Changes and prognostic impact of noninvasive myocardial work indices in patients undergoing transcatheter aortic valve implantation.

PURPOSE: The prognostic significance of noninvasive myocardial work (MW) indices in patients undergoing transcatheter aortic valve implantation (TAVI) has not been adequately examined. METHODS: We retrospectively selected 88 consecutive patients (mean age 79.9 ±â€Š6.4 years, 40% males) with severe aortic stenosis scheduled for TAVI enrolled in the EffecTAVI registry. Exclusion criteria were prior valve surgery, atrial fibrillation, and left bundle branch block (LBBB) at baseline. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) were measured by echocardiography at baseline and at 30 days. Accuracy of the noninvasive measures was assessed by invasive evaluation of MW. RESULTS: In the overall population, a significant reduction in GWI (2406 ±â€Š567 vs. 2063 ±â€Š515 mmHg% before and after TAVI respectively, P < 0.001), GCW (2783 ±â€Š616 vs. 2380 ±â€Š495 mmHg%, P < 0.001) and GWW (238 ±â€Š203 vs. 186 ±â€Š135 mmHg%, P = 0.015) was observed at 30 days after TAVI. GWE improved only in patients who did not develop left ventricular dyssynchrony due to new-onset LBBB or pacemaker implantation following TAVI. In a multivariable Cox-regression analysis, GWE after TAVI (hazard ratio 0.892, 95% confidence interval 0.81-0.97; P = 0.011) was the strongest predictor of adverse events (a composite of all-cause death, worsening of dyspnea, or rehospitalization for cardiovascular events) at 1-year follow-up. CONCLUSIONS: TAVI results in significant changes in MW indices, including an early decrease in GWI, GCW and GWW, and an improvement in GWE in patients without left ventricle dyssynchrony. A GWE equal or less than 92% at 30 days is indicative of poor clinical outcomes at 1 year.

Stress echocardiography in heart failure patients: additive value and caveats.

Heart failure (HF) is a clinical syndrome characterized by well-defined signs and symptoms due to structural and/or myocardial functional impairment, resulting in raised intracardiac pressures and/or inadequate cardiac stroke volume at rest or during exercise. This could derive from direct ischemic myocardial injury or other chronic pathological conditions, including valvular heart disease (VHD) and primary myocardial disease. Early identification of HF etiology is essential for accurate diagnosis and initiation of early and appropriate treatment. Thus, the presence of accurate means for early diagnosis of HF symptoms or subclinical phases is fundamental, among which echocardiography being the first line diagnostic investigation. Echocardiography could be performed at rest, to identify overt structural and functional abnormalities or during physical or pharmacological stress, in order to elicit subclinical myocardial function impairment e.g. wall motion abnormalities and raised ventricular filling pressures. Beyond diagnosis of ischemic heart disease, stress echocardiography (SE) has recently shown its unique value for the evaluation of diastolic heart failure, VHD, non-ischemic cardiomyopathies and pulmonary hypertension, with recommendations from international societies in several clinical settings. All these features make SE an important additional tool, not only for diagnostic assessment, but also for prognostic stratification and therapeutic management of patients with HF. In this review, the unique value of SE in the evaluation of HF patients will be described, with the objective to provide an overview of the validated methods for each setting, particularly for HF management.

Echocardiographic and clinical features of patients developing prosthesis-patient mismatch after transcatheter aortic valve replacement: Insights from the Recovery-TAVR registry.

BACKGROUND: The impact of prosthesis-patient mismatch (PPM) on major endpoints after transcatheter aortic valve replacement (TAVR) is controversial and the effects on progression of heart damage are poorly investigated. Therefore, our study aims to evaluate the prevalence and predictors of PPM in a "real world" cohort of patients at intermediate and low surgical risk, its impact on mortality and the clinical-echocardiographic progression of heart damage. METHODS: 963 patients who underwent TAVR procedure between 2017 and 2021, from the RECOVERY-TAVR international multicenter observational registry, were included in this analysis. Multiparametric echocardiographic data of these patients were analyzed at 1-year follow-up (FU). Clinical and echocardiographic features were stratified by presence of PPM and PPM severity, as per the most current international recommendations, using VARC-3 criteria. RESULTS: 18% of patients developed post-TAVR. PPM, and 7.7% of the whole cohort had severe PPM. At baseline, 50.3% of patients with PPM were male (vs 46.2% in the cohort without PPM, P = .33), aged 82 (IQR 79-85y) years vs 82 (IQR 78-86 P = .46), and 55.6% had Balloon-Expandable valves implanted (vs 46.8% of patients without PPM, P = .04); they had smaller left ventricular outflow tract (LVOT) diameter (20 mm, IQR 19-21 vs 20 mm, IQR 20-22, P = .02), reduced SVi (34.2 vs 38 mL/m2, P < .01) and transaortic flow rate (190.6 vs 211 mL/s, P < .01). At predischarge FU patients with PPM had more paravalvular aortic regurgitation (moderate-severe AR 15.8% vs 9.2%, P < .01). At 1-year FU, maladaptive alterations of left ventricular parameters were found in patients with PPM, with a significant increase in end-systolic diameter (33 mm vs 28 mm, P = .03) and a significant increase in left ventricle end systolic indexed volume in those with moderate and severe PPM (52 IQR 42-64 and 52, IQR 41-64 vs 44 IQR 35-59 in those without, P = .02)). No evidence of a significant impact of PPM on overall (P = .71) and CV (P = .70) mortality was observed. Patients with moderate/severe PPM had worse NYHA functional class at 1 year (NYHA III-IV 13% vs 7.8%, P = .03). Prosthesis size≤23 mm (OR 11.6, 1.68-80.1) was an independent predictor of PPM, while SVi (OR 0.87, 0.83-0.91, P < .001) and LVOT diameter (OR 0.79, 0.65-0.95, P = .01) had protective effect. CONCLUSIONS: PPM was observed in 18% of patients undergoing TAVR. Echocardiographic evaluations demonstrated a PPM-related pattern of early ventricular maladaptive alterations, possibly precursor to a reduction in cardiac function, associated with a significant deterioration in NYHA class at 1 year. These findings emphasize the importance of prevention of PPM of any grade in patients undergoing TAVR procedure, especially in populations at risk.

New perspectives in the echocardiographic hemodynamics multiparametric assessment of patients with heart failure.

International Guidelines consider left ventricular ejection fraction (LVEF) as an important parameter to categorize patients with heart failure (HF) and to define recommended treatments in clinical practice. However, LVEF has some technical and clinical limitations, being derived from geometric assumptions and is unable to evaluate intrinsic myocardial function and LV filling pressure (LVFP). Moreover, it has been shown to fail to predict clinical outcome in patients with end-stage HF. The analysis of LV antegrade flow derived from pulsed-wave Doppler (stroke volume index, stroke distance, cardiac output, and cardiac index) and non-invasive evaluation of LVFP have demonstrated some advantages and prognostic implications in HF patients. Speckle tracking echocardiography (STE) is able to unmask intrinsic myocardial systolic dysfunction in HF patients, particularly in those with LV preserved EF, hence allowing analysis of LV, right ventricular and left atrial (LA) intrinsic myocardial function (global peak atrial LS, (PALS)). Global PALS has been proven a reliable index of LVFP which could fill the gaps "gray zone" in the previous Guidelines algorithm for the assessment of LV diastolic dysfunction and LVFP, being added to the latest European Association of Cardiovascular Imaging Consensus document for the use of multimodality imaging in evaluating HFpEF. The aim of this review is to highlight the importance of the hemodynamics multiparametric approach of assessing myocardial function (from LVFP to stroke volume) in patients with HF, thus overcoming the limitations of LVEF.

Role of speckle tracking echocardiography beyond current guidelines in cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is a device-based treatment applied to patients with a specific profile of heart failure. According to current guidelines, indication for CRT is given on the basis of QRS morphology and duration, and traditional transthoracic echocardiography is mainly used to estimate left ventricular (LV) ejection fraction. However, the identification of patients who may benefit from CRT remains challenging, since the application of the above-mentioned guidelines is still associated with a high rate of non-responders. The assessment of various aspects of LV mechanics (including contractile synchrony, coordination and propagation, and myocardial work) performed by conventional and novel ultrasound technologies, first of all speckle tracking echocardiography (STE), may provide additional, useful information for CRT patients' selection, in particular among non-LBBB patients, who generally respond less to CRT. A multiparametric approach, based on the combination of ECG criteria and echocardiographic indices of LV dyssynchrony/discoordination would be desirable to improve the prediction of CRT response.

Arrhythmic mitral valve prolapse: a practical approach for asymptomatic patients.

Mitral valve prolapse (MVP) is usually regarded as a benign condition though the proportion of patients with a life-threatening arrhythmic MVP form remains undefined. Recently, an experts' consensus statement on arrhythmic MVP has proposed approaches for risk stratification across the spectrum of clinical manifestation. However, sudden cardiac death may be the first presentation, making clinicians focused to early unmasking this subset of asymptomatic patients. Growing evidence on the role of cardiac imaging in the in-deep stratification pathway has emerged in the last decade. Pathology findings have suggested the fibrosis of papillary muscles and inferobasal left ventricular wall as the malignant hallmark. Cardiac magnetic resonance, while of limited availability, allows the identification of this arrhythmogenic substrate. Therefore, speckle-tracking echocardiography may be a gateway to prompt referring patients to further advanced imaging investigation. Our review aims to summarize the phenotypic features linked to the arrhythmic risk and to propose an image-based algorithm intended to help stratifying asymptomatic MVP patients.

Exercise Stress Echocardiography in Athletes: Applications, Methodology, and Challenges.

This comprehensive review explores the role of exercise stress echocardiography (ESE) in assessing cardiovascular health in athletes. Athletes often exhibit cardiovascular adaptations because of rigorous physical training, making the differentiation between physiological changes and potential pathological conditions challenging. ESE is a crucial diagnostic tool, offering detailed insights into an athlete's cardiac function, reserve, and possible arrhythmias. This review highlights the methodology of ESE, emphasizing its significance in detecting exercise-induced anomalies and its application in distinguishing between athlete's heart and other cardiovascular diseases. Recent advancements, such as LV global longitudinal strain (GLS) and myocardial work (MW), are introduced as innovative tools for the early detection of latent cardiac dysfunctions. However, the use of ESE also subsumes limitations and possible pitfalls, particularly in interpretation and potential false results, as explained in this article.

Echocardiographic Evaluation of Aortic Stenosis: A Comprehensive Review.

Echocardiography represents the most important diagnostic tool in the evaluation of aortic stenosis. The echocardiographic assessment of its severity should always be performed through a standardized and stepwise approach in order to achieve a comprehensive evaluation. The latest technical innovations in the field of echocardiography have improved diagnostic accuracy, guaranteeing a better and more detailed evaluation of aortic valve anatomy. An early diagnosis is of utmost importance since it shortens treatment delays and improves patient outcomes. Echocardiography plays a key role also in the evaluation of all the structural changes related to aortic stenosis. Detailed evaluation of subtle and subclinical changes in left ventricle function has a prognostic significance: scientific efforts have been addressed to identify the most accurate global longitudinal strain cut-off value able to predict adverse outcomes. Moreover, in recent years the role of artificial intelligence is increasingly emerging as a promising tool able to assist cardiologists in aortic stenosis screening and diagnosis, especially by reducing the rate of aortic stenosis misdiagnosis.

Beyond Aortic Stenosis: Addressing the Challenges of Multivalvular Disease Assessment.

Aortic stenosis (AS) can often coexist with other valvular diseases or be combined with aortic regurgitation (AR), leading to unique pathophysiological conditions. The combination of affected valves can vary widely, resulting in a lack of standardized diagnostic or therapeutic approaches. Echocardiography is crucial in assessing patients with valvular heart disease (VHD), but careful consideration of the hemodynamic interactions between combined valvular defects is necessary. This is important as it may affect the reliability of commonly used echocardiographic parameters, making the diagnosis challenging. Therefore, a multimodality imaging approach, including computed tomography or cardiac magnetic resonance, is often not just beneficial but crucial. It represents the future of diagnostics in this intricate field due to its unprecedented capacity to quantify and comprehend valvular pathology. The absence of definitive data and guidelines for the therapeutic management of AS in the context of multiple valve lesions makes this condition particularly challenging. As a result, an individualized, case-by-case approach is necessary, guided primarily by the recommendations for the predominant valve lesion. This review aims to summarize the pathophysiology of AS in the context of multiple and mixed valve disease, with a focus on the hemodynamic implications, diagnostic challenges, and therapeutic options.

Effects on Right Ventricular Function One Year after COVID-19-Related Pulmonary Embolism.

The aim of this study was to investigate the presence of subclinical cardiac dysfunction in recovered coronavirus disease 2019 (COVID-19) patients, who were stratified according to a previous diagnosis of pulmonary embolism (PE) as a complication of COVID-19 pneumonia. Out of 68 patients with SARS-CoV-2 pneumonia followed up for one year, 44 patients (mean age 58.4 ± 13.3, 70% males) without known cardiopulmonary disease were divided in two groups (PE+ and PE-, each comprising 22 patients) and underwent clinical and transthoracic echocardiographic examination, including right-ventricle global longitudinal strain (RV-GLS), and RV free wall longitudinal strain (RV-FWLS). While no significant differences were found in the left- or right-heart chambers' dimensions between the two study groups, the PE+ patients showed a significant reduction in RV-GLS (-16.4 ± 2.9 vs. -21.6 ± 4.3%, p < 0.001) and RV-FWLS (-18.9 ± 4 vs. -24.6 ± 5.12%, p < 0.001) values compared to the PE- patients. According to the ROC-curve analysis, RV-FWLS < 21% was the best cut-off with which to predict PE diagnosis in patients after SARS-CoV-2 pneumonia (sensitivity 74%, specificity 89%, area under the curve = 0.819, p < 0.001). According to the multivariate logistic regression model, RV-FWLS < 21% was independently associated with PE (HR 34.96, 95% CI:3.24-377.09, p = 0.003) and obesity (HR 10.34, 95% CI:1.05-101.68, p = 0.045). In conclusion, in recovered COVID-19 patients with a history of PE+, there is a persistence of subclinical RV dysfunction one year after the acute phase of the disease, detectable by a significant impairment in RV-GLS and RV-FWLS. A reduction in RV-FWLS of lower than 21% is independently associated with COVID-related PE.

Inter-center reproducibility of standard and advanced echocardiographic parameters in the EACVI-AFib echo registry.

AIM: we sought to test the inter-center reproducibility of 16 echo laboratories involved in the EACVI-Afib Echo Europe. METHODS: This was done on a dedicated setting of 10 patients with sinus rhythm (SR) and 10 with persistent atrial fibrillation (AF), collected by the Principal Investigator. Images and loops of echo-exams were stored and made available for labs. The tested measurements included main echo-Doppler parameters, global longitudinal strain (GLS) and peak atrial longitudinal strain (PALS). RESULTS: Single measures interclass correlation coefficients (ICCs) of left ventricular mass and ejection fraction were suboptimal in both patients with SR and AF. Among diastolic parameters, ICCs of deceleration time were poor, in particular in AF (=.50). ICCs of left atrial size and function, besides optimal in AF, showed an acceptable despite moderate concordance in SR. ICC of GLS was .81 and .78 in SR and AF respectively. ICCs of PALS were suitable but lower in 4-chamber than in 2-chamber view. By depicting the boxplot of the 16 laboratories, GLS distribution was completely homogeneous in SR, whereas GLS of AF and PALS of both SR and AF presented a limited number of outliers. GLS mean ± SE of the 16 labs was 19.7 ± .36 (95% CI: 18.8-20.4) in SR and 16.5 ± .29 (95% CI: 15.9-17.1) in AF, whereas PALS mean ± SE was 43.8 ± .70 (95% CI: 42.3-45.3) and 10.2 ± .32 (95% CI: 9.5-10.9) respectively. CONCLUSION: While the utilization of some standard-echo variables should be discouraged in registries, the application of GLS and PALS could be largely promoted because their superior reproducibility, even in AF.

Echocardiographic Evaluation after Transcatheter Aortic Valve Implantation: A Comprehensive Review.

Transcatheter aortic valve implantation (TAVI) is an increasingly popular treatment option for patients with severe aortic stenosis. Recent advancements in technology and imaging tools have significantly contributed to the success of TAVI procedures. Echocardiography plays a pivotal role in the evaluation of TAVI patients, both before and after the procedure. This review aims to provide an overview of the most recent technical advancements in echocardiography and their use in the follow-up of TAVI patients. In particular, the focus will be on the examination of the influence of TAVI on left and right ventricular function, which is frequently accompanied by other structural and functional alterations. Echocardiography has proven to be key also in detecting valve deterioration during extended follow-up. This review will provide valuable insights into the technical advancements in echocardiography and their role in the follow-up of TAVI patients.

Is There Still a Role for Invasive Assessment of Aortic Gradient?

Advances in technology and imaging have expanded the range of tools for diagnosing aortic stenosis (AS). The accurate assessment of aortic valve area and mean pressure gradient is crucial to determine which patients are appropriate candidates for aortic valve replacement. Nowadays, these values can be obtained noninvasively or invasively, with similar results. Contrariwise, in the past, cardiac catheterization played a major role in the evaluation of AS severity. In this review, we will discuss the historical role of the invasive assessment of AS. Moreover, we will specifically focus on tips and tricks for properly performing cardiac catheterization in patients with AS. We will also elucidate the role of invasive methods in current clinical practice and their additional value to the information provided through non-invasive techniques.

Hemodynamic Performance of Transcatheter Aortic Valves: A Comprehensive Review.

Transcatheter aortic valve implantation (TAVI) is a widely adopted treatment option for patients with severe aortic stenosis. Its popularity has grown significantly in recent years due to advancements in technology and imaging. As TAVI use is increasingly expanded to younger patients, the need for long-term assessment and durability becomes paramount. This review aims to provide an overview of the diagnostic tools to evaluate the hemodynamic performance of aortic prosthesis, with a special focus on the comparison between transcatheter and surgical aortic valves and between self-expandable and balloon-expandable valves. Moreover, the discussion will encompass how cardiovascular imaging can effectively detect long-term structural valve deterioration.

Multimodality imaging in decompensated heart failure.

Heart failure (HF) is usually suspected by clinical history, symptoms, physical examination, electrocardiogram findings, and natriuretic peptides' values. However, echocardiography and other imaging techniques play an essential role in supporting HF diagnosis. Thanks to its non-invasiveness and safety, transthoracic echocardiography is the first-level technique of choice to assess myocardial structure and function, trying to establish the diagnosis of HF with reduced, mildly reduced, and preserved ejection fraction. The role of echocardiography is not limited to diagnosis but it represents a crucial tool in guiding therapeutic decision-making and monitoring response to therapy. Over the last decades, several technological advancements were made in the imaging field, aiming at better understanding the morphofunctional abnormalities occurring in cardiovascular diseases. The purpose of this review article is to summarize the incremental role of imaging techniques (in particular cardiac magnetic resonance and myocardial scintigraphy) in HF, highlighting their essential applications to HF diagnosis and management.

Acute advanced aortic stenosis.

Acute decompensation often represents the onset of symptoms associated with severe degenerative aortic stenosis (AS) and usually complicates the clinical course of the disease with a dismal impact on survival and quality of life. Several factors may derange the faint balance between left ventricular preload and afterload and precipitate the occurrence of symptoms and signs of acute heart failure (HF). A standardized approach for the management of this condition is currently lacking. Medical therapy finds very limited application in this setting, as drugs usually indicated for the control of acute HF might worsen hemodynamics in the presence of AS. Urgent aortic valve replacement is usually performed by transcatheter than surgical approach whereas, over the last decades, percutaneous balloon valvuloplasty gained renewed space as bridge to definitive therapy. This review focuses on the pathophysiological aspects of acute advanced AS and summarizes current evidence on its management.

The efficacy of PCSK9 inhibitors on major cardiovascular events and lipid profile in patients with diabetes: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the specific effects of PCSK9 inhibitors (i.e. alirocumab and evolocumab) on major cardiovascular events (MACE) and lipid profile in patients with diabetes. METHODS AND RESULTS: We conducted a systematic review of literature according to the PRISMA statement. A total of eight randomized control trials (RCTs) enrolling 20 651 patients with diabetes were included. The mean follow-up was 51 weeks. We included RCTs that had compared the subtilisin-kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab with placebo in subjects with hypercholesterolaemia and diabetes mellitus.MACE occurred in 8.7% of patients with diabetes randomized to PCSK9i vs. 11.0% of those randomized to placebo. Thus, the use of alirocumab or evolocumab reduced MACE by 18% [odds ratio (OR): 0.82; 95% confidence interval (CI): 0.74-0.90]. Compared with control group, the use of PCSK9 inhibitors was associated with a significant percentage change from baseline in low-density lipoprotein cholesterol [mean difference (MD) -58.48%; 95% CI: -63.73 to -53.22%, P < 0.0001], high-density lipoprotein cholesterol (HDL-C) (MD 5.21%; 95% CI: 3.26-7.17%), triglycerides (MD -14.59%; 95% CI: -19.42 to -9.76%), non-HDL-C (MD -48.84%; 95% CI: -54.54 to -43.14%), and total cholesterol (MD -33.76%; 95% CI: -38.71 to -28.8%). Moreover, a significant reduction of lipoprotein(a) (MD -32.90%; 95% CI: -38.55 to -27.24%) and apolipoprotein B (MD -46.83%; 95% CI: -52.71 to --40.94%) were observed in PCSK9i group compared with placebo. CONCLUSION: PCSK9i appear to be effective in reducing the risk of MACE and in improving lipid profiles of subjects with diabetes and dyslipidaemia.

Stroke volume index and transvalvular flow rate trajectories in severe aortic stenosis treated with TAVR.

AIMS: The prognostic impact of flow trajectories according to stroke volume index (SVi) and transvalvular flow rate (FR) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) remains poorly assessed. We evaluated and compared SVi and FR prior and after TAVR for severe AS. METHODS AND RESULTS: Patients were categorized according to SVi (<35 mL/m2) and FR (<200 mL/s). The association of pre- and post-TAVR SVi and FR with all-cause mortality up to 3 years was assessed with multivariable Cox regression models. Among 980 patients with pre-TAVR flow assessment, SVi was reduced in 41.3% and FR in 48.1%. Baseline flow status was not an independent mortality predictor [SVi: hazard ratio (HR) 1.22, 95% confidence interval (CI) 0.85-1.82, FR: HR 0.78, 95% CI 0.48-1.27]. Among 731 patients undergoing early (5 days, interquartile range 2-29) post-TAVR flow assessment, SVi recovered in 40.1% and FR in 49.0% patients with baseline low flow. Reduced FR following TAVR was an independent predictor of mortality (HR 1.67, 95% CI 1.02-2.74), whereas SVi was not (HR 0.97, 95% CI 0.53-1.78). Three-year estimated mortality in patients with recovered FR was lower than that in patients with reduced FR (13.3 vs. 37.7% vs, P = 0.003) and similar to that in patients with normal baseline FR (P = 0.317). CONCLUSION: Baseline flow status was not an independent predictor of mid-term mortality among all-comers with severe AS undergoing TAVR. Flow recovery early after TAVR was frequent. Post-TAVR FR, but not SVi, was independently associated with mid-term all-cause mortality. By impacting flow status, AV replacement modifies the association of flow status with outcomes.

Bedside Ultrasound for Hemodynamic Monitoring in Cardiac Intensive Care Unit.

Thanks to the advances in medical therapy and assist devices, the management of patients hospitalized in cardiac intensive care unit (CICU) is becoming increasingly challenging. In fact, Patients in the cardiac intensive care unit are frequently characterized by dynamic and variable diseases, which may evolve into several clinical phenotypes based on underlying etiology and its complexity. Therefore, the use of noninvasive tools in order to provide a personalized approach to these patients, according to their phenotype, may help to optimize the therapeutic strategies towards the underlying etiology. Echocardiography is the most reliable and feasible bedside method to assess cardiac function repeatedly, assisting clinicians not only in characterizing hemodynamic disorders, but also in helping to guide interventions and monitor response to therapies. Beyond basic echocardiographic parameters, its application has been expanded with the introduction of new tools such as lung ultrasound (LUS), the Venous Excess UltraSound (VexUS) grading system, and the assessment of pulmonary hypertension, which is fundamental to guide oxygen therapy. The aim of this review is to provide an overview on the current knowledge about the pathophysiology and echocardiographic evaluation of perfusion and congestion in patients in CICU, and to provide practical indications for the use of echocardiography across clinical phenotypes and new applications in CICU.