Collinearity and Dimensionality Reduction in Radiomics: Effect of Preprocessing Parameters in Hypertrophic Cardiomyopathy Magnetic Resonance T1 and T2 Mapping.

Radiomics and artificial intelligence have the potential to become a valuable tool in clinical applications. Frequently, radiomic analyses through machine learning methods present issues caused by high dimensionality and multicollinearity, and redundant radiomic features are usually removed based on correlation analysis. We assessed the effect of preprocessing-in terms of voxel size resampling, discretization, and filtering-on correlation-based dimensionality reduction in radiomic features from cardiac T1 and T2 maps of patients with hypertrophic cardiomyopathy. For different combinations of preprocessing parameters, we performed a dimensionality reduction of radiomic features based on either Pearson's or Spearman's correlation coefficient, followed by the computation of the stability index. With varying resampling voxel size and discretization bin width, for both T1 and T2 maps, Pearson's and Spearman's dimensionality reduction produced a slightly different percentage of remaining radiomic features, with a relatively high stability index. For different filters, the remaining features' stability was instead relatively low. Overall, the percentage of eliminated radiomic features through correlation-based dimensionality reduction was more dependent on resampling voxel size and discretization bin width for textural features than for shape or first-order features. Notably, correlation-based dimensionality reduction was less sensitive to preprocessing when considering radiomic features from T2 compared with T1 maps.

Image resampling and discretization effect on the estimate of myocardial radiomic features from T1 and T2 mapping in hypertrophic cardiomyopathy.

Radiomics is emerging as a promising and useful tool in cardiac magnetic resonance (CMR) imaging applications. Accordingly, the purpose of this study was to investigate, for the first time, the effect of image resampling/discretization and filtering on radiomic features estimation from quantitative CMR T1 and T2 mapping. Specifically, T1 and T2 maps of 26 patients with hypertrophic cardiomyopathy (HCM) were used to estimate 98 radiomic features for 7 different resampling voxel sizes (at fixed bin width), 9 different bin widths (at fixed resampling voxel size), and 7 different spatial filters (at fixed resampling voxel size/bin width). While we found a remarkable dependence of myocardial radiomic features from T1 and T2 mapping on image filters, many radiomic features showed a limited sensitivity to resampling voxel size/bin width, in terms of intraclass correlation coefficient (> 0.75) and coefficient of variation (< 30%). The estimate of most textural radiomic features showed a linear significant (p < 0.05) correlation with resampling voxel size/bin width. Overall, radiomic features from T2 maps have proven to be less sensitive to image preprocessing than those from T1 maps, especially when varying bin width. Our results might corroborate the potential of radiomics from T1/T2 mapping in HCM and hopefully in other myocardial diseases.

Case Series: Recovery of Chemotherapy-Related Acute Heart Failure by the Combined Use of Sacubitril Valsartan and Wearable Cardioverter Defibrillator: A Novel Winning Combination in Cardio-Oncology.

Effective anticancer treatments have dramatically improved the outcome of patients with cancer, but cardiac toxicity reduces their clinical efficacy in a non-negligible percentage of patients. Sacubitril/valsartan is a new paradigm in the treatment of chronic heart failure, with a reduced ejection fraction due to the enhancement of natriuretic peptides' properties when coupled with a blocking effect on the angiotensin II type 1 (AT1) receptors. As with other clinical conditions of heart failure with potentially reversible declines in cardiac function, a wearable cardioverter defibrillator (WCD) is a valid tool for protection against sudden death until recovery occurs. We report a case series of four patients with chemotherapy-related acute cardiac failure with severely reduced cardiac function. They were successfully treated with sacubitril/valsartan while being protected from malignant arrhythmias using a wearable cardioverter defibrillator until the recovery of cardiac function. Sacubitril/valsartan was confirmed to be effective in anthracycline-related cardiac toxicity and the wearable cardioverter defibrillator should be considered as a support tool even in the oncology patient.

Epidemiology and pathophysiologic insights of coronary atherosclerosis relevant for contemporary non-invasive imaging.

In the past few years significant changes have taken place in the diagnostic and therapeutic approach to patients with coronary artery disease (CAD) and/or ischemic heart disease (IHD). New discoveries about the development and progression of coronary atherosclerosis have changed the clinical landscape. At the same time a marked decrease in cardiovascular (CV) mortality and CAD incidence have been observed in many Countries but particularly in the most industrialized ones. This fall has been also observed in the incidence of stroke, sudden death, myocardial ischemia, myocardial infarction (MI), and prevalence of CAD. As a consequence, an increasing number of patients with chest pain exhibits non-significant stenosis at both invasive and non-invasive coronary angiography and the rate of coronary vessels revascularizations has greatly reduced. Coronary atherosclerosis and its characteristics have shown to be both diagnostic and therapeutic targets beyond obstructive CAD. The decreased prevalence of CAD in the general population has modified the pre-test probability (PTP) of disease. In this landscape the conventional stress imaging tests appear to have limited accuracy making the diagnosis of obstructive CAD very challenging. These diagnostic tests have been introduced and tested in a population with a much higher probability of disease and therefore the contemporary accuracy of these old tests appear much lower than in the past. In addition, in the past few years the relevance of the traditional ischemia guided coronary intervention strategy has been questioned. Given the low CV events granted by an optimal medical therapy in CAD the major attention has been directed on detecting coronary atherosclerosis. The earlier the better. At the same time, a growing number of data from clinical studies have shown a significant prognostic role for non-obstructive CAD and coronary atherosclerosis. All these facts have shifted the clinicians' attention from the functional evaluation of the coronary circulation to the anatomic burden of disease.

Incidence of Pericardial Effusion in Patients with Advanced Non-Small Cell Lung Cancer Receiving Immunotherapy.

INTRODUCTION: Cardiovascular toxicity of immunotherapy represents an underreported but potentially fatal side effect. A relatively high incidence of pericardial disease has been noticed in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed a population of patients with advanced NSCLC receiving immune checkpoint inhibitors (ICIs) looking for the presence of pericardial effusion at baseline or during treatment. The study population was compared with a control group treated with chemotherapy. All patients were checked for the presence of concomitant pleural effusion. RESULTS: We identify 60 patients (36 male/24 female, median age 70 years [range 43-81]). Prevalent histology was adenocarcinoma (65%) followed by squamous cell carcinoma (28%) and large cell or not otherwise specified (NOS) carcinoma (7%). Treatment consisted of nivolumab 3 mg/kg every 14 days (52 cases; 45 as second-line and 7 as third-line treatment) or pembrolizumab 200 mg (8 cases; all first-line treatment) for a total of 302 cycles delivered. Four out of 60 patients (6.7%) developed pericardial effusion during treatment, in two cases (3.3%) without concomitant pleural effusion, compared to 2 out of 60 (3.3%) in the control group in one case without concomitant pleural effusion (1.6%). Median time of onset was 40 days. Myocarditis was not observed. CONCLUSION: Our findings confirm pericardial effusion as a relatively frequent side effect of immunotherapy in NSCLC. Clinicians should be aware of this specific toxicity in patients with metastatic NSCLC receiving immunotherapy and refer to a cardiologist for a multidisciplinary approach.

Cardiovascular Risk Factors and Timing of Anthracyclines and Trastuzumab Cardiac Toxicity.

BACKGROUND/AIM: Cardiovascular risk factors (CVRFs) predict cardiotoxicity in cancer patients but their role in late cardiac toxicity is less clear. PATIENTS AND METHODS: This was a retrospective analysis of patients treated with anthracyclines (A) and/or trastuzumab (T) and a correlation with early (≤5 years) or late (>5 years) cardiac toxicity, and baseline CVRFs and CVRFs at toxicity time. RESULTS: A total of 610 patients were included, 422 with (Group A) and 188 without (Group B) baseline CVRFs. In group A toxicity incidence was 4.7% with all events during treatment or immediately after [mean onset time 0.7 years (range=0.2-1.6)]. Events rate was 3.2% in group B with all events after five years [mean time onset 6.9 years (range=5.2-7.5)]. All group B patients who developed late cardiac toxicity presented with CVRFs at the time of toxicity not reported before. CONCLUSION: CVRFs could predict late cardiac toxicity and their control should be part of the survivorship program.

Diagnostic and Prognostic Role of Cardiac Magnetic Resonance Before Implantable Cardioverter Defibrillator.

The use of cardiac magnetic resonance (cMR) to assess remodeling and tissue characterization in primitive and secondary cardiomyopathies has progressively increased, and it carries important prognostic informations. The aim of this study was to assess the overall clinical value of cMR before implantable cardioverter defibrillator (ICD). All patients referred to our center for an ICD implantation and submitted to cMR (n = 134) were analyzed. All the cMR diagnostic findings and following clinical events were reviewed to assess clinical relevance in patients care. The use of cMR before ICD implantation has progressively increased during the decade studied (13% to 53%, p <0.001). Subjects who underwent cMR were younger, more often female, with lower NYHA class and higher ejection fraction (p <0.05 for all). Unexpected diagnostic findings were observed in 34 patients (25%), resulting in an immediate therapeutic strategy modification in 13%. A pattern of fibrosis leading to a change in the disease's etiology and thrombus detection were the most frequent cMR findings, followed by anatomical incidental findings. Any grade of fibrosis carried a higher annual incidence of combined death or ventricular arrhythmias (9.92% vs 1.83%, p = 0.02). Annual event rate was related to the extent of scarring. In conclusion, we observed a progressively increase of cMR utilization before ICD implantation during the last decade. This practice has yielded a significant increase of new diagnostic findings, carrying unique prognostic information linked to tissue characterization.

T1 and T2 mapping in the identification of acute myocardial injury in patients with NSTEMI.

AIMS: To test T1 and T2 mapping in the assessment of acute myocardial injury in patients with non-ST-segment elevation myocardial infarction (NSTEMI), evaluated before revascularization. METHODS: Forty-seven patients with acute NSTEMI underwent cardiac magnetic resonance (CMR) at 1.5 T, including T1 and T2 mapping. RESULTS: Coronary angiography (CA) evidenced an obstructive coronary artery disease (CAD) in 36 patients (80%) and a non-obstructive CAD in 11 patients (20%). Edema was detected in 51.1/65.9% of patients in T1/T2 maps, respectively. This difference was due to artifacts in T1 maps. T1/T2 values were significantly higher in the infarcted myocardium (IM) compared with the remote myocardium (RM) (in T1: 1151.6 ± 53.5 ms vs. 958.2 ± 38.6 ms, respectively; in T2: 69 ± 6 ms vs. 51.9 ± 2.9 ms, respectively; p < 0.0001 for both). We found both an obstructive CAD at CA and myocardial edema at CMR in 53.2% of patients, while 8.5% of patients had a non-obstructive CAD and no edema. However, 25.5% of patients had an obstructive CAD without edema, while 12.8% of patients showed edema despite a non-obstructive CAD. Furthermore, in 6 of the edema-positive patients with multi-vessels obstructive CAD, CMR identified myocardial edema in a vascular territory different from that of the lesion supposed to be the culprit at CA. CONCLUSIONS: In a non-negligible percentage of NSTEMI patients, T1 and T2 mapping detect myocardial edema without significant stenosis at CA and vice versa. Therefore, CA and CMR edema imaging might provide complementary information in the evaluation of NSTEMI.

[Application of a shared interdisciplinary and multiprofessional cardio-oncology in-hospital pathway]. / Applicazione di un percorso diagnostico-terapeutico assistenziale di cardioncologia per la rilevazione e la gestione del danno cardiaco da trattamenti oncologici in ambito ospedaliero.

The burden of cardiac side effects in oncology patients will dramatically increase in the near future as a result of the widespread use of anticancer agents affecting the cardiovascular system, the general population aging, the heightened attention in the detection of cardiac toxicity and the absolute gain in terms of overall survival. The relationship between cardiologists and oncologists should therefore be closer leading to the definition of cardio-oncology. The increased number of such patients requires the creation of a dedicated patient assistance program in order to guarantee every patient the possibility of an interdisciplinary and multiprofessional approach. A dedicated care pathway needs a reorganization of internal resources to ensure high standards of care. The proposed pathway is actually active at our institution and has been implemented taking into account available facilities and planned work amount. Our patient cardio-oncology program could be adapted with minimal changes to different hospitals.

[Teamwork for cardiac imaging: coronary computed tomography angiography and low-dose radiation exposure: a cardiology center experience]. / Teamwork per l'imaging cardiaco: tomografia computerizzata coronarica e bassa dose di esposizione radiologica, esperienza di un centro cardiologico.

BACKGROUND: Multidetector coronary computed tomography angiography (CCTA) is increasingly used for noninvasive imaging of the coronary arteries. Radiation exposure, however, is a potential limitation to a more extensive use of this imaging modality. We aimed to demonstrate that a professional teamwork approach, including a cardiologist and a radiologist in performing CCTA, may allow to obtain best quality exams with very low radiation doses. METHODS: A total of 998 consecutive patients underwent CCTA in accordance with the most recent guidelines. The following procedures were undertaken to reduce the radiation dose: (a) preliminary cardiological evaluation to check for CCTA eligibility; (b) optimized heart rate control with beta-blockers and/or ivabradine; and (c) the use of nonstandardized computed tomography protocols and algorithms for dose reduction. RESULTS: All the patients underwent a preliminary cardiological evaluation; 89% of them were pretreated with oral or intravenous beta-blockers and/or ivabradine; 806 patients (81%) were scanned by means of prospective gating, which allowed a radiation dose exposure of 161 ± 68.64 mGy; 192 patients (19%) underwent a retrospective gating protocol, with a radiation dose exposure of 1135.15 ± 485.87 mGy. In 13 patients (1%) CCTA was uninterpretable because of artifacts. Exam quality was not affected by the use of low-dose computed tomography scanning. Coronary calcium score and/or left ventricular functional analysis were never performed. CONCLUSIONS: The preliminary selection and preparation of patients and optimized scanner utilization allow a substantial reduction in radiation dose for most of the patients submitted to CCTA without affecting image quality. In our experience, a team approach was necessary to allow a "low-dose learning curve" and a progressive reduction in radiation doses administered to patients by means of the prospective gating protocol.

Simultaneous strain-volume analysis by three-dimensional echocardiography: validation in normal subjects with tagging cardiac magnetic resonance.

OBJECTIVE: The aim of this study is to compare three-dimensional echocardiography strain-volume analysis with tagging cardiac magnetic resonance (cMR) measurements. BACKGROUND AND METHODS: Strain-volume analysis represents a noninvasive method to assess myocardial function and volumes simultaneously. It can be derived from echocardiography and speckle-tracking; however, it shows some variability that can limit clinical utilization. A three-dimensional approach partially overcomes these limitations since full-volume acquisition avoids images being foreshortened and geometrical reconstruction. In the study presented here, 23 healthy subjects were studied by three-dimensional echocardiography and cMR during the same session. Images were stored and the better cardiac cycle was chosen for simultaneous analysis of volumes and longitudinal (Long) and circumferential (Circ) strain. By means of full-volume acquisition all parameters can be calculated for each frame of the cardiac cycle using the speckle-tracking method. With cMR, left ventricle volumes were calculated as recommended; myocardial strains were computed in short-axis and long-axis views using the tagging technique. For each patient, volumes and strain values were plotted in a Cartesian system for strain-volume analysis. Data were compared between the two methods using Bland-Altman analysis based on mean difference and 95% limits of agreement (LoA). RESULTS: The volume as measured by three-dimensional echocardiography and cMR was comparable with the slightly higher end-diastolic volumes measured by cMR (mean difference 15.24 ml; LoA -53.6 to 26.5 ml, end-systolic volume 0.3 ml; LoA -19.9 to 20.5 ml). Long shortening was very similar in the two methods (1.5%; LoA -3.9 to 7%), whereas Circ strain was systematically lower with cMR (-8.5%; LoA -15.5 to -1.5%). Very similar values between three-dimensional echo and cMR both for Slope of strain-volume curves (-0.015; LoA -0.08 to 0.05) and ratio (-0.001; LoA -0.04 to 0.04) were observed in the longitudinal plane. Analysis of strain-volume per patient showed a significant correlation coefficient between techniques for both Long Slope (r = 0.65; P = 0.001) and Long Ratio (r = 0.70; P = 0.001). CONCLUSION: Longitudinal strain-volume analysis performed with three-dimensional speckle-tracking echocardiography is closely comparable with cMR, which is usually considered the gold standard for volume and function assessment.

[Prevalence of cardiac and extracardiac incidental findings in the evaluation of coronary artery disease by multidetector computed tomography]. / Prevalenza di reperti occasionali cardiaci ed extracardiaci nella valutazione delle coronarie con tomografia computerizzata multidetettore.

BACKGROUND: With the widespread use of multidetector computed tomography (MDCT) coronary angiography, cardiac and extracardiac incidental findings in cardiac imaging might be detected. The aim of this study was to determine the prevalence of cardiac and extracardiac incidental findings in a population of consecutive patients undergoing coronary MDCT. METHODS: A total of 840 consecutive patients with known or suspected heart disease underwent cardiac MDCT. All patients were assessed with 64-slice MDCT; the examination was performed by limiting the anatomical region examined between the bifurcation of the trachea and the cardiac apex with the aim of obtaining excellent image quality and low cardiac radiological exposure. RESULTS: Overall, 81 incidental findings in 72 patients (9%) were identified, of which 18 were cardiac (2%) and 63 extracardiac (7%). Extracardiac incidental findings were mainly represented by pulmonary nodules (19%). CONCLUSIONS: A significant number of cardiac and extracardiac incidental findings were observed at cardiac MDCT, with the prevalence depending on technical aspects of image acquisition and patient characteristics. Incidental findings should be carefully searched for and reported because they may have an impact on clinical follow-up indications that is not without cost and risk.

Myocardial T1 and T2 mapping in diastolic and systolic phase.

The aim of this study was to evaluate the regional (i.e. myocardial segments) variability as well as the overall image quality of cardiac T1 and T2 maps obtained in diastole and in systole. In 22 healthy subjects (group-1), diastolic T1 and T2 maps were obtained at 1.5 T in short-axis view at basal, mid-ventricular and apical level, as well as in 4-chamber (4 ch) and in 2-chamber (2 ch) views. In another group of 25 patients (group-2), the maps were obtained in both diastole and systole. In the group-1, 15.4% of myocardial segments in T1 maps and 0.8% of myocardial segments in T2 maps, mainly located at apical level, showed relevant artifacts and/or partial-volume effect and had to be discarded. We found no significant difference in T1 values among basal, mid-ventricular and apical segments. T2 values at apical level were significantly higher than at basal and mid-ventricular level (short-axis, p < 0.0001; 4 ch, p < 0.009; 2 ch, p = 0.0002 at ANOVA tests). In the group-2, 21.1%/5.3% and 4.0%/0.8% of segments showed relevant artifacts in diastolic/systolic T1 and T2 maps, respectively. Apical T2 values were significantly lower in systole than in diastole. In systole, there were no significant differences in T1/T2 among basal, mid-ventricular and apical segments. The overall quality of T1 and T2 maps drops in apical segments. This could be problematic when evaluating focal myocardial changes. The acquisition in systole increases the number of evaluable segments.

[T1 and T2 mapping: new perspectives in cardiac magnetic resonance imaging]. / T1 e T2 mapping: nuove prospettive in risonanza magnetica cardiaca.

Cardiac magnetic resonance (MR) imaging is currently considered the gold standard for characterizing changes in myocardial structure, in particular to assess myocardial edema and focal fibrosis. In spite of this potential capability, the traditional MR sequences usually employed for these purposes have significant limitations and provide only qualitative information. Recent developments in cardiac MR imaging techniques currently provide clinically-feasible mapping of T1 and T2 relaxation times, thus providing a quantitative assessment of the parameters of interest. Myocardial edema can be evaluated using T2 mapping techniques. These have shown a superior performance compared to the traditional T2-weighted and STIR sequences, both in acute inflammatory cardiomyopathies and in acute ischemic injury. T1 mapping techniques, performed both with and without contrast medium, enable to quantify diffuse myocardial fibrosis and to assess myocardial edema and infiltration. This article will review current methodologies for cardiac T1 and T2 parametric mapping and their potential and limitations in the assessment of myocardial damage.

Left ventricular rotation and twist assessed by four-dimensional speckle tracking echocardiography in healthy subjects and pathological remodeling: a single center experience.

BACKGROUND: Left ventricular (LV) twist represents a main aspect of ejection. It is defined as the difference between the apical and basal rotation and can be assessed by speckle tracking echocardiography (STE). Twist may be underestimated when assessed by two-dimensional-echocardiography due to the difficulty of identifying the real apex. Aim of this study was to evaluate the LV twist by means of three-dimensional (3D)-STE and verify if the inclusion of the apex can modify the assessment of the global twist. METHODS: LV volume acquisition with a fully sampled matrix array transducer was performed in 30 healthy subjects and 79 patients with cardiomyopathy secondary to different etiologies. Thirty-nine patients had a LV ejection fraction (EF) ≥50% (Group A), 16 showed an EF between 40 and 50% (Group B), and 24 patients had an EF ≤40%(Group C). LV rotation was assessed by 3D-STE at basal, medium, apical, and apical-cap levels. Twist was computed considering the apex either at the apical level (Twist(Api) ) or at the apical-cap level (Twist(AC) ). RESULTS: LV rotation resulted to be progressively higher from base to apical-cap (P < 0.0001) with a significant difference between the apex and the apical-cap level (6.20 ± 3.90° vs. 10.23 ± 7.52°; P < 0.001). Such a difference was constantly found in all Groups (P < 0.01 for Group A, P < 0.05 for Group B and C). Twist(Api) was also significantly lower than Twist(AC) both in the overall population (6.2 ± 3.89° vs. 10.23 ± 7.51°; P < 0.001) and in the different subgroups ( CONTROLS: 9.61 ± 3.39° vs. 13.75 ± 6.51°; Group A: 10.49 ± 4.77° vs. 16.37 ± 8.49°; Group B: 6.67 ± 3.44° vs. 9.14 ± 5.55°; Group C: 33 ± 2.62° vs. 5.26 ± 3.74°; P < 0.05 for all the comparisons). CONCLUSIONS: Identification and inclusion of apical-cap is relevant for twist assessment and can be carried out efficiently by 3D-STE. The inclusion of the true apex in the calculation significantly affects the analysis of twist both in normal individuals and patients with different myocardial diseases.

[Role of cardiovascular magnetic resonance in the differential diagnosis of cardiomyopathies]. / Ruolo della risonanza magnetica cardiaca nella diagnosi differenziale delle cardiomiopatie.

Cardiovascular magnetic resonance (CMR) is a unique diagnostic imaging tool for the assessment of cardiomyopathies, allowing a non-invasive detection of the most common diseases of the heart muscle. In the real world, patients with suspected cardiomyopathies who show signs and symptoms of heart failure should undergo a thorough diagnostic evaluation. Besides clinical and echocardiographic assessment, coronary angiography is the most important and common examination performed to detect or rule out coronary artery disease. This approach is relevant for the clinical decision-making, as it may obviate the need for further diagnostic evaluation of the heart structure and muscle function. CMR can reliably detect a variety of heart muscle diseases without requiring bioptic confirmation of the diagnosis. In addition, CMR provides anatomo-functional information that possesses incremental and independent prognostic value. This represents a new paradigm shift as it moves the attention from the coronary arteries to the heart muscle. CMR is useful in establishing the correct diagnosis of several clinical conditions and cardiomyopathies, thus guiding therapeutic strategies and influencing patient prognosis.

Evaluation of Brugada syndrome by cardiac magnetic resonance.

Brugada syndrome (BrS) has been originally considered to occur in structural normal hearts. However recent pathological and imaging data suggest that structural and functional changes may be present in this syndrome. This study was designed to elucidate whether any macroscopic heart abnormality is detectable in patients with BrS. For this purpose we used cardiac magnetic resonance (CMR). Twenty-nine patients displaying the BrS type-1 ECG pattern and 29 healthy controls underwent CMR (1.5 Tesla). Left (LV) and right ventricular (RV) dimensions, function and regional contractility were evaluated. Late-gadolinium-enhancement (LGE) imaging was obtained in 24 patients. We found no difference between BrS patients and controls regarding LV and RV dimensions and ejection fraction. RV wall motion abnormalities (WMA) were detected in 19 patients (65.5%) and in 22 control subjects (75.9%). The majority of these WMA were attributable to areas of hypokinesia and found in the RV inferior wall. None of the patients showed LGE. No differences were detected between controls and the different subgroups of BrS patients according to symptoms, family history and spontaneous type-1 ECG pattern. BrS patients do not differ from normal subjects with regard to dimensions and global function of both LV and RV. BrS patients may show RV-WMA, however similar changes are also present in healthy subjects and may therefore represent a physiological behaviour of RV. The lack of LGE further confirms the absence of myocardial structural damage. Our results indicate that BrS seems to occur in individuals with structurally and functionally normal heart.