Left ventricular assist device in cardiac amyloidosis: friend or foe?

The prevalence of cardiac amyloidosis has progressively increased over the last years, being recognized as a significant cause of heart failure. In fact, the management of advanced heart failure is a cornerstone treatment of amyloid cardiomyopathy due to the frequent delay in its diagnosis. Left ventricular assist devices (LVADs) have been gaining importance in the scenario of end-stage heart failure, representing an alternative to heart transplant. However, only few studies have investigated the role of LVAD in restrictive cardiomyopathies such as cardiac amyloidosis, since there are several problems to consider. In fact, both anatomical factors and the restrictive physiology of this condition make LVAD implant a relevant challenge in this subset of patients. Furthermore, due to the systemic involvement of amyloidosis, several factors have to be considered after LVAD implant, such as an increased risk of bleeding and right ventricular failure. This review attempts to summarize the current evidence of LVAD in cardiac amyloidosis, especially focusing on the challenges that this cardiomyopathy imposes both to the implant and to its management thereafter.

Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice.

The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.

Detection of early left ventricular and atrial dysfunction in overweight patients with preserved ejection fraction: a speckle tracking analysis.

BACKGROUND: Little remains known about the role of overweight to promote progressive atrial and ventricular myocardial dysfunction. Aim of this study was to investigate the potential influence of overweight on left ventricular (LV) and atrial (LA) function, as assessed by speckle tracking strain analysis, in patients at low-to-moderate global cardiovascular risk. METHODS: Seventy patients presenting 1 or more cardiovascular risk factor, with preserved ejection fraction, were enrolled. Peak atrial longitudinal strain (PALS) and Peak ventricular longitudinal strain (PVLS) were calculated by averaging values observed in all LV or LA segments, in four- and two-chamber views (global PALS and global PVLS), using a commercially available semiautomated two-dimensional (2D) strain software. RESULTS: Global PALS was similar in the 2 groups, while global PVLS was significantly lower in the overweight group as compared to normal weight (-17.2 ± 3.3 vs. -18.7 ± 2.8, P < 0.05). Univariate analysis of correlation showed a significantly correlation between global PALS and PVLS (r = -0.43, P < 0.01), as well as with E/A ratio (r = 0.40, P < 0.01) and with LV mass index (r = -0.34, P < 0.05). In multivariate linear regression analysis, these parameters were confirmed as independent predictors of PALS. CONCLUSION: In subjects at low-to-moderate cardiovascular risk, overweight is a key determinant of the reduction of global LV longitudinal function as assessed by 2D strain.

Prevalence of transthyretin-related amyloidosis in Tuscany: Data from the regional population-based registry.

The limited available data regarding the prevalence of transthyretin amyloidosis, both for wild-type (ATTRwt) and hereditary form (ATTRv), is inferred from highly selected patients and subsequent extrapolations that limit the comprehension of the clinical disease impact. The Tuscan healthcare system in 2006 developed a web-based rare disease registry, to monitor and profile patients affected by rare diseases. Clinicians belonging to regional validated healthcare data centres can register patients at the diagnosis, with a rigorous approach and distinguishing the types of amyloidosis, i.e., ATTRwt versus ATTRv. Thanks to this data collection method, available from July 2006 and extended with electronic therapy plans related to a diagnosis since May 2017, we analysed prevalence and incidence of ATTR and its subtypes. On November 30th 2022, ATTRwt prevalence in Tuscany is 90.3 per 1,000,000 persons and ATTRv prevalence is 9.5 per 1,000,000 persons, whereas the annual incidence ranges from 14.4 to 26.7 per 1,000,000 persons and from 0.8 to 2.7 per 1,000,000 persons, respectively. The male gender is predominant in both forms. All except one patient showed evidence of cardiomyopathy. This epidemiological data requires attention, not only to increase the effort for the clinical management and earlier diagnosis, but also to underline the need for the disease-specific treatments.

Diagnostic and prognostic value of low QRS voltages in cardiomyopathies: old but gold.

The interpretation of 12-lead resting electrocardiogram (ECG) in patients with a definitive diagnosis or with the suspicion of a cardiomyopathy represents a cornerstone for the diagnostic work up and management of patients. Although low electrocardiographic QRS voltages (LQRSV) detected by 12-lead resting ECG have historically been acknowledged by physicians, in view of recent evidence on the demonstration of myocardial scar by cardiac magnetic resonance and its relevance as a cause of sudden cardiac death even in young individuals, a new interest has been raised about the utility of LQRSV in the clinical practice. Beyond their diagnostic value, LQRSV have also demonstrated a prognostic role in different cardiomyopathies. The present review summarizes the diagnostic and prognostic value of LQRSV in cardiomyopathies, reporting the new evidence, primarily based on advanced imaging studies, supporting the clinical utility of this parameter.

Unmasking the prevalence of amyloid cardiomyopathy in the real world: results from Phase 2 of the AC-TIVE study, an Italian nationwide survey.

AIM: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions. METHODS AND RESULTS: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%. CONCLUSION: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy.

Chronic mitral regurgitation: left atrial deformation analysis by two-dimensional speckle tracking echocardiography.

BACKGROUND: Speckle tracking echocardiography (STE) is a novel method for the angle-independent and objective quantification of myocardial deformation; it has recently evolved, enabling the quantification of longitudinal myocardial left atrial (LA) deformation dynamics. To investigate the effects of chronic mitral regurgitation (MR) on these functional atrial indices, we analyzed LA function by STE in a group of asymptomatic patients with chronic degenerative MR. METHODS: The study population included 36 patients with mild MR, 38 with moderate MR, and 42 with severe MR. 52 age-matched controls were also recruited. Global peak atrial longitudinal strain (global PALS) was measured in all subjects by averaging all atrial segments. RESULTS: Age, gender, and LV ejection fraction in all pathological groups were comparable to those in the controls. Global PALS was higher in the mild MR group (46.7 ± 9.1%) in comparison with the controls (40.5 ± 6.2%; P < 0.001); instead global PALS was lower in the moderate MR group (25.7 ± 7.1%) and further reduced in the severe MR group (13.2 ± 5.2%) in comparison with the controls (40.5 ± 6.2%; overall P < 0.0001 by ANOVA, P < 0.05 for all pairwise comparisons). In multivariate analysis, E/Em ratio emerged as the principal independent determinant of global PALS. CONCLUSIONS: Our study provides new insight for the LA function analysis in response to different degrees of MR, showing that STE measurements of LA longitudinal strain may be considered a promising tool for the early detection of impairment of LA compliance in patients with asymptomatic chronic MR.

Left ventricular twisting as determinant of diastolic function: a speckle tracking study in patients with cardiac hypertrophy.

PURPOSE: Left ventricular hypertrophy (LVH) can develop in response to training with morphological changes in the heart and to pathological increase in afterload such as in essential hypertension. Deformation analysis using two-dimensional (2D) strain echocardiography can detect early systolic function abnormalities in patients with LVH. The aim of this study was to characterize left ventricular twisting (LVT) modifications, in professional athletes, compared with control subjects and with patients with hypertensive cardiopathy. METHODS: Seventy-six patients were enrolled: 37 professional athletes with cardiac hypertrophy (group A), 22 patients with early hypertensive cardiopathy (group B) cross-matched for LV mass index, and 17 healthy controls (group C), with no evidence of cardiac hypertrophy. All patients had no concomitant cardiac disease. All patients were investigated at rest using transthoracic echocardiography. LVT was obtained with speckle tracking analysis, using dedicated software. RESULTS: LVT was reduced in group A compared to group B and C (group A: 8.0° ± 2.4°; group C: 10.3° ± 2.3°; group B: 16.0° ± 4.2°; P < 0.01). In overall population, LVT showed a significant correlation with transmitral flow pattern (r =-0.58, P < 0.01) and with age (r =-0.57, P < 0.01). LVT showed the best predictive value to diagnose diastolic dysfunction (AUC: 0.86, P < 0.0001). CONCLUSIONS: 2D strain can identify specific patterns of myocardial deformation in professional athletes, controls, and patients with early hypertensive cardiopathy. In our study LVT showed a parallel trend with modifications of diastolic function and could represent a promising tool to differentiate functional cardiac hypertrophy from hypertensive cardiac hypertrophy.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Advanced Thyroid Cancer.

BACKGROUND: Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMA approved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatment related toxicities occur frequently with these drugs and can be severe or life-threatening. OBJECTIVES: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field. METHODS: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions. RESULTS: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer. CONCLUSION: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.

Acute effects of caffeine and cigarette smoking on ventricular long-axis function in healthy subjects.

BACKGROUND: Few data exist regarding the direct effects of caffeine and smoking on cardiac function. We sought to explore the acute effects of caffeine assumption, cigarette smoking, or both on left ventricular (LV) and right ventricular (RV) function in a population of young normal subjects. METHODS: Forty-five healthy subjects aged 25 +/- 2 years underwent echocardiography. Fifteen of them were non-smokers and habitual coffee consumers (group 1), 15 were smokers and not habitual coffee consumers (group 2), and 15 were smokers and habitual coffee consumers (group 3). Peak systolic (Sa), early diastolic Ea, and late diastolic (Aa) velocity of mitral annulus were measured by pulsed Tissue Doppler, and left atrioventricular plane displacement was determined by M-mode. Tricuspid annular velocities and systolic excursion (TAPSE) were also determined. Measurements were performed at baseline and after oral assumption of caffeine 100 mg in group 1, one cigarette smoking in group 2, and both in group 3. RESULTS: No changes in ventricular function were observed in group 1 after caffeine administration. In group 2, cigarette smoking yielded an acute increase in mitral Aa (+12.1%, p = 0.0026), tricuspid Sa (+9.8%, p = 0.012) and TAPSE (+7.9%, p = 0.017), and a decrease in the mitral Ea/Aa ratio (-8.5%, p = 0.0084). Sequential caffeine assumption and cigarette smoking in group 3 was associated with an acute increase in mitral Aa (+13.0%, p = 0.015) and tricuspid Aa (+11.6%, p < 0.0001) and a reduction in mitral Ea/Aa ratio (-8.5%, p = 0.0084) tricuspid Ea (-6.6%, p = 0.048) and tricuspid Ea/Aa ratio (-9.6%, p = 0.0003). In a two-way ANOVA model controlling for hemodynamic confounding factors, changes in the overall population remained significant for mitral Aa and Ea/Aa ratio, and for tricuspid Aa and Ea/Aa ratio. CONCLUSION: In young healthy subjects, one cigarette smoking is associated to an acute impairment in LV diastolic function and a hyperdynamic RV systolic response. Caffeine assumption alone does not exert any acute effect on ventricular long-axis function, but potentiates the negative effect of cigarette smoking by abolishing RV supernormal response and leading to a simultaneous impairment in both LV and RV diastolic function.

Safety and efficacy evaluation of albumin-bound paclitaxel.

INTRODUCTION: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel, which was developed to avoid toxicities associated with Cremophor EL® vehicle used in solvent-based paclitaxel. It is approved as monotherapy for treatment of metastatic breast cancer (MBC) in Europe and the US; in combination therapy for non-small-cell lung cancer (NSCLC) and for first-line treatment of advanced pancreatic cancer (PC) only in the US. The European Medicines Agency has recently released only a positive opinion for use of nab-paclitaxel in PC. AREAS COVERED: This review reports the clinical findings and the safety data of nab-paclitaxel for MBC, NSCLC and PC. EXPERT OPINION: In MBC, nab-paclitaxel has demonstrated a good safety and an efficacy profile compared with other taxanes, but no strong data on overall survival are available. Considering the role of markers or predictive factors for nab-paclitaxel effectiveness in the metastatic setting would be useful. In PC, nab-paclitaxel and gemcitabine represent a new therapeutic choice with significant improvement in survival. In a Phase III study with NSCLC patients, nab-paclitaxel showed better results in a subgroup of patients with squamous histology, for whom results with conventional therapies are still poor and improved therapeutic options are needed.

Cancer vaccines in phase II/III clinical trials: state of the art and future perspectives.

The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.

Impact of obesity on left ventricular systolic function in hypertensive subjects with normal ejection fraction.

We sought to investigate the potential impact of obesity on left ventricular (LV) systolic function in patients with hypertension and normal ejection fraction (EF). In 112 hypertensive subjects with echocardiographic evidence of normal EF, M-mode left atrio-ventricular plane displacement, and Tissue Doppler-derived peak systolic velocity of the mitral annulus were measured and used as sensitive indices of longitudinal LV systolic dysfunction. The midwall stress-shortening relation was considered as a sensitive load-independent measure of circumferential LV myocardial contractility. There were no differences in either atrio-ventricular plane displacement or peak systolic velocity between normal weight, overweight, and obese subjects. In contrast, circumferential myocardial contractility tended to be reduced in overweight (90.3+/-14.4%) and was significantly depressed in obese (85.9+/-14.3%) as compared to normal weight individuals (95.3+/-14.8%; P=0.042). Multivariate analysis confirmed an independent negative association between body mass index (BMI) and myocardial contractility. The impact of BMI category on circumferential function did not differ between the study population and age- and gender-matched controls, suggesting additive interaction, rather than synergistic, between overweight-obesity and hypertension.

Impact of diabetes and hypertension on left ventricular longitudinal systolic function.

BACKGROUND: The assessment of the longitudinal component of left ventricular (LV) function is of major clinical importance for the early detection of LV contractile impairment. The aim of this study was to compare the impact of isolated type-2 diabetes, isolated hypertension, and co-existence of both on LV longitudinal systolic performance, with particular focus on their potential interaction effect. METHODS: The study population included 163 consecutive patients: 84 patients with hypertension, 36 with diabetes, and 43 who have both hypertension and diabetes; 70 healthy controls were also recruited. Systolic mitral annulus velocity (S(m)) by Tissue Doppler and left atrioventricular plane displacement (AVPD) by M-mode were measured in all subjects. RESULTS: AVPD was similarly reduced in hypertensives (13.2±2.2mm) and diabetics (13.5±2.3mm) when compared with the controls (15.1±2.4mm), and further depressed in diabetic hypertensives (11.5±3.0mm). Similar results were found for S(m). General linear model analysis revealed no significant interaction terms between diabetes and hypertension. CONCLUSIONS: Normotensive diabetics and nondiabetic hypertensives show comparable depression in LV longitudinal systolic indices when compared with age- and gender-matched healthy controls; the co-existence of diabetes and hypertension leads to further impairment in LV longitudinal systolic function in an additive manner.

Assessment of left ventricular diastolic events interrelations: an integrated approach.

BACKGROUND: Left ventricular (LV) diastolic function represents a complex performance that involves long axis displacement, myocardial lengthening velocities as well as cavity filling. The aim of this study was to assess the various diastolic event interrelations in a group of patients with different degrees of diastolic dysfunction. METHODS: 128 consecutive subjects with various degrees of diastolic impairment were studied by Doppler echocardiography. The amplitude of early diastolic (El) and late diastolic (Al) long axis lengthening was measured by M-mode and corresponding myocardial velocities (Ea and Aa) by Tissue Doppler. LV filling velocities were also acquired by spectral pulsed wave Doppler. RESULTS: Early diastolic long axis amplitudes and velocities correlated (r=0.73, P<0.0001) as did late diastolic ones (r=0.67, P<0.0001). El of ≤5.6 mm was 80.6% sensitive and 70.5% specific in predicting Ea of <8.0 cm/s, a feature of LV impaired relaxation. El/Al correlated with Ea/Aa (r=0.78, P<0.0001), as did E/El with E/Ea ratios (r=0.74, P<0.0001). An E/El ratio>17.3 cm/s/mm had 94.1% sensitivity and 87.4% specificity for predicting an E/Ea ratio>15, a marker for raised LV filling pressures. El≤6.8 mm, total amplitude of diastolic motion (El+Al)≤11.5 mm, and E/El>14.2 cm/s/mm were the best criteria to discriminate between normal diastolic function and pseudonormal/restrictive LV filling. CONCLUSION: Diastolic LV components of motion, amplitude and velocities are not independent, neither from each other nor from filling pressures. An integrated approach towards using them all in assessing diastolic function, particularly in patients with raised filling pressure should be of great clinical value.

mTOR pathway and mTOR inhibitors as agents for cancer therapy.

Research into mTOR, mammalian Target Of Rapamycin as an important drug target continues to be extremely interesting, both in terms of the increased molecular knowledge being acquired at the basis of various human diseases, and also for possible applications in drug cancer therapy. The mTOR signaling system plays a key role in several transduction pathways that are necessary for cell cycle progression and cellular proliferation. Drugs known as mTOR inhibitors have been included in ongoing and in recently completed cancer trials. New insights into the mTOR signaling system are helping to clarify the functionality of key mTOR components, and especially their possible role in apoptosis, angiogenesis and tumor progression. Three other molecules, already approved for therapeutic use and being commercialized (Everolimius, Temsirolimus and Zotarolimus) are added to Rapamycin (also known as Sirolimus), the parent drug of the mTOR inhibitors. Of these, only Temsirolimus is currently approved in the treatment of renal cell carcinoma, while the others are approved for organ transplant rejection and coronary artery restenosis. There are at least 10 other molecules currently under development for clinical and preclinical studies. This review offers an updated synopsis of the mTOR signaling system, in particular as regards relevant aspects of cancer research, looks at the known mTOR inhibitors and gives a systematic vision of current trials for each individual molecule subject to clinical investigation.

Circumferential versus longitudinal systolic function in patients with hypertension: a nonlinear relation.

BACKGROUND: Depressed circumferential midwall performance and impaired left ventricular (LV) longitudinal function are both early markers of LV systolic dysfunction in patients with hypertension. The relation between midwall and longitudinal indices in these patients has never been analyzed. METHODS: In 126 patients with hypertension, midwall fractional shortening (mFS), stress-corrected mFS, M-mode left atrioventricular plane displacement, and tissue Doppler-derived peak mitral annular systolic velocity were determined. RESULTS: Regression analysis showed that the relations of midwall indices to atrioventricular plane displacement and mitral annular systolic velocity were all nonlinear. Reductions in atrioventricular plane displacement or mitral annular systolic velocity within their higher ranges corresponded to relatively smaller decreases in mFS and stress-corrected mFS. Relative wall thickness was the strongest determinant of the relative efficiency of circumferential and longitudinal LV contraction. CONCLUSION: The relation between circumferential midwall and longitudinal function in patients with hypertension is nonlinear and dependent on LV geometry. In these patients, systolic impairment occurs earlier in longitudinal than circumferential performance.

Right-sided heart failure in carcinoid syndrome.

We reported the case of a 63-year-old man with a history of carcinoid syndrome evaluated for an exertional dyspnoea. Two-dimensional echocardiogram showed the characteristic right-sided cardiac valves involvement associated with this uncommon enterochromaffin malignancy.