Incidence of cardiovascular events in patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors.

BACKGROUND: The introduction of imatinib and tyrosine kinase inhibitors as therapeutic strategy for Philadelphia chromosome-positive chronic myeloid leukaemia (CML) has represented an important step forward for treatment of this disease. The aim of this study was therefore to evaluate the incidence of cardiovascular adverse events (CVEs) in patients affected by CML treated with TKI in an observational prospective study. METHODS: All consecutive patients affected by CML and treated with TKI in our Institution were enrolled in the study from February 2005 to September 2018 with a clinical, laboratory and instrumental follow-up. RESULTS: Sixty-one consecutive patients were enrolled, 29 with imatinib, 15 with nilotinib, 11 with dasatinib, 3 with bosutinib and 3 with ponatinib. Neither patients in therapy with bosutinib nor with nilotinib had CVE during follow-up. Incidence rates per person/year were 0 for bosutinib and nilotinib, 0.15 for dasatinib, 0.19 for imatinib and 1.69 for ponatinib (Log Rank p < 0.05); differences in terms of incidence of adverse outcomes remained significant also after multivariate correction. CONCLUSIONS: In patients with CML treated with TKIs, therapy with ponatinib was associated with a higher risk of CVE than other TKIs. The lowest incidence of CVE was associated with bosutinib and nilotinib.

Meta-Regression Analysis of the Impact of Medical Therapy on Long-Term Mortality in Type 2 Myocardial Infarction.

The first approach for Type-2 myocardial infarction (T2MI) consists of the elimination of the condition determining the oxygen supply/demand mismatch. However, the long-term impact of medical therapy with beta blockers, statins, aspirin, and P2Y12 inhibitors, used in the case of Type-1 myocardial infarction has been poorly investigated and remains unclear. We, therefore, sought to assess the impact of medical therapy on 1-year mortality in patients with T2MI using a meta-regression analysis. A meta-regression analysis was performed with studies involving in patients with T2MI: 1-year all-cause mortality, rates of beta blockers, statins, aspirin, and P2Y12 inhibitors use were recorded and analyzed. After careful study selection, 8 observational studies were pooled in the analysis, including 3,756 in patients. During meta-regression analysis, a borderline correlation between rates of aspirin, P2Y12 inhibitors, and statins use and 1-year mortality (p = 0.087, p = 0.05, and p = 0.067, respectively) was found; no significant correlation was found at multivariable analysis. In conclusion, in a meta-regression analysis, no significant correlation was found between rates of use of usual drug therapy indicated for Type-1 myocardial infarction (statins, aspirin, P2Y12 inhibitors, ß-blockers) and 1-year mortality in T2MI patients.

Prognostic role of neoplastic markers in Takotsubo syndrome.

Takotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9-14.8, HR = 7.8 95% CI 2.4-25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6-52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE.

Concealed structural heart disease discovered at cardiac magnetic resonance in patients with ventricular extrasystoles from ventricular outflow tract and apparently normal hearts.

BACKGROUND: Outflow tract (OT) premature ventricular contractions (PVCs) are commonly found in clinical practice; in most cases, PVCs are benign and observed in structurally normal hearts, not requiring any therapeutic intervention. In this study, we therefore sought to evaluate with cardiac magnetic resonance (CMR) patients with PVC and apparently normal heart at echocardiographic examination, in order to identify possible substrates linked with higher prevalence of arrhythmias or structural heart disease. METHODS: Thirty-three consecutive patients with frequent PVCs originating from the ventricular OT (right and left) were enrolled in the study and assessed by echocardiography and CMR. All patients had normal baseline electrocardiogram. RESULTS: CMR showed structural changes in 5 patients out of 33; in 3 cases, areas of fibrosis limited in one case to the middle basal segments of the interventricular septum and in two patients to the middle basal segments of the inferior-lateral wall were found. In 2 other cases, however, late gadolinium enhancement showed significant anomalies characterized in one patient by extensive areas of subepicardial fibrosis of the left ventricle, suitable with arrhythmogenic left dominant dysplasia; in another patient, a marked trabeculation of left ventricular medium apical segments suitable with non-compaction myocardium was present. CONCLUSIONS: CMR may identify cases of structural heart disease in subjects with OT PVCs and apparently normal electrocardiogram and echocardiogram examinations. A preliminary screening with CMR may be considered before any further invasive electrophysiology assessment and therapeutic planning.

Ventilatory power, a cardiopulmonary exercise testing parameter for the prediction of pulmonary hypertension at right heart catheterization.

BACKGROUND: Several cardiopulmonary exercise test (CPET) parameters (peak VO2, PetCO2 and VE/VCO2) emerged as tools for the prediction of pulmonary arterial hypertension (PAH). Less is known on ventilatory power (VP) in patients with suspect PAH. AIM: To ascertain possible correlations between VP derived at CPET and hemodynamic parameters at right heart catheterization (RHC) indicative of PH. METHODS: Forty-seven consecutive outpatients with suspect of PAH were assessed by CPET and RHC; VP was defined as peak SBP divided by the minute ventilation-CO2 production slope at CPET and Diastolic Pressure Gradient (DPG), Trans-pulmonary Pressure Gradient (TPG), mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) at RHC were also assessed and compared with VP. RESULTS: VP values were inversely related to mPAP (r -0.427, p 0.003), DPG (r -0.36, p 0.019), TPG (r: -0.43, p 0.004), and PVR (r -0.52, p 0.001). Correlations remained significant even after correction at multivariate analysis for age and gender. VP values below median identified subjects with mPAP ≥ 25 mmHg with an odds ratio of 4.5 (95% confidence interval 1.05-19.36, p < 0.05), an accuracy of 0.712 at ROC curve analysis (95% confidence interval 0.534-0.852, p < 0.05) and a positive predictive power 82%. CONCLUSIONS: In patients with suspected PAH, VP assessed at CPET might provide further information in predicting PAH at RHC. Correlations with PVR and DPG may be helpful in differentiating patients with isolated post-capillary PH from those with combined post-capillary and pre-capillary.

Pulmonary Embolism and Thrombus in Transit Through Patent Foramen Ovale.

Thrombus-in-transit through a patent foramen ovale (PFO) in a patient with pulmonary embolism (PE) is a rare event with high mortality rates. We report the case a of 53-year-old woman admitted for dyspnea, cough, hemoptysis, presyncope, tachycardia, and hypotension. A recent fall down the stairs with costal trauma was also reported. At transthoracic echocardiography, dilated right atrium with the presence of a large floating thrombus was found, protruding into the left atrium through a PFO; lower extremity vascular ultrasound showed right great saphenous vein thrombosis extended over the saphenofemoral junction up to the common femoral vein. CT scan showed submassive thromboembolism; surgical thrombectomy was, therefore, performed with the closure of the PFO; an inferior vena cava filter was also positioned for the prevention of recurrent episodes of thromboembolism. The patient was discharged in therapy with apixaban 5 mg twice a day. Two-month follow up was uneventful. Large thrombi in transit through PFO can be found at transthoracic echocardiography. The management, either medical or surgical, should be aimed at preventing systemic thromboembolism.

Direct oral anticoagulants more effective than low-molecular-weight heparin for venous thrombo-embolism in cancer: an updated meta-analysis of randomized trials.

In the recent past, low-molecular-weight heparin (LMWH) was the first choice in the treatment of cancer related venous thrombo-embolism (VTE). Evidence supporting the preferential use of direct anticoagulants (DOACs) in patients with cancer, instead, is less robust so far. We therefore aimed to assess in an updated meta-analysis of randomized controlled trials whether the use of DOACs may be associated with a more favorable profile when compared to LMWH. We performed a meta-analysis of RCTs enrolling patients with VTE and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for recurrence of VTE, major bleeding, and mortality comparing subjects treated with DOACs with those with LMWH. After study selection, three RCTs (HOKUSAI-Cancer, SELECT-D and ADAM-VTE) were included for the analysis with an overall population of 1739 patients. DOACs patients had a lower incidence of 6-month recurrent VTE when compared to LMWHs (RR 0.56, 95% CI 0.40-0.79; p < 0.001). Incidence of major bleeding was not significantly different between DOACs and LMWH treated patients (RR 1.56, 95% CI 0.95-2.47, p = n.s.), and mortality rates were comparable (RR 1.03, 95% CI 0.91-2.47, p = n.s.). In a meta-analysis of RCTs therapy with DOACs was superior to LMWH in terms of efficacy and lower recurrence of VTE with a comparable safety profile in terms of bleeding events and complications.

Liver disease and heart failure.

INTRODUCTION: Several systemic conditions, inflammatory disease, infections and alcoholism, may affect both the heart and the liver. Common conditions, such as the non-alcoholic fatty liver disease (NAFLD), may increase the risk of cardiac dysfunction. Patients with acute decompensated HF (ADHF) may develop acute ischemic hepatitis and, chronic HF patients may develop congestive hepatopathy (CH). EVIDENCE ACQUISITION: Laboratory anomalies of hepatic function may predict the outcome of patients with advanced HF and the evaluation of both cardiac and hepatic function is very important in the management of these patients. In clinically apparent ischemic hepatitis more than 90% of patients have some right-sided HF. There are systemic disorders characterized by the accumulation of metals or by metabolism defects that may affect primarily the liver but also the heart leading to symptomatic hypertrophic cardiomyopathy (HCM). EVIDENCE SYNTHESIS: Abnormal LFTs indicate the mechanism of liver injury: liver congestion or liver ischemia. In AHF, it's important an adequate evaluation of heart and liver function in order to choose the treatment in order to ensure stable hemodynamic as well as optimal liver function. CONCLUSIONS: Measurements of LFTs should be recommended in the early phase of ADHF management. Physicians with interest in HF should be trained in the evaluation of LFTs. It's very important for cardiologists to know the systemic diseases affecting both heart and liver and the first imaging or laboratory findings useful for a diagnosis. it is very important for internists, nephrologists, cardiologists, primary physicians and any physicians with interest in treating HF to recognize such signs and symptoms belong to rare diseases and liver diseases that could be mistaken for HF.

Malignancies and outcome in Takotsubo syndrome: a meta-analysis study on cancer and stress cardiomyopathy.

Takotsubo syndrome (TTS) can be induced by a large variety of physical/emotional triggers; several cases, however, are related to either an overt or occult malignancy, as shown in retrospective studies and case reports. The aim of this study was therefore to evaluate the clinical outcome of patients with TTS and cancer in a meta-analysis study. In June 2018, a Pubmed systematic research was conducted for studies assessing outcome in patients with TTS and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for adverse events at follow-up. After paper retrieval, four studies were included in the meta-analysis, with a total of 123,563 patients. The prevalence of current or previous malignancy among patients admitted with TTS was 6.7% (8258 patients). When compared to control patients, patients with cancer showed an increased risk of clinical events (RR 3.24, 95% CI 3.04-3.45, p < 0.01). The risk of in-hospital events was significantly higher in the cancer group (RR 2.08 95% CI, 1.50-2.87, p < 0.01) and was mainly due to higher need for respiratory support (RR 1.67, 95% CI, 1.58-1.77, p < 0.01). The risk of adverse events at follow-up was also higher in the cancer group (RR 3.30, 95% CI 3.09-3.51, p < 0.01). Cancer, either history or active, is associated with an increased risk of adverse events in TTS.

Parachute mitral valve assessed by cardiac magnetic resonance.

Parachute mitral valve (PMV) is a congenital cardiac malformation where typically all tendons chordae converge and insert into one major papillary muscle. We report the case of 27-year-old man affected by Hodgkin's lymphoma-mixed cellularity subtype with polychemotherapy treatment and Barrett's esophagus who came to our attention for routine echocardiographic exam and evaluation of left ventricular function. In the presence of normal left ventricular systolic function and mild-moderate mitral regurgitation, a careful examination of mitral apparatus showed a single papillary muscle suspected for PMV. In the presence of Barrett's esophagus, the patient was further assessed cardiac magnetic resonance (CMR) that confirmed the diagnosis of PMV and excluded other associated congenital anomalies. Despite the rare incidence of PMV and a diagnosis generally based on transesophageal echocardiography, CMR could represent a useful tool, in selected cases, to confirm the diagnosis of PMV, identify other possible congenital anomalies, and assess ventricular and valvular function.

Mitral annular calcification: Can CMR be useful in identifying caseous necrosis?

Mitral annular calcification (MAC) can resemble an intracardiac mass and it is defined as a chronic degeneration of the mitral annulus. Often reported is caseous mitral annulus calcification (CMAC), a periannular, extensive calcification resembling a tumor. We report the case of a 68-year-old woman who had been hospitalized for palpitations and dyspnea. The transthoracic and transesophageal echocardiography revealed a non-homogeneous, slightly mobile, round mass, attached to the ventricular side of posterior mitral leaflet, with central echo-lucent area and without acoustic shadowing. Therefore, a cardiac magnetic resonance (CMR) was performed; delayed enhancement sequences showed a non-enhanced central core surrounded by a hyperenhanced rim (fibrous cap). To confirm the diagnosis, a multidetector computed tomography (MDCT) was performed; the MDCT showed a hyperdense mass with a hypodense center and a calcified peripheral rim. The central content had heterogeneous fluid density without significant contrast enhancement. The MDCT findings were considered highly suggestive of CMAC. CMR may be useful for the identification and definition of pericardial and myocardial masses and CMAC.

Don't stop at first glance: pulmonary artery angiosarcoma mimicking chronic thromboembolic pulmonary hypertension.

We report the case of an incomplete diagnosis of chronic thromboembolic pulmonary hypertension, with relevant prognostic implications, missing the presence of a primary pulmonary artery angiosarcoma. After the late neoplasm diagnosis, the patient, treated for months with riociguat, was considered inoperable and died soon after. This case highlights the need to manage patients with suspected pulmonary arterial hypertension by expert referral centers with specific and multi-professional expertise (heart and thoracic imaging) in order to avoid incomplete or delayed diagnoses.

Tricuspid Papillary Fibroelastoma at Multimodal Imaging.

Papillary fibroelastoma is a rare benign cardiac tumor, second after cardiac myxoma as more frequent cardiac valvular tumor. The therapy is usually based on surgery according to size, mobility, symptoms, and risks of surgery. We report the case of a 67-year old female with transient ischemic attack. Echocardiography showed the presence of a round mobile formation localized on the atrial side of septal leaflets of tricuspid valve, first identified as an endocarditis vegetation. Cardiac magnetic resonance (cMRI) confirmed the presence of the mass and showed an isointense signal in T1-turbo spin echo sequences, hypointense in cine steady-state free precession and in first-pass sequences, and hyperintense in T2 and phase-sensitive inversion recovery with central hypointense core, with a suspected diagnosis of fibroelastoma. The patient underwent cardiac surgery and histology confirmed the presence of fibroelastic tissue with papillary extroflexions compatible with diagnosis of fibroelastoma. The use of cMRI may be useful in the evaluation of the exact position, dimensions, and nature of cardiac masses and fibroelastomas, diagnostic workup, and preliminary assessment before surgery.

Predictive value of very low frequency at spectral analysis among patients with unexplained syncope assessed by head-up tilt testing.

BACKGROUND: The role of heart rate variability (HRV) in the prediction of vasovagal syncope during head-up tilt testing (HUTt) is unclear. AIM: To evaluate the ability of the spectral components of HRV at rest to predict vasovagal syncope among patients with unexplained syncope referred for HUTt. METHODS: Twenty-six consecutive patients with unexplained syncope were enrolled in the study. All patients underwent HRV evaluation at rest (very low frequency [VLF], low frequency [LF], high frequency [HF] and LF/HF ratio) and during HUTt. HUTt was performed using the Westminster protocol. Continuous electrocardiogram and blood pressure monitoring were performed throughout the test. RESULTS: Eight (31%) patients developed syncope during HUTt. There were no baseline differences in terms of clinical features and HRV variables among patients who developed syncope and those who did not, except for VLF (2421 vs 896ms2; P<0.001). In the multivariable logistic regression analysis, including age and sex, VLF was the only independent variable associated with syncope during HUTt (odds ratio 1.002, 95% confidence interval 1.0003-1.0032; P=0.02). The area under the curve at rest was 0.889 for VLF, 0.674 for HF and 0.611 for LF. A value of VLF>2048ms2 was the optimal cut-off to predict syncope during HUTt (sensitivity 87.5%, specificity 72.2%). CONCLUSIONS: VLF at rest predicted the incidence of syncope during HUTt. Further studies are warranted to confirm these preliminary data.

Relation between calcium burden, echocardiographic stent frame eccentricity and paravalvular leakage after corevalve transcatheter aortic valve implantation.

AIMS: Paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) is a complication with potentially severe consequences. The relation between native aortic root calcium burden, stent frame eccentricity and PVL was not studied before. METHODS AND RESULTS: Two-hundred-and-twenty-three consecutive patients with severe aortic stenosis who underwent TAVI with a Medtronic CoreValve System© and who had available pre-discharge transthoracic echocardiography were studied. Echocardiographic stent inflow frame eccentricity was defined as major-minor diameter in a short-axis view >2 mm. PVL was scored according to the updated Valve Academic Research Consortium (VARC-2) recommendations. In a subgroup of 162 (73%) patients, the calcium Agatston score was available. Stent frame eccentricity was seen in 77 (35%) of patients. The correlation between the Agatston score and stent frame eccentricity was significant (ρ = 0.241, P = 0.003). Paravalvular leakage was absent in 91 cases (41%), mild in 67 (30%), moderate in 51 (23%), and severe in 14 (6%) cases. The correlation between stent frame eccentricity and PVL severity was significant (ρ = 0.525, P < 0.0001). There was a relation between particular eccentric stent frame shapes and the site of PVL. CONCLUSION: Calcification of the aortic annulus is associated with a subsequent eccentric shape of the CoreValve prosthesis. This eccentric shape results in more PVL, with the localization of PVL related to the shape of stent frame eccentricity.

Direct oral anti-coagulants compared with vitamin-K inhibitors and low-molecular-weight-heparin for the prevention of venous thromboembolism in patients with cancer: A meta-analysis study.

BACKGROUND: Prior meta-analysis studies showed that direct oral anticoagulants (DOAs) are as effective and safe as warfarin for the prevention of recurrences in patients with venous thrombo-embolism(VTE) and cancer. However, randomized studies also showed that low-molecular-weight-heparin (LMWH) performs better than warfarin in subjects with cancer. We therefore aimed to assess whether, even after pooling data with warfarin and LMWH, the use of DOAs remains safe and effective. METHODS: We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOAs in patients with VTE and cancer. Data on recurrent VTE and major and clinically relevant nonmajor bleeding were analyzed. Data were pooled and compared by ORs and 95% CIs. RESULTS: Nine studies were included in the meta-analysis, seven in comparison with VKI, 2 with LMWH, accounting for a total of 1952 patients. VTE recurred in 5.4% and in 5.9% of patients with cancer treated with DOAs and conventional treatment, respectively (OR 0.79; 95% CI, 0.53-1.17; I2 0%). Bleeding occurred in 10.8% and 11% of patients receiving DOAs and conventional treatment, respectively (OR 0.96; 95% CI, 0.71-1.30; I2, 44%). Higher bleeding rates were found when DOAs are compared with LMWH (OR 2.72, 95% CI, 1.05-7.01). CONCLUSIONS: DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer in comparison with VKI. Higher bleeding rates were found when DOAs are compared with LMWH.

Optimal duration of dual anti-platelet therapy after percutaneous coronary intervention: 2016 consensus position of the Italian Society of Cardiology.

Definition of the optimal duration of dual anti-platelet therapy (DAPT) is an important clinical issue, given the large number of patients having percutaneous coronary intervention (PCI), the costs and risks of pharmacologic therapy, the consequences of stent thrombosis, and the potential benefits of DAPT in preventing ischaemic outcomes beyond stent thrombosis. Nowadays, the rationale for a prolonged duration of DAPT should be not only the prevention of stent thrombosis, but also the prevention of ischaemic events unrelated to the coronary stenosis treated with index PCI. A higher predisposition to athero-thrombosis may persist for years after an acute myocardial infarction, and even stable patients with a history of prior myocardial infarction are at high risk for major adverse cardiovascular events. Recently, results of pre-specified post-hoc analyses of randomized clinical trials, including the PEGASUS-TIMI 54 trial, have shed light on strategies of DAPT in various clinical situations, and should impact the next rounds of international guidelines, and also routine practice. Accordingly, the 2015 to 2016 the Board of the Italian Society of Cardiology addressed newer recommendations on duration of DAPT based on most recent scientific information. The document states that physicians should decide duration of DAPT on an individual basis, taking into account ischaemic and bleeding risks of any given patient. Indeed, current controversy surrounding optimal duration of DAPT clearly reflects the fact that, nowadays, a one size fits all strategy cannot be reliably applied to patients treated with PCI. Indeed, patients usually have factors for both increased ischaemic and bleeding risks that must be carefully evaluated to assess the benefit/risk ratio of prolonged DAPT. Personalized management of DAPT must be seen as a dynamic prescription with regular re-evaluations of the risk/benefit to the patient according to changes in his/her clinical profile. Also, in order to derive more benefit than harm from new treatments, a multi-parametric approach using several risk scores of the ischaemic and bleeding risks might improve the process of risk factor characterization. In patients with high ischaemic risk, particularly those with a history of myocardial infarction, the benefits of extended DAPT (particularly with ticagrelor up to 3 years) are likely to outweigh the risks.