Myocardial work-A new tool for early detection of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy induced-cardiotoxicity in hematological patients.

BACKGROUND: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP) chemotherapy in non-Hodgkin's lymphoma (NHL) has risk of cardiotoxicity. PURPOSE: To determine the role of myocardial work and biomarkers in subclinical diagnosis and prediction of cardiotoxicity. METHODS: The 130 NHL patients (52 ± 9 years, 62% men) scheduled for RCHOP, with LVEF>50%, were evaluated at baseline, after third cycle and chemotherapy completion for 3D LVEF, 2D myocardial deformation (longitudinal, radial, circumferential strain - LS, RS, CS) and myocardial work (global constructive work, waste work, work index and work efficiency - GCW, GWW, GWI, GWE). NT-pro-BNP and troponin I were determined. RESULTS: After chemotherapy ended, 37 patients (28%) (group I) developed asymptomatic cardiotoxicity (8 mild form, 25 moderate form, 4 severe form); 93 patients (group II) did not. After third cycle, all patients had decreased LS, CS, RS, GCW, GWI, GWE and increased GWW, persistent after chemotherapy completion, with significant changes in group I. After third cycle, GWE and GCW were the best independent predictors for LVEF reduction; GWE decrease with>5% after third cycle predicted cardiotoxicity after chemotherapy completed (91% sensitivity, 94% specificity). CONCLUSIONS: In NHL, myocardial work can diagnose subclinical cardiotoxicity and predict LVEF decline. These parameters should be used for sensitive evaluation of myocardial function during chemotherapy.

Mechanisms and Genetic Susceptibility of Chemotherapy-Induced Cardiotoxicity in Patients With Breast Cancer.

BACKGROUND: Cardiotoxicity remains an important adverse reaction of chemotherapy used in the treatment of breast cancer, leading to increased morbidity and mortality. DATA SOURCES: Anthracyclines, taxanes, and trastuzumab are the most commonly used cytotoxic drugs for the treatment of breast cancer. Cardiotoxicity may vary from asymptomatic forms to irreducible heart failure and death. AREAS OF UNCERTAINTY: Susceptibility for the occurrence of chemotherapy-induced cardiotoxicity and treatment resistance is multifactorial, with interindividual variability, determined by the interaction between genetic and phenotypic factors. Implementation of pharmacogenomic findings into clinical practice might be useful, to predict cardiotoxicity and to allow appropriate therapeutic measures. RESULTS AND CONCLUSIONS: This review will summarize the cellular mechanisms of chemotherapy-induced cardiotoxicity in breast cancer patients and will discuss the role of the genetic susceptibility for cardiac dysfunction.

Comparison of pulse wave velocity assessed by three different techniques: Arteriograph, Complior, and Echo-tracking.

Arterial stiffness estimated by pulse wave velocity (PWV) is an independent predictor of cardiovascular morbidity and mortality. Although recommended by the current guidelines, clinical applicability of this parameter is difficult, due to differences between the various techniques used to measure it and to biological variability. Our aim was to compare PWV assessed by 3 different commercially available systems. 100 subjects (51 ± 16 years, 45 men) were evaluated using the 3 methods: an oscillometric technique (Arteriograph, PWV-A); a piezo-electric method (Complior, PWV-C); and an high-resolution ultrasound technique implemented with an Echo-tracking system (Aloka, PWV-E). Conventional biological markers were measured. Correlations of PWV measured by the 3 methods were poor (r = 0.39, r = 0.39, and r = 0.31 for PWV-A vs. PWV-C, PWV-A vs. PWV-E, and PWV-C vs. PWV-E, respectively, all p < 0.05). By Bland-Altman analysis, mean difference (±SD) of PWV-A vs. PWV-C was -1.9 ± 2.0 m/s, of PWV-A vs. PWV-E -3.6 ± 1.9 m/s, and of PWV-C vs. PWV-E -2.7 ± 1.9 m/s, with a wide coefficient of variation (22.3, 25.7, and 25.7 %, respectively). As expected, PWV-A, PWV-C, and PWV-E correlated with other arterial stiffness parameters, such as intima-media thickness (r = 0.22, r = 0.22, and r = 0.36, respectively), E p (r = 0.37, r = 0.26, and r = 0.94, respectively), and augmentation index measured by Arteriograph method (r = 0.66, r = 0.35, and r = 0.26, respectively); all p < 0.05. Assessment of PWV is markedly dependent on the technique used to measure it, related to various methods for measuring traveled distance of the arterial wave. Our results suggest the urgent need to establish reference values of PWV for each of these techniques, separately, to be used in routine clinical practice.

Current Insights into the Significance of the Renal Resistive Index in Kidney and Cardiovascular Disease.

Initially, the renal resistive index (RRI) was investigated with the aim of improving diagnosis in kidney diseases, but this goal was not met. Recently, many papers have highlighted the prognostic significance of the RRI in chronic kidney disease: specifically, in estimating the revascularization success of renal artery stenoses or the evolution of the graft and the recipients in renal transplantation. Moreover, the RRI has become significant in the prediction of acute kidney injury in critically ill patients. Studies in renal pathology have revealed correlations of this index with parameters of systemic circulation. The theoretical and experimental premises of this connection were then reconsidered, and studies analyzing the link between RRI and arterial stiffness, central and peripheral pressure, and left ventricular flow were conducted with this purpose. Many data currently indicate that RRI is influenced more by pulse pressure and vascular compliance than by renal vascular resistance-assuming that RRI reflects the complex interplay between systemic circulation and renal microcirculation and should be considered a marker of systemic cardiovascular risk beyond its prognostic relevance for kidney disease. In this review, we overview the clinical research that reveals the implications of RRI in renal and cardiovascular disease.

Cardiovascular Toxicity Induced by Vascular Endothelial Growth Factor Inhibitors.

Cardiotoxicity is an important side effect of vascular endothelial growth factor (VEGF) inhibitors therapy used in the treatment of various malignancies, leading to increased morbidity and mortality. Arterial hypertension, cardiac ischemia with the acceleration of atherosclerosis, arrhythmias, myocardial dysfunction and thromboembolic disease are the most feared cardiovascular adverse reactions due to VEGF inhibitors. Susceptibility for the occurrence of VEGF inhibitors-induced cardiotoxicity has multifactorial determinants, with a significant inter-individual variation. Baseline cardiovascular risk assessment of the patient, type and stage of cancer, dose and duration of VEGF inhibitors treatment and adjuvant chemotherapy or radiotherapy are the main predictors for cardiotoxicity. The role of the cardio-oncology team becomes essential for achieving maximum therapeutic anti-angiogenic effects with minimum cardiovascular side effects. This review will summarize the incidence, risk factors, mechanisms, management and treatment of VEGF inhibitors-induced cardiovascular toxicity.

Multimodality Imaging and Biomarker Approach to Characterize the Pathophysiology of Heart Failure in Left Ventricular Non-Compaction with Preserved Ejection Fraction.

Left ventricular non-compaction (LVNC) with preserved ejection fraction (EF) is still a controverted entity. We aimed to characterize structural and functional changes in LVNC with heart failure with preserved EF (HFpEF). METHODS: We enrolled 21 patients with LVNC and HFpEF and 21 HFpEF controls. For all patients, we performed CMR, speckle tracking echocardiography (STE), and biomarker assessment for HFpEF (NT-proBNP), for myocardial fibrosis (Galectin-3), and for endothelial dysfunction [ADAMTS13, von Willebrand factor, and their ratio]. By CMR, we assessed native T1 and extracellular volume (ECV) for each LV level (basal, mid, and apical). By STE, we assessed longitudinal strain (LS), globally and at each LV level, base-to-apex gradient, LS layer by layer, from epicardium to endocardium, and transmural deformation gradient. RESULTS: In the LVNC group, mean NC/C ratio was 2.9 ± 0.4 and the percentage of NC myocardium mass was 24.4 ± 8.7%. LVNC patients, by comparison with controls, had higher apical native T1 (1061 ± 72 vs. 1008 ± 40 ms), diffusely increased ECV (27.2 ± 2.9 vs. 24.4 ± 2.5%), with higher values at the apical level (29.6 ± 3.8 vs. 25.2 ± 2.8%) (all p < 0.01); they had a lower LS only at the apical level (-21.4 ± 4.4 vs. -24.3 ± 3.2%), with decreased base-to-apex gradient (3.8 ± 4.7 vs. 6.9 ± 3.4%) and transmural deformation gradient (3.9 ± 0.8 vs. 4.8 ± 1.0%). LVNC patients had higher NT-proBNP [237 (156-489) vs. 156 (139-257) pg/mL] and Galectin-3 [7.3 (6.0-11.5) vs. 5.6 (4.8-8.3) ng/mL], and lower ADAMTS13 (767.3 ± 335.5 vs. 962.3 ± 253.7 ng/mL) and ADAMTS13/vWF ratio (all p < 0.05). CONCLUSION: LVNC patients with HFpEF have diffuse fibrosis, which is more extensive at the apical level, explaining the decrease in apical deformation and overexpression of Galectin-3. Lower transmural and base-to-apex deformation gradients underpin the sequence of myocardial maturation failure. Endothelial dysfunction, expressed by the lower ADAMTS13 and ADAMTS13/vWF ratio, may play an important role in the mechanism of HFpEF in patients with LVNC.

Reference ranges of tricuspid annulus geometry in healthy adults using a dedicated three-dimensional echocardiography software package.

Background: Tricuspid annulus (TA) sizing is essential for planning percutaneous or surgical tricuspid procedures. According to current guidelines, TA linear dimension should be assessed using two-dimensional echocardiography (2DE). However, TA is a complex three-dimensional (3D) structure. Aim: Identify the reference values for TA geometry and dynamics and its physiological determinants using a commercially available three-dimensional echocardiography (3DE) software package dedicated to the tricuspid valve (4D AutoTVQ, GE). Methods: A total of 254 healthy volunteers (113 men, 47 ± 11 years) were evaluated using 2DE and 3DE. TA 3D area, perimeter, diameters, and sphericity index were assessed at mid-systole, early- and end-diastole. Right atrial (RA) and ventricular (RV) end-diastolic and end-systolic volumes were also measured by 3DE. Results: The feasibility of the 3DE analysis of TA was 90%. TA 3D area, perimeter, and diameters were largest at end-diastole and smallest at mid-systole. Reference values of TA at end-diastole were 9.6 ± 2.1 cm2 for the area, 11.2 ± 1.2 cm for perimeter, and 38 ± 4 mm, 31 ± 4 mm, 33 ± 4 mm, and 34 ± 5 mm for major, minor, 4-chamber and 2-chamber diameters, respectively. TA end-diastolic sphericity index was 81 ± 11%. All TA parameters were correlated with body surface area (BSA) (r from 0.42 to 0.58, p < 0.001). TA 3D area and 4-chamber diameter were significantly larger in men than in women, independent of BSA (p < 0.0001). There was no significant relationship between TA metrics with age, except for the TA minor diameter (r = -0.17, p < 0.05). When measured by 2DE in 4-chamber (29 ± 5 mm) and RV-focused (30 ± 5 mm) views, both TA diameters resulted significantly smaller than the 4-chamber (33 ± 4 mm; p < 0.0001), and the major TA diameters (38 ± 4 mm; p < 0.0001) measured by 3DE. At multivariable linear regression analysis, RA maximal volume was independently associated with both TA 3D area at mid-systole (R 2 = 0.511, p < 0.0001) and end-diastole (R 2 = 0.506, p < 0.0001), whereas BSA (R 2 = 0.526, p < 0.0001) was associated only to mid-systolic TA 3D area. Conclusions: Reference values for TA metrics should be sex-specific and indexed to BSA. 2DE underestimates actual 3DE TA dimensions. RA maximum volume was the only independent echocardiographic parameter associated with TA 3D area in healthy subjects.

New insights into the potential utility of the left atrial function analysis in heart failure with preserved ejection fraction diagnosis.

AIMS: None of the conventional echocardiographic parameters alone predict increased NTproBNP level and symptoms, making diagnosis of heart failure with preserved ejection fraction (HFpEF) very difficult in some cases, in resting condition. We evaluated LA functions by 2D speckle tracking echocardiography (STE) on top of conventional parameters in HFpEF and preHF patients with diastolic dysfunction (DD), in order to establish the added value of the LA deformation parameters in the diagnosis of HFpEF. METHODS: We prospectively enrolled 125 patients, 88 with HFpEF (68±9 yrs), and 37 asymptomatic with similar risk factors with DD (preHF) (61±8 yrs). We evaluated them by NTproBNP, conventional DD parameters, and STE. Global longitudinal strain (GS) was added. LA reservoir (R), conduit (C), and pump function (CT) were assessed both by volumetric and STE. 2 reservoir strain (S) derived indices were also measured, stiffness (SI) and distensibility index (DI). RESULTS: LA R and CT functions were significantly reduced in HFpEF compared to preHF group (all p<0.001), whereas conduit was similarly in both groups. SI was increased, whereas DI was reduced in HFpEF group (p<0.001). By adding LA strain analysis, from all echocardiographic parameters, SR_CT<-1.66/s and DI<0.57 (AUC = 0.76, p<0.001) demonstrated the highest accuracy to identify HFpEF diagnosis. However, by multivariate logistic regression, the model that best identifies HFpEF included only SR_CT, GS and sPAP (R2 = 0.506, p<0.001). Moreover, SR_CT, DI, and sPAP registered significant correlation with NTproBNP level. CONCLUSIONS: By adding LA functional analysis, we might improve the HFpEF diagnosis accuracy, compared to present guidelines. LA pump function is the only one able to differentiates preHF from HFpEF patients at rest. A value of SR_CT < -1.66/s outperformed conventional parameters from the scoring system, reservoir strain, and LA overload indices in HFpEF diagnosis. We suggest that LA function by STE could be incorporated in the current protocol for HFpEF diagnosis at rest as a major functional criterion, in order to improve diagnostic algorithm, and also in the follow-up of patients with risk factors and DD, as a prognostic marker. Future studies are needed to validate our findings.

The Pathophysiological Link between Right Atrial Remodeling and Functional Tricuspid Regurgitation in Patients with Atrial Fibrillation: A Three-Dimensional Echocardiography Study.

BACKGROUND: Atrial fibrillation (AF) itself may lead to functional tricuspid regurgitation (FTR) through tricuspid annulus (TA) dilation. However, the pathophysiological determinants of TA enlargement in AF patients remain to be clarified. The objectives of this study were (1) to compare the TA size and function in AF patients versus healthy subjects; (2) to identify the determinants of TA remodeling in patients with AF and FTR; and (3) to assess the relationships among right heart structures and severity of FTR in AF patients. METHODS: Eighty-three consecutive patients with long-term persistent AF and FTR (61 ± 9.9 years, 67% women) were prospectively enrolled and compared with 83 sex and body surface area-matched healthy subjects. Heart chamber size and function and TA geometry were analyzed using three-dimensional echocardiography. RESULTS: Among AF patients, 33%, 34%, and 33% had mild, moderate, and severe FTR, respectively. Right atrial (RA) dilation was detected in 93% of AF patients, while only 27% and 12% of them showed dilated or dysfunctional right ventricle (RV), respectively. End-diastolic TA area had the strongest correlation with the minimum volume of the RA (RAVmin r = 0.6981, P < .0001) but only mild correlation with RV end-diastolic volume and sex (r = 0.3405, P = .0019; r = 0.2914, P = .0075). At multivariable analysis, only RAVmin was independently associated with TA area in AF patients (r = 0.665, P < .0001). The RAVmin and TA area were the only predictors of FTR severity. CONCLUSIONS: In patients with AF, RA dilation seems to be more important than RV dilation to determine TA enlargement and subsequent FTR development. The RAVmin and TA area were directly correlated to FTR severity.

Atypical Site of Venous Thrombosis Despite Appropriate Anticoagulation in a Patient with Myeloproliferative Neoplasm.

The following case report and literature review will emphasize the individualized therapeutic management of a complex prothrombotic pathology. The onset of acute portal vein thrombosis in a patient with atrial fibrillation and good compliance to anticoagulation with a direct oral anticoagulant, who associates significant thrombocytosis, after excluding predisposing inflammations, infections or solid neoplasia, raises the diagnostic suspicion of myeloproliferative disorder, and imposes a complex interdisciplinary approach.

3D echocardiography, arterial stiffness, and biomarkers in early diagnosis and prediction of CHOP-induced cardiotoxicity in non-Hodgkin's lymphoma.

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) represents standard chemotherapy in non-Hodgkin's lymphoma (NHL) with risk of cardiotoxicity. To define new parameters, such as 3D myocardial deformation, arterial stiffness, and biomarkers for early diagnosis and prediction of cardiotoxicity. 110 NHL patients with LVEF > 50%, scheduled for CHOP, were evaluated at baseline, after third cycle and chemotherapy completion. 3DE assessed LVEF and myocardial deformation: longitudinal (LS), radial, circumferential, area strain. Echo-tracking analysed arterial stiffness: PWV, ß index, wave intensity. Troponin I and NT-pro-BNP were measured. After chemotherapy completion, 18 patients (16%) (group I) developed cardiotoxicity (LVEF decrease < 50%, with > 10% from baseline); 92 patients (group II) did not. Significant reduction of 3D LV deformation and increase of arterial stiffness developed starting with third cycle, with greater changes in group I. LS reduction and PWV increase after third cycle were the best independent predictors for LVEF decrease; the association of LS decrease by > 19% and PWV increase by > 27% after third cycle predicted cardiotoxicity after chemotherapy completion (90% sensitivity and 81% specificity). 3D LS and PWV can detect early chemotherapy-induced cardiotoxicity and predict LVEF decline. These parameters should be incorporated in clinical protocols to monitor cardiovascular function during chemotherapy and early intervention.

Functional Tricuspid Regurgitation and Atrial Fibrillation: Which Comes First, the Chicken or the Egg?

Pathophysiology of "atriogenic" functional tricuspid regurgitation in patients with persistent atrial fibrillation.

Impaired Cardiac Function in Patients with Multiple Sclerosis by Comparison with Normal Subjects.

Multiple sclerosis (MS), neurologic disease affecting young population, may cause cardiovascular dysfunction, due to autonomous nervous dysfunction, physical invalidity, increased oxidative stress, and systemic inflammatory status. However, cardiovascular function is rarely evaluated in these patients. We assessed left and right ventricular (LV and RV) function by 2D, 3D, tissue Doppler, and speckle tracking echocardiography, and vascular function by remodeling, stiffness, and endothelial dysfunction parameters in patients with MS, compared to control subjects. 103 subjects (35 ± 10 years,70 women) were studied: 67 patients with MS and 36 control subjects. Patients with MS had decreased LV systolic function, confirmed by lower 2D and 3D ejection fraction, mitral annular plane systolic excursion, longitudinal myocardial systolic velocities, and 2D and 3D global longitudinal strain. The RV function was also decreased, as demonstrated by lower fractional area change, tricuspid annular plane systolic excursion, longitudinal systolic velocities, and longitudinal strain. Additionally, LV diastolic and left atrial (LA)  function were decreased compared to controls. The parameters of arterial and endothelial function were similar between groups. Patients with MS have impaired biventricular function by comparison with normal subjects, with reduced LA function, but normal arterial and endothelial function. The noninvasive echocardiographic techniques might help to determine patients with MS at risk of developing cardiovascular dysfunction.

Cardiovascular Dysfunction in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurological condition, characterized by recurrent episodes of inflammation and demyelination of the central nervous system called relapsing-remitting episodes, and continuous axonal degeneration that leads to irreversible progressive invalidity. Patients with multiple sclerosis present a higher mortality rate compared to the general population, and the excess of mortality may be explained by the increased cardiovascular risk and occurrence of cardiovascular disease. However, the exact pathways to cardiovascular dysfunction are not yet completely elucidated. This review focuses on the most important mechanisms of cardiovascular dysfunction in MS, such as the cardiomyocite structure alteration, the cardiovascular autonomous nervous system dysfunction, physical invalidity, oxidative stress and endothelial dysfunction, as well as the impact of cardiovascular risk factors in MS. The latest evidence about therapeutic approaches for MS, such as immunomodulatory treatment, vitamin D supplementation and statins are also discussed. There is little knowledge about the cardiovascular dysfunction in MS, and further research is required to improve the understanding of these complex mechanisms.