Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management.

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population. PATIENTS AND METHODS: In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs. RESULTS: A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001). CONCLUSIONS: MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted.

Pulmonary arterial hypertension: guidelines and unmet clinical needs.

The term pulmonary arterial hypertension (PAH) identifies a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. The pathogenesis of PAH is not completely clear: the remodeling of the small pulmonary vessels is crucial, causing an increase in the resistance of the pulmonary circle. Its diagnosis is based on cardiac catheterization of the right heart. According to the present hemodynamic definition of pulmonary hypertension (PH) proposed by the Guidelines of the European Society of Cardiology/European Respiratory Society (ESC-ERS), the mean pulmonary arterial pressure (mPAP) values are ≥25 mmHg. In case of PAH, apart from an mPAP value ≥25 mmHg, patients must have a >3 Wood units increase in PVR and normal pressure values of the left heart. PH is a pathophysiological condition observed in more than 40 different diseases, while PAH is a primary disease of the pulmonary bloodstream potentially treatable with specific drugs. PAH is a severe complication of systemic sclerosis (SSc) affecting about 10% of the patients. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. In fact, despite awareness of the negative impact of SSc-PAH on quality of life and survival, as well as on the severity of lung function, at the moment standardized and shared guidelines and/or screening programs for the diagnosis and the subsequent early treatment of PAH in SSc are not available. The aim of the present paper is to highlight the lights and shadows of SSc-PAH, unraveling the unmet clinical needs on this topic with a proposal of clinical-diagnostic and therapeutic guidelines.

Functional Improvement After Outpatient Cardiac Rehabilitation in Acute Coronary Syndrome Patients is Not Related to Improvement in Left Ventricular Ejection Fraction.

INTRODUCTION: Cardiac rehabilitation (CR) improves the functional capacity and the prognosis of patients with coronary artery disease. AIM: Our study was aimed at assessing the relationship between functional improvement (evaluated with 6-min Walk Test-6MWT) and the improvement in left ventricular ejection fraction (LVEF) after CR. METHODS: We collected data from 249 patients (age 66.79 ± 11.06 years; males 81.52%) with a recent history of Acute Coronary Syndrome that performed CR. The functional improvement after CR was expressed as the Δ between distance covered at the final versus the initial 6-min Walking Test (6-MWT), while LVEF was calculated with transthoracic echocardiogram at the beginning and at the end of the CR. RESULTS: Patients were divided accordingly to their pre-rehab LVEF (≥ 55% vs < 55%). With superimposable age and baseline 6MWT distance covered (434.58 vs 405.12 m, p = 0.08), the latter group presented higher Δ meter values at 6MWT (167.93 vs 193.97 m, p = 0.018). However, no statistically significant positive correlation between Δ meters and Δ LVEF was found. Moreover, linear regression analyses found that nor baseline LVEF nor Δ LVEF were significant determinants of Δ meters when considering the whole group, with age, basal 6MWT and peak CK-MB as additional covariates in the model. CONCLUSION: Although it could be expected that an increase in LVEF is related to the functional improvement after CR, no significant correlation was found in our population.

Pulmonary veno-occlusive disease misdiagnosed as idiopathic pulmonary arterial hypertension.

A 27-yr-old female with a 6-month diagnosis of idiopathic pulmonary arterial hypertension (PAH) confirmed elsewhere was referred to our centre with worsening dyspnoea. On examination, the patient had low systemic oxygen saturation despite high oxygen flow and reduced exercise capacity. Haemodynamics were indicative of severe pre-capillary PAH. High-resolution computed tomography revealed diffuse ground-glass opacity with thickening interlobular septa, and haemosiderin-laden macrophages were identified by bronchoalveolar lavage. Based on clinical and diagnostic findings, the patient was re-diagnosed with pulmonary veno-occlusive disease (PVOD). Treatment with high-dose diuretics and the endothelin-receptor antagonist bosentan improved the patient's exercise capacity, haemodynamics and quality of life. However, 1 yr later there was a progressive, slow deterioration in the patient's functional capacity and oxygen saturation, and inhaled prostanoid and oxygen therapy were initiated. Despite some subjective improvements, the patient's haemodynamics and oxygen saturation continued to decline and she underwent lung transplantation. This case emphasises that PVOD is an under-recognised and often misdiagnosed form of pulmonary hypertension. Therefore, accurate diagnosis of PVOD requires comprehensive clinical and diagnostic work-up. While lung transplantation remains the treatment of choice for patients with PVOD, targeted therapies for PAH in addition to high doses of diuretics merit evaluation.

Pulmonary arterial hypertension associated to connective tissue diseases.

Pulmonary arterial hypertension is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue diseases, and to a lesser extent, rheumatoid arthritis, dermatopolymyositis and primary Sjögren's syndrome. In these patients, pulmonary hypertension may occur in association with left heart disease, interstitial fibrosis or as a result of a isolated pulmonary arteriopathy. The incidence of pulmonary arterial hypertension in the limited form of systemic sclerosis is about 10%. The pathophysiologic mechanisms leading to pulmonary arterial hypertension remain unknown. Symptoms and clinical presentation are very similar to idiopathic pulmonary arterial hypertension but mortality was confirmed to be higher. Echocardiography is the reference investigation for the detection of pulmonary arterial hypertension but the results should be confirmed by right heart catheterization. Treatment appears more complex as compared to idiopathic pulmonary arterial hypertension. Intravenous epoprostenol therapy has been shown to be effective in a special trail. Also, the endothelin receptor antagonists bosentan and sitaxentan, the phosphodyesterase-type-5 sildenafil and subcutaneous treprostinil have shown favourable results.

Pulmonary hypertension in primary Sjögren's syndrome: report of a case and review of the literature.

A 61-year-old female with a history of vaginal dryness, Raynaud's phenomenon, xerostomia and xerophthalmia presented with exertional dyspnoea and weakness. Laboratory and instrumental examinations enabled us to make the diagnosis of primary Sjögren's syndrome, while cardiologic and imaging investigations evidenced isolated pulmonary hypertension and ruled out pulmonary fibrosis. Oral anticoagulant and furosemide therapy induced a partial improvement of exertional dyspnoea and weakness.