The Evolving Phenotypes of Cardiovascular Disease during COVID-19 Pandemic.

COVID-19 pandemic has negatively impacted the management of patients with acute and chronic cardiovascular disease: acute coronary syndrome patients were often not timely reperfused, heart failure patients not adequately followed up and titrated, atrial arrhythmias not efficaciously treated and became chronic. New phenotypes of cardiovascular patients were more and more frequent during COVID-19 pandemic and are expected to be even more frequent in the next future in the new world shaped by the pandemic. We therefore aimed to briefly summarize the main changes in the phenotype of cardiovascular patients in the COVID-19 era, focusing on new clinical challenges and possible therapeutic options.

Atrial paced rhythm and heart rate-dependent worsening of left atrial and ventricular function.

BACKGROUND AND AIM OF THE STUDY: The response to the increase in heart rate (HR) could be characterized by failure in both left ventricular (LV) and left atrial (LA) functions. This study aimed to evaluate the relationship between the increase in paced HR and the changes in LV and LA functions, assessed by two-dimensional speckle tracking analysis. METHODS: In a group of patients with an implantable cardioverter defibrillator (ICD) or pacemaker, the atrial paced rhythm was progressively increased from 60 to 70, from 70 to 80, and from 80 to 90 beats per minute (bpm). For each paced HR, using two-dimensional speckle tracking analysis, LA reservoir (LAr), LA conduit (LAc), LA contraction (LAct), and LV global longitudinal strain (LV-GLS) were evaluated every 10 bpm. RESULTS: Of the 45 patients enrolled, a significant reduction in LAr was observed at higher HR. However, when the patients were dichotomized according to the HR-related response of LV-GLS, the worsening of LAr was observed in those with LV-GLS worsening and not in those without (maximum LAR absolute changes -2.7 ± 7.2% vs. +2.7 ± 7.2%, respectively, p .028). Moreover, the worsening of LA and LV strain measures was associated with an increase in the estimated filling pressures. CONCLUSIONS: In patients with atrial paced rhythm, the increase in HR could be associated with worsening of LA and LV functions, as assessed by two-dimensional speckle tracking analyses. These results offer new data on HR-related atrioventricular function and could be useful for guiding the optimal HR responsiveness of the implanted devices.

Relationship between the strain measures of left atrial function and heart failure worsening.

BACKGROUND: Two-dimensional speckle tracking evaluation (2D-STE) is a useful tool to evaluate the complexity of atrial function by the analysis of the different phases of atrial deformation and by the combination with Doppler measurements of diastolic function. AIM OF THE STUDY: To evaluate the role of the left atrial (LA) strain parameters to predict worsening chronic heart failure (CHF). METHODS: We enrolled outpatients affected by CHF referred to our heart failure unit. Each patient underwent a medical visit, an electrocardiogram (ECG), and an echocardiographic examination. LA function was assessed by 2D-STE. The three phases of LA strain, that is, the reservoir (LAr), the conduit (LAcd), and the contraction (LAct)-were evaluated. Moreover, the ratio between E and LAr (E/LAr) and those between LAr and septal (LAr/Ees), lateral (LAr/Eel), and septal-lateral (LAr/Eem) E/e' were measured. During follow-up, the events related to worsening of heart failure were evaluated. RESULTS: Two hundred eleven patients were enrolled. During a mean follow-up of 14 ± 7 months, 37 patients showed at least one event related to heart failure worsening. At univariate Cox regression analysis, LAr, LAcd, LAct, E/LAr, LAr/Ees, LAr/Eel, and LAr/Eem were all associated with events related to heart failure worsening, but at multivariate regression analyses, only LAr (Hazard Ratio, HR: .95; 95% Confidence Interval, CI: .92-.99; p: .031), LAct (HR: 1.06; 95% CI: 1.01-1.12; p: .027), E/LAr (HR: 1.10; 95%CI: 1.0-1.16; p < .001), LAr/Ees (HR: .57; 95% CI: .37-.87; p: .010), and LAr/Eem (HR: .71; 95% CI: .53-.96; p: .026) remained significantly associated with the events. Finally, in a predictive model including the other relevant echocardiographic parameters LAr < 18%, LAct > -10.0%, LAr/Ees < 1.28, and E/LAr > 3.70 were associated with a statistically significant overall net reclassification improvement. CONCLUSIONS: In CHF patients, the measure of the LA reservoir and contraction by 2D-STE is independently associated with heart failure worsening, but the accuracy in predicting the events is even greater when the reservoir is combined with the Doppler measures of diastolic function.

Stepwise approach for diagnosis and management of Takotsubo syndrome with cardiac imaging tools.

Takotsubo syndrome is featured by transient left ventricle dysfunction in the absence of significant coronary artery disease, mainly triggered by emotional or physical stress. Its clinical presentation is similar to acute coronary syndrome; therefore, cardiac imaging tools have a crucial role. Coronary angiography is mandatory for exclusion of pathological stenosis. On the other side, transthoracic echocardiography is the first non-invasive imaging modality for an early evaluation of left ventricle systolic and diastolic function. Left ventricle morphologic patterns could be identified according to the localization of wall motion abnormalities. Moreover, an early identification of potential mechanical and electrical complications such as left ventricle outflow tract obstruction, mitral regurgitation, thrombus formation, right ventricular involvement, cardiac rupture, and cardiac rhythm disorders could provide additional information for clinical management and therapy. Because of the dynamic evolution of the syndrome, comprehensive serial echocardiographic examinations should be systematically performed. Advanced techniques, including speckle-tracking echocardiography, cardiac magnetic resonance, and nuclear imaging can provide mechanistic and pathophysiologic insights into this syndrome. This review focuses on these aspects and provide a stepwise approach of all cardiac imaging tools for the diagnosis and the management of Takotsubo syndrome.

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure.

PURPOSE: The use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study. METHODS: Twenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up. RESULTS: Three months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p < 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p < 0.001). CONCLUSIONS: Switch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function.

Revascularization rates with coronary angioplasty and mortality in type 2 myocardial infarction: A meta-regression analysis.

BACKGROUND: Percutaneous coronary intervention (PCI) represents the best therapeutic option for type-1 myocardial infarction (T1MI) in the majority of clinical settings; its role in the treatment of type-2 myocardial infarction (T2MI), however, remains unclear. We therefore sought to assess in a meta-regression analysis the impact of PCI rates on mortality in patients with T2MI according to available observational studies. METHODS: We performed a meta-regression analysis including all the studies involving in-patients affected by T2MI. We excluded studies not reporting the rate of T2MI patients undergoing PCI and not specifying absolute in-hospital or 1-year all-cause mortality. In the meta-regression analysis we used the in-hospital mortality and 1-year mortality as dependent variables and the rate of PCI as independent; regression was weighted for studies' size. RESULTS: After careful examination, 8 studies were selected for the assessment of in-hospital mortality and 8 for 1-year-mortality. We included 3155 and 3756 in-patients for in-hospital and 1-year mortality respectively. At meta-regression analysis, a borderline correlation between PCI rate and in-hospital mortality (p 0.05) and a statistically significant correlation with 1-year mortality (p < 0.01) in T2MI patients were found. CONCLUSIONS: In a meta-regression analysis higher rates of PCI on T2MI in-patients were associated with lower mortality rates both in-hospital and at 1 year. Whether this association is related to the direct effect of PCI or better general conditions of T2MI patients undergoing a PCI still remains unclear.

Delirium in heart failure.

Despite relative frequency of delirium in elderly hospitalized heart failure patients, skills and expertise in managing such complication are usually poor for physicians and nurses facing this clinical condition. International guidelines on heart failure do not provide detailed indication for such clinical condition, and evidence on this topic is limited. A multi-disciplinary approach (cardiologists, internists, geriatricians, psychologists, and psychiatrists) is often required; this review will therefore focus on diagnosis and clinical management of delirium in heart failure patients from a multidisciplinary point of view.

Lower Major Bleeding Rates with Direct Oral Anticoagulants in Catheter Ablation of Atrial Fibrillation: an Updated Meta-analysis of Randomized Controlled Studies.

INTRODUCTION: Catheter ablation (CA) of atrial fibrillation (AF) is an important rhythm control strategy for patients with drug-refractory AF. We aimed to perform an updated meta-analysis of direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs) as uninterrupted anticoagulation in patients undergoing AF ablation to assess safety and efficacy of DOAC, after the publication of recent data on edoxaban in CA of AF. METHODS: We performed a meta-analysis of RCTs enrolling patients undergoing AF ablation. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for thromboembolic events, major bleeding (MB), and non-major bleeding (NMB). RESULTS: A total of 2118 patients have been included in the analysis. Compared with patients receiving VKA, patients receiving DOACs had a lower, although non-significant, risk of thromboembolic events (RR, 0.40; 95% CI, 0.09-1.76; P = 0.23). MB rates in patients treated with DOACs were statistically significantly lower than VKA (RR, 0.61; 95% CI, 0.39-0.93, P = 0.02). The incidence of NMB was not significantly different (RR, 0.98; 95% CI, 0.83-1.57, p n.s.). CONCLUSIONS: In a meta-analysis of RCTs, an uninterrupted DOACs strategy for CA of AF appears to be superior to uninterrupted VKA in terms of safety; a non-significant trend favoring DOACs in terms of efficacy is also evident.

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.

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.

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.

Advanced heart failure: non-pharmacological approach.

Patients with advanced heart failure have poor prognosis despite traditional pharmacological therapies. The early identification of these subjects would allow them to be addressed on time in dedicated centers to select patients eligible for heart transplantation or ventricular assistance. In this article we will report the current management of these patients based on latest international guidelines, underlining some critical aspects, with reference to future perspectives.

Drug-Induced Pulmonary Arterial Hypertension: Mechanisms and Clinical Management.

Pulmonary arterial hypertension is a rare disease, with drug-induced causes even more uncommon, accounting for only 10% of cases in large registry series. Predisposing factors for drug-induced PAH have not been completely defined. This review summarizes drugs with definite, possible, or likely association to pulmonary hypertension and possible mechanisms involved in the occurrence of pulmonary hypertension. Controversies on mechanisms and on their role in pathophysiology were also shown. The possible synergism between drug abuse and HIV was discussed and the possible interactions of antiretroviral therapy in HIV subjects were analyzed. Furthermore, we reported clinical findings and possible management, specific for each class of drugs, in case of drug-induced PAH. Finally, we summarized into a unified algorithm possible management of drug-induced PAH.

Double de novo mutations in dilated cardiomyopathy with cardiac arrest.

Here we report the identification of two novel mutations in a previously asymptomatic young man who suffered an out-of-hospital sudden cardiac arrest. During following evaluation, diagnosis of early stage dilated cardiomyopathy was established, while electrocardiogram monitoring showed frequent complex ventricular arrhythmias, incomplete right bundle branch block and prolonged QT duration. No reversible causes explaining the clinical presentation were established and an automatic implantable cardioverter defibrillator was therefore implanted. Heterozygous mutations in human protein coding genes NKX2-5 and RBM20 are associated with a wide array of pathological phenotypes some of which are sudden cardiac death, unexplained syncope and either combined or isolated congenital heart diseases such as dilated cardiomyopathy.

Redefining biomarkers in heart failure.

Heart failure (HF) is the end result of many different cardiac and non-cardiac abnormalities leading to a complex clinical entity. In this view, the use of biomarkers in HF should be deeply reconsidered; indeed, the same biomarker may carry a different significance in patients with preserved or reduced EF. The aim of this review is to reconsider the role of biomarkers in HF, based on the different clinical characteristics of this syndrome. The role of cardiac and non-cardiac biomarkers will be reviewed with respect of the different clinical manifestations of this syndrome.

Hyperacute Hemodynamic Effects of BiPAP Noninvasive Ventilation in Patients With Acute Heart Failure and Left Ventricular Systolic Dysfunction in Emergency Department.

BACKGROUND: Acute heart failure (AHF) is one of the leading causes of admission to emergency department (ED); severe hypoxemic AHF may be treated with noninvasive ventilation (NIV). Despite the demonstrated clinical efficacy of NIV in relieving symptoms of AHF, less is known about the hyperacute effects of bilevel positive airway pressure (BiPAP) ventilation on hemodynamics of patients admitted to ED for AHF. We therefore aimed to assess the effect of BiPAP ventilation on principal hemodynamic, respiratory, pulse oximetry, and microcirculation indexes in patients admitted to ED for AHF, needing NIV. METHODS: Twenty consecutive patients admitted to ED for AHF and left ventricular systolic dysfunction, needing NIV, were enrolled in the study; all patients were treated with NIV in BiPAP mode. The following parameters were measured at admission to ED (T0, baseline before treatment), 3 hours after admission and initiation of BiPAP NIV (T1), and after 6 hours (T2): arterial blood oxygenation (pH, partial pressure of oxygen in the alveoli/fraction of inspired oxygen ratio, Paco2, lactate concentration, HCO3-), hemodynamics (tricuspid annular plane systolic excursion, transpulmonary gradient, transaortic gradient, inferior vena cava diameter, brain natriuretic peptide [BNP] levels), microcirculation perfusion (end-tidal CO2 [etco2], peripheral venous oxygen saturation [SpvO2]). RESULTS: All evaluated indexes significantly improved over time (analysis of variance, P < .001 in quite all cases.). CONCLUSIONS: The BiPAP NIV may rapidly ameliorate several hemodynamic, arterial blood gas, and microcirculation indexes in patients with AHF and left ventricular systolic dysfunction.

Direct oral anti-coagulants compared to vitamin-K antagonists in cardioversion of atrial fibrillation: an updated meta-analysis.

Pharmacological or electrical cardioversion allows immediate symptoms improvement in the setting of paroxysmal or persistent atrial fibrillation (AF), although the periprocedural risk of systemic embolism should be considered. Recently, there was a great interest on the safety and efficacy of direct oral anticoagulants (DOACs) when used for the cardioversion of non-valvular AF. We performed a random-effects meta-analysis of patients undergoing both electrical and pharmacologic cardioversion for non-valvular AF in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48, X-VeRT, ENSURE-AF, and EMANATE trials. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for stroke/systemic embolism (SSE) and major bleeding (MB) at follow-up. A total of 8564 patients have been included in the analysis. When compared with patients receiving vitamin-K antagonists (VKAs), patients receiving DOACs had a lower risk of SSE (RR 0.70, 95% CI 0.33-1.546, P = 0.34), as well as of MB (RR 0.86;,95% CI 0.47-1.58, P = 0.62), although both were non-significant. Funnel plot analysis showed, however, lower RRs with more recent ad hoc studies in comparison with registrational studies, even though statistical significance was not reached. DOACs are as effective and as safe as VKAs for thromboembolic prevention in non-valvular AF in the setting of cardioversion. There are differences, although non-significant, between registrational studies and studies enrolling exclusively patients undergoing cardioversion of AF.

"Lambda-wave" ST-elevation is associated with severe prognosis in stress (takotsubo) cardiomyopathy.

BACKGROUND: Persistent ST-segment elevation in acute coronary syndrome is associated with both short and long-term complications. By contrast, there is limited information about ST-elevation and its evolution during takotsubo (stress) cardiomyopathy (TTC). AIM: To evaluate whether persistent downsloping ST-elevation in the early stages of TTC might correlate with short and long-term clinical events. METHODS: One-hundred fifty-eight consecutive subjects with TTC were prospectively enrolled and assessed by electrocardiogram. Patients were classified in two groups according to the presence of downsloping ST-elevation ≥5 mm lasting at least 24 hr ("lambda-wave" ST-elevation group vs. without downsloping ST-elevation) in at least one/two contiguous leads. RESULTS: Five (3.2%) patients, all female with a mean left ventricular ejection fraction 32 ± 5%, were included in the lambda-wave ST-elevation group. These patients were characterized by a higher prevalence of physical stressor (100% vs. 49%, p = 0.04) and higher admission and peak levels of troponin-I levels during hospitalization. Peak of ST-elevation in the lambda-wave ST-elevation group was reached 6 hr after admission and gradually decreased after 24 hr. In-hospital complications were observed in all the patients presenting lambda ST-elevation (100% vs. 23%, p = 0.03, OR: 29.1, p = 0.04); one patient presented endoventricular thrombosis and two died of cardiogenic shock. At long-term follow-up (mean 443 days), adverse events were observed in 80% of patients with lambda-wave ST-elevation (RR of adverse events at follow-up 32, p < 0.01). CONCLUSION: Persistent downsloping lambda-wave ST-elevation during the acute phase of stress cardiomyopathy may be associated with a higher risk of adverse events at short and long-term follow-up.

Cardiopulmonary exercise test predicts right heart catheterization.

BACKGROUND: Right heart catheterization (RHC) is usually required to confirm the diagnosis of pulmonary artery hypertension (PAH). As an invasive test, RHC may be associated with possible complications, so noninvasive parameters able to predict PAH at RHC would be extremely useful. AIM: To ascertain possible correlations between cardiopulmonary exercise testing (CPET) and hemodynamic parameters at RHC indicative of pulmonary hypertension (PH). METHODS: Thirty-six consecutive outpatients with suspect of PAH underwent CPET and RHC; the intercept of ventilation (VEint) on the VE vs carbon dioxide production (VE/VCO2 ) and VE/VCO2 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 assessed and compared. RESULTS: Ventilation VCO2 slope was directly related to DPG (r: .41, P: .019), TPG (r: .45, P: .01), mean pulmonary arterial pressure (mPAP, r: .36, P: .031), PVR (r: .41, P: .029), VEint and VE/VCO2 slope inversely related to DPG (r: -.63, P < .001), TPG (r: -.67, P < .001), mPAP (r: -.68, P < .001) and PVR (r: -.5, P < .001). CONCLUSION: In patients with suspected PAH, VEint during exercise and the VE/VCO2 slope might provide useful information to predict results of RHC. Their correlations with PVR and with DPG may be helpful in discriminating patients with isolated postcapillary PH from those with combined postcapillary and precapillary.

Left Atrial Appendage Closure Guided by 3D Printed Cardiac Reconstruction: Emerging Directions and Future Trends.

INTRODUCTION: Percutaneous left atrial appendage (LAA) occlusion has emerged as an alternative therapeutic approach to medical therapy for stroke prevention in patients with atrial fibrillation. 3D printing is a novel technology able to create a patient specific model of any given anatomical portion of the heart. RESULTS: Herein we report the first 2 cases of LAA occlusion procedure with 2 different systems, the Wave Crest device (Coherex Medical, Inc., USA) and the Amplatzer Amulet device (St. Jude Medical, St. Paul, MN, USA), in which a 3D printed LAA model (Care Tronik, Prato, Italy) was used in a rehearse phase. Both patients had history of paroxysmal AF and previous transient ischemic attack (TIA) occurred during oral anticoagulation with correct INR. In the first patient the occlusive device was positioned within the LAA after a rehearse occlusion using the 3D printed LAA plus a 27 mm Coherex Wavecrest device, demonstrating a good compression and sealing, particularly considering a proximal lobe of the appendage. In the second patient an attempt with the 27 mm Amulet device delivered within the 3D printed LAA, based on angiography and transesophageal echocardiographic (TEE), revealed insufficient covering of the proximal part of LAA vestibule; the device was released only after a second test with the 31 mm Amulet demonstrating a good sealing. CONCLUSION: These 2 cases demonstrated that 3D model could help in finding the correct position within LAA, sizing the device and guiding the choice of the closure device despite the measurements provided by angiography and TEE.