for treatment of severe noncalcific isolated aortic regurgitation (AR) complicated by advanced heart failure or cardiogenic shock has been previously reported only in isolated case reports. Current self-expanding transcatheter aortic valves are designed to treat aortic valve stenosis, and have also been implanted in cases of severe AR due to degenerated bioprosthesis and in very few cases of native aortic valves. We report 13 consecutive inoperable patients with noncalcific, pure AR, and advanced heart failure treated with emergency percutaneous transfemoral implantation with self-expandable CoreValves at our institution between July 2012 and September 2017. The immediate and long-term clinical outcome was prospectively assessed according to the Valve Academic Research Consortium-2 criteria for device success and safety. All but 3 patients had previous surgery of the aortic root, including 2 implants of Heart Mate-II left ventricle assist device; none had surgical aortic bioprosthesis at the time of the TAVI. Valve implantation was successful in 12 of 13 patients (92%) and 1 patient required a second unplanned valve procedure within 18 hours. Oversizing the prosthesis by approximately 15% yielded better results with 1 valve. Two patients with left ventricle assist device died within 30 days of TAVI. All patients who survived to hospital discharge had none or just mild residual AR, improved their cardiac function, and survived at long-term without recurrence of clinical events. In conclusion, implanting self-expandable transcatheter valves in patients pure AR in this small study was safe and effective, and represented an important option for inoperable patients with noncalcific severe AR.

Analysis of the 3'UTR of the prostaglandin synthetase-2 (PTGS-2/COX-2) gene in non-melanoma skin cancer after organ transplantation.

To define the potential involvement of polymorphisms in the 3'untranslated region (3'UTR) of the prostaglandin synthetase-2 (PTGS-2) gene to non-melanoma skin cancer (NMSC) predisposition after transplantation, we screened for genetic variant, relevant parts of this region. It contains binding sites for trans-acting factors, an alternative polyadenylation site and putative target sequences for miRNAs. Variant +8473T>C did not appear to play a functional role in the regulation of gene expression in human keratinocyte-transfected cells. In addition to the well-known +8473T>C, we identified four polymorphisms: +8293G>C, +10259T>G, +10267G>A and +10335G>A. No allele frequency differences were observed between cases and controls neither for +8473T>C nor for any of the identified polymorphisms, suggesting that polymorphisms in the 3'UTR of the PTGS2 gene are rare and unlikely to represent risk factor for NMSC after transplantation.

Myocardial protection in heart transplantation using blood cardioplegia: 12-year outcome of a prospective randomized trial.

BACKGROUND: Blood cardioplegia yields a lower prevalence of right heart failure, arrhythmias, and myocardial ischemia early after heart transplantation (HTx). Because depolarizing (high [K(+)]) cardioplegic solutions may alledgedly cause endothelial damage, the 12-year outcome of a prospective randomized trial was reviewed. METHODS: Between January 1997 and March 1998, 47 consecutive patients received crystalloid (Group 1, n = 27) or blood cardioplegia (Group 2, n = 20). The groups were similarly matched: recipient age (54 ± 11 vs 55 ± 7 years, p = 0.9), sex (89% vs 90% males, p = 0.9), diagnosis (63% vs 65% dilated cardiomyopathy, p = 0.8), elevated (>4 WU) pulmonary vascular resistance (30% vs 30%, p = 0.9), prior operations (22% vs 30%, p = 0.5), urgent HTx (7% vs 20%, p = 0.2), donor age (32 ± 11 vs 31 ± 13 years, p = 0.7), donor sex (78% vs 70% males, p = 0.5), donor cause of death (33% vs 40% vascular, p = 0.5), and global myocardial ischemia (176 ± 51 vs 180 ± 58 minutes p = 0.5). Hemodynamically unstable donors were more prevalent in Group 2 (15% vs 45%, p = 0.02). The 45 hospital survivors underwent yearly echocardiography, coronary angiography, and coronary intravascular ultrasound (IVUS) imaging during follow-up. RESULTS: During follow-up (10.4 ± 5.2, range, 0.9-12.7 years), Groups 1 and 2 had comparable mortality (46% vs 42%, p = 0.7) and cause of death (chronic rejection: 50% vs 50%; neoplasia: 33% vs 25%, p = 0.8). Survival at 12 years was 50% ± 12% vs 52% ± 11% (p = 0.9). Follow-up echocardiogram showed similar mean left ventricular ejection fraction (LVEF; 47% ± 12% vs 49% ± 11%, p = 0.7) and prevalence of LVEF < 35% (21% vs 18%, p = 0.8). Prevalence of chronic rejection was comparable (42% vs 32%, p = 0.1), yet severe allograft vasculopathy (International Society for Heart and Lung Transplantation cardiac allograft vasculopathy 3) was more prevalent in Group 1 (64% vs 17%, p = 0.04). Freedom from chronic rejection was higher in Group 2 (44% ± 15% vs 63% ± 13%), albeit not significantly (p = 0.5). A trend toward greater prevalence of intimal disease at IVUS (thickness > 0.5 mm) in the proximal and distal left anterior descending artery (67% vs 40%; 58% vs 45%) and higher number of percutaneous coronary interventions (2.7 ± 0.5 vs 1.8 ± 0.3, p = 0.3) was noted in Group 1. CONCLUSIONS: Use of blood cardioplegia is safe and results in comparable survival and prevalence of adverse events late after HTx. The trend towards greater freedom from chronic rejection and more limited extent of coronary artery disease in grafts protected with blood cardioplegia awaits confirmation.

Impact of donor quality on outcome of heart transplantation.

OBJECTIVE: Over the last few years, there have been changes in both donor and recipient profiles in heart transplantation. Encouraging clinical outcome of marginal donors in candidates older than 60 years of age led us to allocate suboptimal donors for younger recipients as well. We reviewed our experience retrospectively so as to assess the impact of donor quality on heart transplantation. METHODS: Among 181 patients who underwent heart transplantation between January 2000 and February 2009, there were 75 patients (41%) aged 61-70 years and 106 patients (59%) ranging in age between 18 and 60 years. According to the recipient's age, they were classified into four groups. The younger recipients (106 patients) had either optimal donors (70 patients, group 1) or marginal donors (36 patients, group 2). The older recipients (75 patients) had either marginal grafts (64 patients, group 3) or optimal grafts (11 patients, group 4). Sex distribution, cause of end-stage heart failure, preoperative pulmonary hypertension, pre-heart-transplantation clinical status or mean follow-up duration did not show any statistically significant difference among the four groups. RESULTS: Overall, the 9-year actuarial survival rate was 78%±1%. The 30 days and 9-year actuarial survival rates were 94%±2% and 80%±1% in group 1; 86%±5% and 55%±12% in group 2; 90%±4% and 73%±7% in group 3; 99%±1% and 82%±7% in group 4 (P=0.07). Comparison among the four groups did not show any statistical difference in terms of freedom from graft failure (P=0.3), right ventricular failure (P=0.3), acute rejection (P=0.2), chronic rejection (P=0.2), neoplasia (P=0.5) and chronic renal failure (P=0.2). Older recipients of marginal donors (group 3) had slightly higher prevalence of permanent pacemaker implants: eight permanent pacemakers versus two in group 2, and none in group 1 and group 4 (P=0.4). CONCLUSIONS: Our results suggest that extended donor acceptance criteria may not compromise clinical outcome after heart transplantation. Further follow-up is warranted.

Incidence and clinical predictors of a subsequent nonmelanoma skin cancer in solid organ transplant recipients with a first nonmelanoma skin cancer: a multicenter cohort study.

OBJECTIVE: To compare the long-term risk of primary nonmelanoma skin cancer (NMSC) and the risk of subsequent NMSC in kidney and heart transplant recipients. DESIGN: Partially retrospective cohort study. SETTING: Two Italian transplantation centers. PATIENTS: The study included 1934 patients: 1476 renal transplant recipients and 458 heart transplant recipients. MAIN OUTCOME MEASURES: Cumulative incidences and risk factors of the first and subsequent NMSCs. RESULTS: Two hundred patients developed a first NMSC after a median follow-up of 6.8 years after transplantation. The 3-year risk of the primary NMSC was 2.1%. Of the 200 patients with a primary NMSC, 91 (45.5%) had a second NMSC after a median follow-up after the first NMSC of 1.4 years (range, 3 months to 10 years). The 3-year risk of a second NMSC was 32.2%, and it was 49 times higher than that in patients with no previous NMSC. In a Cox proportional hazards regression model, age older than 50 years at the time of transplantation and male sex were significantly related to the first NMSC. Occurrence of the subsequent NMSC was not related to any risk factor considered, including sex, age at transplantation, type of transplanted organ, type of immunosuppressive therapy, histologic type of the first NMSC, and time since diagnosis of the first NMSC. Histologic type of the first NMSC strongly predicted the type of the subsequent NMSC. CONCLUSIONS: Development of a first NMSC confers a high risk of a subsequent NMSC in transplant recipients. Intensive long-term dermatologic follow-up of these patients is advisable.

[Early interventricular septum rupture after systemic thrombolysis in a patient with STEMI]. / Rottura precoce di setto interventricolare dopo trombolisi sistemica nell'infarto miocardico acuto con ST elevation.

Intraventricular septal rupture (ISR) is one of the most dreadful complications during AMI, requiring early diagnosis and urgent surgery. However, medical (90%) and surgical (50%) mortality remain elevated. We report a case of a 59 years old patient with infero-posterior AMI complicated by ISR after thrombolysis. Despite early recognition of this complication by trans-thoracic echocardiography at bedside and prompt surgical intervention the patient died on the second post-surgical day.

Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients.

Solid organ transplant recipients are at higher risk of non-melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S-transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1-2.5); P = 0.017]. Homozygosity for allele GSTP1 Val(105) was lower in cases [OR 0.3 (0.1-0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0-0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4-6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val(462) genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val(462), show a higher risk of developing NMSC [OR 4.5 (1.1-21.4); P = 0.03], especially SCC [OR 6.5 (1.4-34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val(462) are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.

Risk stratification and prognosis of patients with known or suspected coronary artery disease by use of supine bicycle exercise stress echocardiography.

BACKGROUND: The aim of this study was to assess the long-term predictive values of supine bicycle exercise stress echocardiography (ESE), and the ESE additional role compared to other traditional clinical and rest echocardiographic variables, in 607 patients with low, intermediate and high pretest risk of cardiac events. METHODS: Clinical status and long-term outcome were assessed for a mean period of 46 months (range 12-60 months). ESE was performed for the diagnosis of suspected coronary artery disease (CAD) in 267 patients (43.9%), and for risk stratification of known CAD in 340 patients (56.1%). At baseline, the mean value of wall motion score index (WMSI) was 1.22 +/- 0.36, and the mean left ventricular ejection fraction was 58.5 +/- 10.9%. RESULTS: ESE was positive for ischemia in 210 patients (34.9%), while ECG was suggestive for ischemia in 157 patients (25.8%). During the test only 97 patients (15.9%) experienced angina. At peak effort, the mean WMSI was 1.38 +/- 0.46. A low workload was achieved by 158 patients (26.1%). During the follow-up period there were 222 events, including 82 hard events (36.9%), 48 deaths (21.6%) and 34 acute non-fatal myocardial infarction (15.3%). At stepwise multivariate model, cigarette smoking (p < 0.01), peak WMSI (p < 0.001), ESE positive for ischemia (p < 0.001) and low workload (p < 0.01) were the only independent predictors of cardiac death, while positive ESE, peak WMSI, angina during the test and hypercholesterolemia were the only independent determinants of hard cardiac events. The cumulative 5-year mean survival rate according to ESE response was 95.9% in patients with negative ESE, and 83.7% in patients with positive ESE (log rank 13.6; p < 0.00001). CONCLUSIONS: ESE yields prognostic information in known or suspected CAD, especially in patients with intermediate pretest risk level. The combined evaluation of clinical variables and other ESE variables, such as peak WMSI and exercise capacity, may further select patients at greatest risk of cardiac death in the overall population.

Prognostic value of supine bicycle exercise stress echocardiography in patients with known or suspected coronary artery disease.

AIMS: To assess the prognostic significance of supine bicycle exercise stress echocardiography (ESE) for cardiac events, and the ESE additional role compared to other traditional clinical and echo variables, in patients with proven or suspected coronary artery disease (CAD). METHODS AND RESULTS: Clinical status and long-term outcome were assessed in 607 patients, for a mean period of 49.9 +/- 12.5 months. ESE was performed for the diagnosis of suspected CAD in 267 patients, and for the risk stratification in 340 patients. At baseline, the mean value of WMSI was 1.22 +/- 0.36, and the mean left ventricular ejection fraction was 58.2 +/- 10.9%. The ESE was positive for ischemia in 210 patients (34.9%), while the ECG was suggestive for ischemia in 157 patients. At peak effort, the mean WMSI was 1.38 +/- 0.46. Low work load was achieved by 158 patients (26.1%). During the follow-up period there were 222 events, including 48 cardiac deaths and 34 acute non-fatal myocardial infarction. By multivariable model, cigarette smoking, peak WMSI, positive ESE for ischemia and low work load were the only independent predictors of cardiac death. The cumulative 5-year mean survival rate according to ESE response was 95.9% in patients with negative ESE, and 81.7% in positive ESE (p < 0.00001). CONCLUSIONS: In patients with known or suspected CAD able to perform a physical stress, bicycle ESE is able to stratify patients at higher risk of cardiac events. The final report of an ESE performed for prognostic purpose should include both the assessment of induced dyssinergy and the evaluation of indexes of the extent and the severity of myocardial ischemia.

Malignant melanoma in a candidate for heart transplantation.

A superficial spreading melanoma (Breslow thickness 0.4 mm) was diagnosed in a 65-year-old candidate for heart transplantation due to refractory end stage heart failure. After extensive review of the literature (USA and Europe), no clear guidelines about the management of candidates for transplantation with a previous diagnosis of melanoma were found. As this patient had a 5-year probability of survival higher than 95% and heart transplantation was necessary for saving his life, the final decision was to perform the transplantation. Unfortunately, the patient died of heart failure before a suitable heart became available. This case stresses the need for early and continuous dermatological evaluation of all candidates for solid organ transplantation. Clear guidelines for screening of skin cancer before transplantation are needed.