Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

Left Ventricular-Arterial Coupling and Vascular Function in Childhood Cancer Survivors Exposed to Anthracycline Chemotherapy.

Background: Cardiovascular (CV) diseases are a cause of increased long-term morbidity and mortality in childhood cancer survivors (CCSs) treated with anthracyclines. These drugs may affect not only the heart, but also the vascular system. Left ventricular-arterial coupling (LVAC) represents a reliable parameter of altered ventricular and vascular performance, with validated prognostic value and never investigated in this setting. Aim of this study was to assess, in CCSs and matched controls, LVAC changes, performed with different echocardiographic modalities, and their relationship with endothelial function. Methods: Twenty survivors treated with anthracyclines for childhood malignancies and a matched control group of 20 healthy subjects were enrolled. Arterial elastance (Ea), end-systolic elastance (Ees), Ea/Ees ratio, as well as three-dimensional (3D) LVAC (assessed by measurement of End Systolic Volume [ESV]/Stroke Volume [SV] ratio) were performed at rest. Endothelial function was evaluated by measurement of flow-mediated dilatation (FMD) of the brachial artery. Results: 3D SV and 3D ESV/SV ratio resulted respectively significantly lower and higher in CCSs than in controls, while Ea, Ees and Ea/Ees ratio were not different among groups. A positive correlation between 3D ESV/SV ratio and cumulative anthracycline doses, as well as with time after drug exposure were also found. Mean FMD was similar in CCSs and controls (8.45 ± 1.79 versus 9.41 ± 3.41, p = 0.34). Conclusions: In conclusion, conventional LVAC parameters were not shown to be significantly different between CCSs and controls; however, 3D SV and LVAC were significantly impaired in our population. In these patients, endothelial function was comparable to controls. Larger validation studies are therefore needed.

Relation of endothelial and cardiac autonomic function with left ventricle diastolic function in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Diabetes mellitus (DM) is a risk factor for left ventricle (LV) diastolic dysfunction. Aim of this study was to investigate whether endothelial and/or autonomic dysfunction are associated with LV diastolic dysfunction in DM patients. METHODS: We studied 84 non-insulin-dependent type 2 DM (T2DM) patients with no heart disease by assessing: 1) LV diastolic function by echocardiography; 2) peripheral vasodilator function, by measuring flow-mediated dilation (FMD) and nitrate-mediate dilation (NMD); 3) heart rate variability (HRV) on 24-h Holter electrocardiographic monitoring. RESULTS: Twenty-five patients (29.8%) had normal LV diastolic function, while 47 (55.9%) and 12 (14.3%) showed a mild and moderate/severe diastolic dysfunction, respectively. FMD in these 3 groups was 5.25 ± 2.0, 4.95 ± 1.6 and 4.43 ± 1.8% (p = 0.42), whereas NMD was 10.8 ± 2.3, 8.98 ± 3.0 and 8.82 ± 3.2%, respectively (p = 0.02). HRV variables did not differ among groups. However, the triangular index tended to be lower in patients with moderate/severe diastolic dysfunction (p = 0.09) and a significant correlation was found between the E/e' ratio and both the triangular index (r = -0.26; p = 0.022) and LF amplitude (r = -0.29; p = 0.011). CONCLUSIONS: In T2DM patients an impairment of endothelium-independent, but not endothelium-dependent, dilatation seems associated with LV diastolic dysfunction. The possible role of cardiac autonomic dysfunction in diastolic dysfunction deserves investigation in larger populations of patients.

Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review.

Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype- phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single-center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid-shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

Electrocardiographic findings at presentation and clinical outcome in patients with SARS-CoV-2 infection.

AIMS: The main severe complications of SARS-CoV-2 infection are pneumonia and respiratory distress syndrome. Recent studies, however, reported that cardiac injury, as assessed by troponin levels, is associated with a worse outcome in these patients. No study hitherto assessed whether the simple standard electrocardiogram (ECG) may be helpful for risk stratification in these patients. METHODS AND RESULTS: We studied 324 consecutive patients admitted to our Emergency Department with a confirmed diagnosis of SARS-CoV-2 infection. Standard 12-lead ECG recorded on admission was assessed for cardiac rhythm and rate, atrioventricular and intraventricular conduction, abnormal Q/QS wave, ST segment and T wave changes, corrected QT interval, and tachyarrhythmias. At a mean follow-up of 31 ± 11 days, 44 deaths occurred (13.6%). Most ECG variables were significantly associated with mortality, including atrial fibrillation (P = 0.002), increasing heart rate (P = 0.002), presence of left bundle branch block (LBBB; P < 0.001), QRS duration (P <0 .001), a QRS duration of ≥110 ms (P < 0.001), ST segment depression (P < 0.001), abnormal Q/QS wave (P = 0.034), premature ventricular complexes (PVCs; P = 0.051), and presence of any ECG abnormality [hazard ratio (HR) 4.58; 95% confidence interval (CI) 2.40-8.76; P < 0.001]. At multivariable analysis, QRS duration (P = 0.002), QRS duration ≥110 ms (P = 0.03), LBBB (P = 0.014) and presence of any ECG abnormality (P = 0.04) maintained a significant independent association with mortality. CONCLUSION: Our data show that standard ECG can be helpful for an initial risk stratification of patients admitted for SARS-CoV-2 infectious disease.

Severity of spleep apnea syndrome and life-threatening tachyarrhythmias in patients with implantable cardioverter defibrillator.

BACKGROUND: Sleep apnea syndrome (SAS) has been reported to be associated with a higher incidence of ventricular arrhythmias. The aim of this study was twofold: (1) to investigate whether in SAS patients receiving an implantable cardioverter defibrillator (ICD) the severity of SAS was associated with the occurrence of ventricular arrhythmias; (2) to assess whether changes in nocturnal apnoic/hypopnoic episodes may favor the occurrence of life-threatening arrhythmias, that is, sustained ventricular tachycardia (VT)/fibrillation (VF), requiring ICD intervention. METHODS: We enrolled 46 patients with documented SAS at polysomnography (apnea/hypopnea index [AHI] > 5) who also had a left ventricle ejection fraction (LVEF) < 35% and, according to primary prevention indications, implanted an ICD (Boston Scientific Incepta) able to daily monitor apnoic/hypopnoic episodes occurring during sleep. Patients were followed at 3-month intervals. RESULTS: At a mean follow-up of 18 months, 21 episodes of sustained VT/FV requiring ICD intervention were documented in eight patients (17.4%). Baseline AHI was significantly higher in patients with compared to those without ICD intervention. ICD interventions, however, were not preceded by any worsening of apnoic/hypopnoic episodes. The respiratory disturbance index (RDI) of the week during the event, indeed, was not different from that recorded during the previous 2 weeks (25.4 ± 11, 25.6 ± 10 and 25.1 ± 10, respectively; p = .9). CONCLUSIONS: In patients with SAS who received an ICD for primary prevention of sudden death, those with ICD interventions showed a more severe form of the disease at baseline. ICD interventions, however, were not preceded by any significant changes in SAS severity.

Endothelial dysfunction and cardiovascular outcome in asymptomatic patients with type 2 diabetes: A pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular events, but risk stratification of asymptomatic T2DM patients remains a challenging issue. We conducted a pilot study to assess whether endothelial dysfunction might help identify, among asymptomatic T2DM patients, those at increased risk of cardiovascular events. METHODS: We studied 61 consecutive T2DM patients with no evidence of cardiovascular disease and no insulin therapy. Endothelial function was assessed by flow-mediated dilation (FMD) of the right brachial artery. The primary endpoint was a combination of major cardiovascular events (MACE: cardiovascular death, acute coronary events, coronary interventions, and acute cerebrovascular accidents). FMD was repeated at follow-up in 48 patients (79%). RESULTS: A total of 10 MACE (16.4%) occurred during a mean follow-up of 48 months, including three acute myocardial infarctions, five coronary revascularizations for stable angina, and two acute ischaemic strokes. FMD at enrolment was lower in patients with compared with patients without MACE (3.78 ± 0.97% vs 4.70 ± 1.33%, respectively; P = .04). No other clinical or laboratory variables (age, diabetes duration, glycated haemoglobin, cardiovascular risk factors, drug therapy, and nitrate-mediated dilation) were associated with MACE. FMD at follow-up was also lower in patients with (n = 10) compared with those without (n = 38) MACE (3.66 ± 1.29 vs 4.85 ± 1.92; P = .006). CONCLUSIONS: Our data suggest that assessment of FMD might be helpful to identify patients at increased risk of MACE among individuals with asymptomatic T2DM; accordingly, a large study is warranted to adequately define the clinical utility of FMD assessment in the management of T2DM patients.

Are implantable cardiac monitors reliable tools for cardiac arrhythmias detection? An intra-patient comparison with permanent pacemakers.

INTRODUCTION: Implantable cardiac monitor (ICM) is an established tool for the management of unexplained syncope and atrial fibrillation (AF) even if its accuracy of arrhythmia detection may be suboptimal. The aim of this study was to perform an intra-patient comparison of the diagnostic capability of ICM with a dual-chamber PM as a gold standard. METHODS: We included 19 patients with a previously implanted ICM (BioMonitor 2 Biotronik, Berlin, Germany), who received a dual-chamber PM for standard indications. ICM-detected arrhythmic events in a 6-month follow-up were compared with those detected by the PM and classified by visual inspection of intracardiac electrograms. RESULTS: During follow up, ICMs generated 15 false asystole and 39 false bradycardia detections in 5 patients (26.3%) due to recurrent premature ventricular contractions. A total of 34 true high ventricular rate (HVR) episodes were detected by the PM. Of them, 30 (88%) events were also recorded by the ICM, which further detected 14 false HVR snapshots, leading to a sensitivity and positive predictive value of 88% and 68%, respectively. In addition, PM identified 234 true AF episodes. Of them, 225 (96%) events were also detected by the ICM, while 8 (42%) ICMs stored 50 AF episodes classified as false positives. The ICM sensitivity for AF was 96% with a positive predictive value of 82%. CONCLUSION: Our intra-patient comparison with permanent PM confirmed that ICM is an effective tool for cardiac arrhythmias detection. ICM algorithms for AF and HVR detection were highly sensitive with an acceptable rate of false positive episodes.

Outcome of Patients Treated by Cardiac Resynchronization Therapy Using a Quadripolar Left Ventricular Lead.

BACKGROUND: Not all heart failure (HF) patients benefit from cardiac resynchronization therapy (CRT). We assessed whether choosing the site of left ventricular (LV) pacing by a quadripolar lead may improve response to CRT. METHODS AND RESULTS: We prospectively randomized 23 patients with HF (67±11 years; 21 males) to CRT with a quadripolar LV lead (group 1, with the LV pacing site chosen on the basis of QRS shortening using simultaneous biventricular pacing), and 20 patients (71±6 years; 16 males) to a bipolar LV lead (group 2, with devices programmed with a conventional tip-to-ring configuration). New York Heart Association (NYHA) class and LV ejection fraction (EF) by 2D echocardiography were assessed at baseline and after 3 months. The baseline EF was not different between the 2 groups (25±6% group 1 vs. 27±3% group 2; P=0.22), but after 3 months EF was higher in group 1 (35±13% group 1 vs. 31±4% group 2; P<0.001). A reduction in at least 1 NYHA class at 3 months was observed in 22 (96%) and 12 (60%) of group 1 and group 2 patients, respectively (P<0.05). CONCLUSIONS: CRT with a quadripolar LV lead was associated with an improvement of EF greater than that observed in patients receiving a bipolar LV lead. In devices with a quadripolar lead, CRT programming based on the best QRS shortening is reliable and effective. (Circ J 2016; 80: 613-618).

Overview of Management of Myocardial Ischemia: a Mechanistic-Based Approach.

Pharmacologic treatment of myocardial ischemia in patients with chronic stable angina (CSA) is mainly based on heart rate lowering drugs and vasodilator agents. Other drugs are available, however, that act by some peculiar mechanism (ranolazine, trimetazidine) and may add potential anti-ischemic and anti-anginal effects to standard therapeutic mechanisms. While anti-ischemic agents are crucial for controlling angina symptoms and improving quality of life, whether myocardial ischemia portends an ominous prognosis and its suppression improves clinical outcome in CSA patients remain debated issues.

Angina Pectoris and Myocardial Ischemia in the Absence of Obstructive Coronary Artery Disease: Role of Diagnostic Tests.

Patients with chest pain and nonobstructive coronary artery disease (NO-CAD) at angiography constitute a heterogeneous population. In most patients with stable exercise-induced chest pain, microvascular angina (MVA) is the likely diagnosis. Some clinical findings and results of diagnostic tests suggest that angina is caused by coronary microvascular (CMV) dysfunction rather than obstructive CAD, but a definitive diagnosis requires demonstration of impaired CMV dilation and/or increased constriction. About 10 % of patients presenting with an acute coronary syndrome also shows NO-CAD at angiography, and CMV constriction can be responsible for the syndrome in a number of cases. Diagnostic tests are not expected to have a prognostic role in patients with stable MVA with normal coronary arteries, due to the excellent prognosis of these patients, whereas their prognostic role in the more general population of NO-CAD patients with chest pain (either stable or acute) needs to be established in adequate studies.

Determinants of heart rate turbulence in individuals without apparent heart disease and in patients with stable coronary artery disease.

AIMS: To assess the characteristics and determinants of heart rate turbulence (HRT) in individuals without any apparent heart disease and in patients with coronary artery disease (CAD). METHODS AND RESULTS: Heart rate turbulence parameters, turbulence onset (TO), and turbulence slope (TS) were calculated on 24 h electrocardiogram recordings in 209 individuals without any heart disease (group 1) and in 157 CAD patients (group 2). In group 1, only age independently predicted abnormal TO (≥0%) [odds ratio (OR), 1.05; P<0.001], while predictors of abnormal TS (≤2.5 ms/RR) were age (OR, 0.85; P < 0.001) and hypertension (OR, 0.19; P = 0.028). In group 2 patients, only age independently predicted TO (OR, 1.03; P = 0.038), while age (OR, 0.90; P = 0.001) and left ventricular ejection fraction (LVEF; OR, 1.07; P = 0.008) predicted TS. Heart rate turbulence values were different in groups 1 and 2. Turbulence onset was (mean, standard deviation) -1.80 ± 2.24 vs. -0.73 ± 1.61%, respectively (P < 0.001), whereas TS was (median, interquartile interval) 5.83 (3.25-10.55) vs. 2.93 (1.73-5.81) ms/RR, respectively (P < 0.001). Coronary artery disease group, however, did not predict abnormal HRT parameters in multivariable analyses, both in the whole population and when comparing two subgroups matched for age and gender. Age and (for TS) LVEF, indeed, were the only independent predictors of abnormal HRT. CONCLUSIONS: Age is a major HRT determinant both in subjects without any apparent heart disease and in stable CAD patients. Hypertension and LVEF contribute independently to HRT in these two groups, respectively. Coronary artery disease group was not by itself associated with abnormal HRT parameters in multivariable analyses.

The association between ICD interventions and mortality is independent of their modality: clinical implications.

BACKGROUND: Patients with severe structural heart disease have increased mortality after implantable cardioverter-defibrillator (ICD) shocks. Whether this is limited to ICD shock therapy only or extends also to no-shock therapies, such as antitachycardia pacing (ATP), is unclear. We investigated the impact of different ICD therapies on long-term mortality. METHODS: We enrolled 573 patients who underwent ICD implantation at our institution from 2004 to 2011. The population was divided into 3 groups: no device interventions (group 1), ATP interventions (group 2), and shock interventions (group 3). The endpoint was the all-cause mortality. RESULTS: Over a follow-up period of 48 months (range 1-110), 447 (78%) had no device interventions, 71 (12%) had ATP therapy only, and 55 (10%) had at least one shock intervention. All-cause mortality occurred in 94 patients in group 1 (21%), 23 patients (43%) in group 2, and 21 patients (38%) in group 3. At multivariable Cox regression analysis, ATP intervention (HR: 1.8; 95% CI 1.1-3; P < 0.001), shock intervention (HR: 1.39; 95% CI 1.09-1.77; P = 0.008), age (HR: 1.05; 95% CI 1.02-1.07; P < 0.001), and LVEF (HR: 0.95; 95% CI 0.93-0.98; P = 0.001) were predictors of all-cause mortality. No significant difference in mortality was found between group 2 and 3. CONCLUSION: Patients with ICDs who receive appropriate interventions are at increased risk of mortality. Such risk is not dependent on different types of ICD therapy, such as shocks or ATP. Our data suggest that sustained ventricular arrhythmias per se have a negative impact on prognosis rather than modality of ICD therapy.

Early cardiac mechanics abnormalities in patients with mitochondrial diseases.

BACKGROUND: Evidence about early cardiac mechanics abnormalities in patients with mitochondrial diseases (MDs) before overt cardiomyopathy is limited. METHODS: In this prospective study, we performed a comparative analysis of conventional and speckle tracking echocardiographic parameters between patients with genetically identified MDs and no overt cardiomyopathy vs controls matched for age, sex and cardiovascular risk factors. The Newcastle mitochondrial disease adult scale (NMDAS) was calculated, using a threshold of > 21 as indicator of high disease severity. RESULTS: We enrolled 24 MDs patients (50 % males, mean age 47.2 ± 14.3 years), the most prevalent mutation was the MT-TL1 m.3243A>G (37.5 %). In MDs patients all dimensional echocardiographic parameters were similar to controls. Conversely, albeit normal, Tissue Doppler septal systolic (p = 0.002) and early diastolic velocities (p = 0.016) were significantly lower and E/e' ratio was higher (p = 0.032) in MDs. Moreover, LV-GLS was significantly reduced in MDs as compared to their counterparties (20.2 ± 1.6 vs 22.6 ± 1.5, p < 0.001). Similarly, LA reservoir and conduit strain were significantly lower in MDs (31.7 ± 7.0 vs 35.9 ± 6.6, p = 0.038; 19.7 ± 5.6 vs 23.1 ± 6.0, p = 0.049 respectively), while LA contractile strain was similar between the two groups. Lower values of LV-GLS were observed in patients with NMDAS > 21 vs patients with NMDAS ≤ 21 (19.0 ± 1.2 vs 21.0 ± 1.3, p = 0.001). CONCLUSIONS: In patients with MDs and no overt cardiomyopathy Tissue Doppler and speckle tracking analysis unveil worse LV systolic and diastolic function indices as compared to controls. Reduced LV-GLS values were found especially in those with worse disease burden.

Insulin pump treatment vs. multiple daily insulin injections in patients with poorly controlled Type 2 diabetes mellitus: a comparison of cardiovascular effects.

AIMS: Both hyperglycaemia and large glycaemic variability are associated with worse outcomes in patients with Type 2 diabetes mellitus (T2DM), possibly causing sympatho-vagal imbalance and endothelial dysfunction. Continuous subcutaneous insulin injection (CSII) improves glycemic control compared to multiple daily insulin injections (MDI). We aimed to assess whether CSII may improve cardiac autonomic and vascular dilation function compared to MDI. METHODS: We enrolled T2DM patients without cardiovascular disease with poor glycaemic control, despite optimized MDI therapy. Patients were randomized to continue MDI (with multiple daily peripheral glucose measurements) or CSII; insulin dose was adjusted to achieve optimal target ranges of blood glucose levels. Patients were studied at baseline and after 6 months by: 1) flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of the brachial artery; 2) heart rate variability (HRV) by 24-hour ECG Holter monitoring (HM). 7-day continuous glucose monitoring (CGM) was performed in 9 and 8 patients of Group 1 and 2, respectively. RESULTS: Overall, 21 patients were enrolled, 12 randomized to CSII (Group 1) and 9 to MDI (Group 2). The daily dose of insulin and Hb1AC did not differ significantly between the 2 groups, both at baseline and at follow-up. Glucose variability showed some significant improvement at follow-up in the whole population, but no differences were observed between the 2 groups. Both FMD and NMD, as well as HRV parameters, showed no significant differences between the 2 groups at 6-month follow-up. CONCLUSIONS: In this randomized small study we show that, in T2DM patients, CSII achieves a similar medium-term glycemic control compared to MDI, without any adverse effect on the cardiovascular system.

Left atrial structural and functional remodelling in Fabry disease and cardiac amyloidosis: A comparative analysis.

BACKGROUND: Fabry disease (FD) and transthyretin cardiac amyloidosis (TTR CA) are cardiomyopathies with hypertrophic phenotype that share several features, including left atrial (LA) enlargement and dysfunction, but direct comparative data are lacking. Aim of the present study was to perform a comparative analysis of LA remodelling between the two diseases. METHODS AND RESULTS: In this prospective study, a total of 114 patients (31 FD and 83 TTR CA) were included; all of them had left ventricular hypertrophy (LVH), defined as left ventricular (LV) wall thickness ≥ 12 mm. Despite similar degree of LVH, patients with TTR CA showed worse LV systolic and diastolic function. LA maximal volume index was not significantly different between the two groups (p = 0.084), while patients with TTR CA showed larger LA minimal volume index (p = 0.001). Moreover, all phases of LA mechanics were more impaired in the TTR CA group vs FD (reservoir: 6.9[4.2-15.5] vs 19.0[15.5-29.5], p < 0.001). After excluding patients with atrial fibrillation (AF), these differences remained clearly significant. In multivariable regression analyses, LA reservoir strain showed an independent correlation with TTR CA, controlling for demographic characteristics, AF and LV systolic and diastolic performance (p ≤ 0.001), whereas LV global longitudinal strain did not. Finally, among echocardiographic parameters, LA function demonstrated the highest accuracy in discriminating the two diseases. CONCLUSIONS: TTR CA is characterized by a more advanced LA structural and functional remodelling in comparison to patients with FD and similar degree of LVH. The association between TTR CA and LA dysfunction remains consistent after adjustment for potential confounders.

Comparison of Baseline and Post-Nitrate Exercise Testing in Patients with Angina but Non-Obstructed Coronary Arteries with Different Acetylcholine Test Results.

Background: Intracoronary acetylcholine testing may induce epicardial coronary artery spasm (CAS) or coronary microvascular spasm (CMVS) in patients with angina syndromes but non-obstructive coronary artery disease, but their causal role in individual patients is not always clear. In this prospective, observational single-center study, we aimed to assess whether (1) the induction of myocardial ischemia/angina by electrocardiogram (ECG) exercise stress test (EST) differs between patients showing different results in response to acetylcholine testing (i.e., CAS, CMVS, or no spasm); (2) the preventive administration of short-acting nitrates has any different effects on the EST of those patients who showed a positive basal EST. We expected that if exercise-induced angina and/or ischemic ECG changes are related to CAS, they should improve after nitrates administration, whereas they should not significantly improve if they are caused by CMVS. Methods: We enrolled 81 patients with angina syndromes and non-obstructive coronary artery disease, who were divided into three groups according to acetylcholine testing: 40 patients with CAS (CAS-group), 14 with CMVS (CMVS-groups), and 27 with a negative test (NEG-group). All patients underwent a basal EST (B-EST). Patients with a positive B-EST repeated the test 24-48 h later, 5 min after the administration of short-acting nitrates (N-EST). Results: There were no significant differences among the groups in terms of the B-EST results. B-EST was positive in eight (20%) patients in the CAS-group, seven (50%) in the CMVS-group, and six (22%) in the NEG-group (p = 0.076). N-EST, performed in eight, six, and five of these patients, also showed similar results in the three groups. Furthermore, the N-EST results also did not significantly differ compared to B-EST in any group, remaining positive in seven (87.5%), four (66.7%), and four (80%) patients in the CAS-group, CMVS-group, and NEG-group, respectively (p = 0.78). Conclusions: Our data show that patients with angina and non-obstructive coronary artery disease show largely comparable results of the ECG exercise stress test and similar poor effects of short-acting nitrates on abnormal ECG exercise stress test results. On the whole, our findings suggest caution in attributing to the results of Ach testing a definite causal role for the clinical syndrome in individual patients.

Impact on clinical outcome of ventricular arrhythmias in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become a largely used treatment for severe aortic stenosis. There are limited data, however, about predictors of long-term prognosis in this population. In this study, we assessed whether ventricular arrhythmias may predict clinical outcomes in patients undergoing TAVI. METHODS AND RESULTS: We performed a 24 h ECG Holter monitoring in 267 patients who underwent TAVI for severe aortic stenosis within 30 days from a successful procedure. The occurrence of frequent premature ventricular complexes (PVCs; ≥30/h), polymorphic PVCs and nonsustained ventricular tachycardia (NSVT) was obtained for each patient. Clinical outcome was obtained for 228 patients (85%), for an average follow-up of 3.5 years (range 1.0-8.6). Cardiovascular events (CVEs; cardiovascular death or resuscitated cardiac arrest) occurred in 26 patients (11.4%) and 63 patients died (27.6%). Frequent PVCs but not polymorphic PVCs and NSVT were found to be associated with CVEs at univariate analysis. Frequent PVCs were indeed found in 12 patients with (46.2%) and 35 without (17.3%) CVEs [hazard ratio 2.30; 95% confidence interval (CI) 1.03-5.09; P  = 0.04], whereas polymorphic PVCs were found in 11 (42.3%) and 54 (26.7%) patients of the two groups, respectively (hazard ratio 1.44; 95% CI 0.64-3.25; P  = 0.38), and NSVT in 9 (34.6%) and 43 patients of the two groups, respectively (hazard ratio 1.18; 95% CI 0.48-2.87; P  = 0.72). Frequent PVCs, however, were not significantly associated with CVEs at multivariate Cox regression analysis (hazard ratio 1.53; 95% CI 0.37-6.30; P  = 0.56). Both frequent PVCs, polymorphic PVCs and NSVT showed no significant association with mortality. CONCLUSION: In our study, the detection of frequent PVCs at Holter monitoring after TAVI was a predictor of CVEs (cardiovascular death/cardiac arrest), but this association was lost in multivariable analysis.

Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study.

AIMS: Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. METHODS: Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. RESULTS: Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). CONCLUSIONS: There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised.