Subclinical Heart Dysfunction in Relation to Metabolic and Inflammatory Markers: A Community-Based Study.

BACKGROUND: Population studies investigating the contribution of immunometabolic disturbances to heart dysfunction remain scarce. We combined high-throughput biomarker profiling, multidimensional network analyses, and regression statistics to identify immunometabolic markers associated with subclinical heart dysfunction in the community. METHODS: In 1,236 individuals (mean age, 51.0 years; 51.5% women), we measured 39 immunometabolic markers and assessed echocardiographic indexes of left ventricular diastolic dysfunction (LVDD) and left atrial (LA) reservoir dysfunction. We used partial least squares (PLS) to filter the most relevant biomarkers related to the echocardiographic characteristics. Subsequently, we assessed the associations between the echocardiographic features and biomarkers selected in PLS while accounting for clinical confounders. RESULTS: Influential biomarkers in PLS of echocardiographic characteristics included blood sugar, γ-glutamyl transferase, d-dimer, ferritin, hemoglobin, interleukin (IL)-4, IL-6, and serum insulin and uric acid. In stepwise regression incorporating clinical confounders, higher d-dimer was independently associated with higher E/e' ratio and LA volume index (P ≤ 0.05 for all). In multivariable-adjusted analyses, the risk for LVDD increased with higher blood sugar and d-dimer (P ≤ 0.048). After full adjustment, higher serum insulin and serum uric acid were independently related to worse LA reservoir strain and higher risk for LA reservoir dysfunction (P ≤ 0.039 for all). The biomarker panels detected LVDD and LA reservoir dysfunction with 87% and 79% accuracy, respectively (P < 0.0001). CONCLUSIONS: Biomarkers of insulin resistance, hyperuricemia, and chronic low-grade inflammation were associated with cardiac dysfunction. These biomarkers might help to unravel cardiac pathology and improve the detection and management of cardiac dysfunction in clinical practice.

The role of cardiovascular imaging for myocardial injury in hospitalized COVID-19 patients.

Recent EACVI recommendations described the importance of limiting cardiovascular imaging during the COVID-19 pandemic in order to reduce virus transmission, protect healthcare professionals from contamination, and reduce consumption of personal protective equipment. However, an elevated troponin remains a frequent request for cardiac imaging in COVID-19 patients, partly because it signifies cardiac injury due to a variety of causes and partly because it is known to convey a worse prognosis. The present paper aims to provide guidance to clinicians regarding the appropriateness of cardiac imaging in the context of troponin elevation and myocardial injury, how best to decipher the mechanism of myocardial injury, and how to guide patient management.

Diagnostic accuracy of stress myocardial computed tomography perfusion imaging to detect myocardial ischemia: a comparison with coronary flow velocity reserve derived from transthoracic Doppler echocardiography.

BACKGROUND: Our aim was to evaluate the ability of adenosine triphosphate (ATP)-stress myocardial computed tomography perfusion (CTP) imaging to detect myocardial ischemia in the left anterior descending artery (LAD) territory, and to compare this method with coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography (TTDE). METHODS: ATP-stress CTP and CFVR were performed in 50 patients with stable angina pectoris. Myocardial ischemia assessed from CTP imaging was defined as qualitative visual perfusion defects and reduced myocardial blood flow (MBF) based on quantitative assessment. A cut-off value of CFVR of 2.0 was used. RESULTS: The mean CFVR was 1.9 ± 0.6 in ischemic regions by CTP, whereas it was 2.9 ± 0.8 in non-ischemic regions (p < 0.001). CTP imaging could accurately predict CFVR <2.0 with 84.0% diagnostic accuracy (94.7% sensitivity, 77.4% specificity, 72.0% positive predictive value, and 96.0% negative predictive value). When receiver operating characteristic curve analysis of the MBF data was performed to detect CFVR <2.0, the area under the curve was 0.89, and the optimal MBF cut-off value was 1.43 mL/g/min. CONCLUSIONS: This study suggests that qualitative and quantitative assessment of ATP-stress CTP exhibits a good correlation with CFVR for evaluation of myocardial ischemia.

Diabetes Mellitus Is an Independent Predictor for the Development of Heart Failure: A Population Study.

OBJECTIVES: To delineate the impact of diabetes mellitus (DM) on the development of cardiovascular diseases in a community population. PATIENTS & METHODS: Cross-sectional survey of residents randomly selected through the Rochester Epidemiology Project, 45 years or older, of Olmsted County as of June 1, 1997, through September 30, 2000. Responders (2042) underwent assessment of systolic and diastolic function using echocardiography. The current analyses included all participants with DM and were compared with a group of participants without DM matched 1:2 for age, sex, hypertension, and coronary artery disease. Baseline characteristics and laboratory and echocardiography findings between groups were compared along with rates of mortality due to various cardiovascular conditions. RESULTS: We identified 116 participants with DM and 232 matched participants without DM. Those with DM had a higher body mass index and plasma insulin and serum glucose levels. Although left ventricular ejection fractions were similar, E/e' ratio (9.7 vs 8.5; P=.001) was higher in DM vs non-DM. During a follow-up of 10.8 (interquartile range, 7.8-11.7) years, participants with DM had a higher incidence of heart failure (HF); hazard ratio, 2.1; 95% confidence limits, 1.2-3.6; P=.01) and 10-year Kaplan-Meier rate of 21% (22 of 116) vs 12% (24 of 232) compared with those without DM. We also examined the subgroup of participants without diastolic dysfunction. In this subgroup, those with DM had an increased risk for HF; hazard ratio, 2.5; 95% confidence limits, 1.0-6.3; P=.04). CONCLUSION: In this cohort, participants with DM have an increased incidence of HF over a 10-year follow-up period even in the absence of underlying diastolic dysfunction. These findings suggest that DM is an independent risk factor for the development of HF and supports the concept of DM cardiomyopathy.

Doppler echocardiography for assessment of systemic vascular resistances in cardiogenic shock patients.

OBJECTIVE: Impaired vascular tone plays an important role in cardiogenic shock. Doppler echocardiography provides a non-invasive estimation of systemic vascular resistance. The aim of the present study was to compare Doppler echocardiography with the transpulmonary thermodilution method for the assessment of systemic vascular resistance in patients with cardiogenic shock. METHODS: This prospective monocentric comparison study was conducted in a single cardiology intensive care unit (Hopital Nord, Marseille, France). We assessed the systemic vascular resistance index by both echocardiography and transpulmonary thermodilution in 28 patients admitted for cardiogenic shock, on admission and after the introduction of an inotrope or vasopressor treatment. RESULTS: A total of 35 paired echocardiographic and transpulmonary thermodilution estimations of the systemic vascular resistance index were compared. Echocardiography values ranged from 1309 to 3526 dynes.s.m2/cm5 and transpulmonary thermodilution values ranged from 1320 to 3901 dynes.s.m2/cm5. A statistically significant correlation was found between echocardiography and transpulmonary thermodilution (r=0.86, 95% confidence interval (CI) 0.74, 0.93; P<0.0001). The intraclass correlation coefficient was 0.84 (95% CI 0.72, 0.92). The mean bias was -111.95 dynes.s.m2/cm5 (95% CI -230.06, 6.16). Limits of agreement were -785.86, 561.96. CONCLUSIONS: Doppler echocardiography constitutes an accurate non-invasive alternative to transpulmonary thermodilution to provide an estimation of systemic vascular resistance in patients with cardiogenic shock.

Takotsubo syndrome in young fertile women.

Background: Takotsubo syndrome (TTS) is an acute heart syndrome characterised by reversible ventricular dysfunction with the absence of significant coronary occlusion, which typically occurs in postmenopausal women after emotional or physical stress. Differences of clinical or instrumental characteristics between fertile women and postmenopausal women with TTS have not yet been studied. The aim of this study was to investigate the differences in clinical, biochemical and echocardiographic characteristics between postmenopausal women and fertile women with TTS.Methods: One hundred and thirty-one patients (mean age 67.8 ± 11.3 years; 14 patients were still fertile) from four different Italian hospitals were enrolled, partially retrospectively and partial longitudinally. Physical examination, clinical history (including presenting symptoms and triggering stress factors), laboratory and ECG findings and Doppler echocardiography were collected at hospital admission. Echocardiography was repeated at discharge (after at least seven days from admission).Results: No significant differences were observed considering trigger events or symptoms at presentation. Significant differences were observed considering left ventricle ejection fraction (LVEF) (37.9 ± 14.4% in fertile women, 43.9 ± 9.7% in postmenopausal women, p = .033) and regional wall motion abnormalities. The apical ballooning pattern was predominant in postmenopausal women, instead the midventricular type was mainly observed in fertile women (36% versus 1% in fertile versus postmenopausal women respectively, p < .001).Conclusions: Echocardiographic involvement of left ventricle is atypical in fertile women compared to women in menopause (midventricular versus apical ballooning, respectively). Moreover, the young group presented with worse LVEF but they had the same LV function at discharge and similar prognosis.

Dynamic fetal cardiac magnetic resonance imaging in four-chamber view using Doppler ultrasound gating in normal fetal heart and in congenital heart disease: comparison with fetal echocardiography.

OBJECTIVES: To investigate the diagnostic performance of dynamic fetal cardiac magnetic resonance imaging (MRI), using a MR-compatible Doppler ultrasound (DUS) device for fetal cardiac gating, in differentiating fetuses with congenital heart disease from those with a normal heart, and to compare the technique with fetal echocardiography. METHODS: This was a prospective study of eight fetuses with a normal heart and four with congenital heart disease (CHD), at a median of 34 (range, 28-36) weeks' gestation. Dynamic fetal cardiac MRI was performed using a DUS device for direct cardiac gating. The four-chamber view was evaluated according to qualitative findings. Measurements of the length of the left and right ventricles, diameter of the tricuspid and mitral valves, myocardial wall thickness, transverse cardiac diameter and left ventricular planimetry were performed. Fetal echocardiography and postnatal diagnoses were considered the reference standards. RESULTS: Direct cardiac gating allowed continuous triggering of the fetal heart, showing high temporal and spatial resolution. Both fetal cardiac MRI and echocardiography in the four-chamber view detected pathological findings in three of the 12 fetuses. Qualitative evaluation revealed overall consistency between echocardiography and MRI. On both echocardiography and MRI, quantitative measurements revealed significant differences between fetuses with a normal heart and those with CHD with respect to the length of the right (P < 0.01 for both) and left (P < 0.01 for both) ventricles and transverse cardiac diameter (P < 0.05 and P < 0.01, respectively). Tricuspid valve diameter on cardiac MRI was found to be significantly different in healthy fetuses from in those with CHD (P < 0.05). CONCLUSIONS: For the first time, this study has shown that dynamic fetal cardiac MRI in the four-chamber view, using external cardiac gating, allows evaluation of cardiac anatomy and diagnosis of congenital heart disease in agreement with fetal echocardiography. Dynamic fetal cardiac MRI may be useful as a second-line investigation if conditions for fetal echocardiography are unfavorable. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Comparison of echocardiographic changes in children with primary hypertension and hypertension due to mild to moderate chronic kidney disease.

BACKGROUND: Chronic systemic hypertension has a well-known association with increased cardiovascular morbidity and mortality. One of the most important target organs affected in systemic hypertension is the heart. In addition, chronic kidney disease (CKD) further increases the mortality from cardiovascular disease. The aim of this study was to evaluate the differences in the cardiovascular changes in pediatric patients with primary hypertension (pHTN) vs. those with secondary hypertension from chronic kidney disease (CKD-HTN). METHODS: This was a retrospective chart review of patients with CKD-HTN and pHTN. The medical records were reviewed for anthropometric data, biochemical assessment of renal function, and for cardiovascular changes on echocardiogram. RESULTS: Twenty-three patients with pHTN and 29 patients with CKD-HTN were included in the study. There were no differences in age, gender, weight, height, body mass index, and blood pressure between the 2 groups. There was a high prevalence of left ventricular diastolic dysfunction among both the groups (CKD-HTN 25 vs. pHTN 26%). Reduced mitral valve inflow Doppler E/A ratio, a marker of left ventricular diastolic dysfunction in echocardiogram, was more pronounced in CKD-HTN patents, in comparison to those with pHTN (p = 0.042). Also, diastolic function worsened with declining glomerular filtration rate in patients with CKD-HTN. Similarly, patients with CKD-HTN had a larger aortic root dimension when compared to patients with pHTN (p = 0.049). CONCLUSIONS: The prevalence of left ventricular diastolic dysfunction is similar in patients with pHTN and CKD-HTN. Patients with CKD-HTN appear to have more severe diastolic dysfunction and larger aortic root dimensions.

Perinatal changes in cardiac geometry and function in growth-restricted fetuses at term.

OBJECTIVE: To evaluate the effect of fetal growth restriction (FGR) at term on fetal and neonatal cardiac geometry and function. METHODS: This was a prospective study of 87 pregnant women delivering at term, comprising 54 normally grown and 33 FGR pregnancies. Fetal and neonatal conventional and spectral tissue Doppler and two-dimensional speckle tracking echocardiography were performed a few days before and within hours after birth. Fetal cardiac geometry, global myocardial deformation and performance and systolic and diastolic function were compared between normal and FGR pregnancies before and after birth. RESULTS: Compared with normally grown fetuses, FGR fetuses exhibited more globular ventricular geometry and poorer myocardial deformation and cardiac function (left ventricular (LV) sphericity index (SI), 0.54 vs 0.49; right ventricular (RV) SI, 0.60 vs 0.54; LV torsion, 1.2 °/cm vs 3.0 °/cm; LV isovolumetric contraction time normalized by cardiac cycle length, 121 ms vs 104 ms; interventricular septum early diastolic myocardial peak velocity/atrial contraction myocardial diastolic peak velocity ratio, 0.60 vs 0.71; P < 0.01 for all). The poorest perinatal outcomes occurred in FGR fetuses with the most impaired cardiac functional indices. When compared with normally grown neonates, FGR neonates showed persistent alteration in cardiac parameters (LV-SI, 0.53 vs 0.50; RV-SI, 0.54 vs 0.44; LV torsion, 1.1 °/cm vs 1.4 °/cm; LV myocardial performance index (MPI'), 0.52 vs 0.42; P < 0.01 for all). Paired comparison of fetal vs neonatal cardiac indices in FGR demonstrated that birth was associated with a significant improvement in some, but not all, cardiac indices (RV-SI, 0.60 vs 0.54; RV-MPI', 0.49 vs 0.39; P < 0.001 for all). CONCLUSIONS: Compared with normal pregnancies, FGR fetuses and neonates at term exhibit altered cardiac indices indicative of myocardial impairment that reflect adaptation to placental hypoxemia and alterations in hemodynamic load around the time of birth. Elucidating potential mechanisms that contribute to the alterations in perinatal cardiac adaptation in FGR could improve management and aid the development of better therapeutic strategies to reduce the risk of adverse pregnancy outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

The impact of tissue Doppler index E/e' ratio on instantaneous wave-free ratio.

BACKGROUND: The instantaneous wave-free ratio (iFR) is a vasodilator-free, invasive pressure wire index of the functional severity of coronary stenosis and is calculated under resting conditions. In a recent study, iFR was found to be more closely linked to coronary flow reserve (CFR) than fractional flow reserve (FFR). E/e' is a surrogate marker of left ventricular (LV) filling pressure and LV diastolic dysfunction. Coronary resting flow was found to be increased in patients with elevated E/e', and higher coronary resting flow was associated with lower CFR. Higher baseline coronary flow induces a greater loss of translesional pressure and may affect iFR. However, no reports have examined the impact of E/e' on iFR. The purpose of this study was to assess the relationship between iFR and E/e' compared with FFR. METHODS AND RESULTS: We retrospectively examined 103 consecutive patients (142 with stenosis) whose iFR, FFR, and E/e' were measured simultaneously. The mean age, LV mass index, and systolic blood pressure of patients with elevated E/e' were higher than those of patients with normal E/e'. Although no significant differences were observed in mean FFR values and % diameter stenosis, the mean iFR value in patients with elevated E/e' was significantly lower than that in patients with normal E/e'. The iFR was negatively correlated with E/e', while there was no correlation between FFR and E/e'. Multivariate analysis showed that E/e' and % diameter stenosis were independent determinants of iFR. CONCLUSION: E/e' ratio affects iFR values. Our results suggest that FFR mainly reflects the functional severity of the epicardial stenosis whereas iFR could potentially be influenced by not only epicardial stenosis but also other factors related to LV filling pressure or LV diastolic dysfunction. Further research is needed to understand the underlying mechanisms that influence the evaluation of iFR in patients with elevated E/e'.

Right Atrial Dysfunction in the Fetus with Severely Regurgitant Tricuspid Valve Disease: A Potential Source of Cardiovascular Compromise.

BACKGROUND: In severe right heart obstruction (RHO), redistribution of cardiac output to the left ventricle (LV) is well tolerated by the fetal circulation. Although the same should be true of severely regurgitant tricuspid valve disease (rTVD) with reduced or no output from the right ventricle, affected fetuses more frequently develop hydrops or suffer intrauterine demise. We hypothesized that right atrium (RA) function is altered in rTVD but not in RHO, which could contribute to differences in outcomes. METHODS: Multi-institutional retrospective review of fetal echocardiograms performed over a 10-year period on fetuses with rTVD (Ebstein's anomaly, tricuspid valve dysplasia) or RHO (pulmonary atresia/intact ventricular septum, tricuspid atresia) and a healthy fetal control group. Offline velocity vector imaging and Doppler measurements of RA size and function and LV function were made. RESULTS: Thirty-four fetuses with rTVD, 40 with RHO, and 79 controls were compared. The rTVD fetuses had the largest RA size and lowest RA expansion index, fractional area of change, and RA indexed filling and emptying rates compared with fetuses with RHO and controls. The rTVD fetuses had the shortest LV ejection time and increased Tei index with a normal LV ejection fraction. RA dilation (odds ratio, 1.27; 95% CI, 1.05-1.54) and reduced indexed emptying rate (odds ratio, 2.49; 95% CI, 1.07-5.81) were associated with fetal or neonatal demise. CONCLUSIONS: Fetal rTVD is characterized by more severe RA dilation and dysfunction compared with fetal RHO and control groups. RA dysfunction may be an important contributor to reduced ventricular filling and output, potentially playing a critical role in the worsened outcomes observed in fetal rTVD.

Larger right atrium than left atrium is associated with all-cause mortality in elderly patients with heart failure.

BACKGROUND: While left atrial (LA) enlargement is known as an early sign of left heart disease with prognostic implications in heart failure (HF), the importance of right atrial (RA) enlargement is less well studied, and the prognostic implications of interatrial size comparison are insufficiently understood. The aim of this study was to test the hypothesis that RA area larger than LA area in apical four-chamber view is associated with all-cause mortality in elderly patients with HF independent of left ventricular ejection fraction (LVEF). METHODS: Retrospectively, 289 patients above 65 years hospitalized for HF between April 2007 and April 2008, and who underwent an echocardiogram, were enrolled. All-cause mortality was registered during a follow-up of at least 56 months. Baseline parameters measured were RA area, LA area, LA volume, LVEF, left ventricular mass (LVM), tissue Doppler systolic velocity of right ventricular free wall (SmRV), presence of severe tricuspid regurgitation (TR), tricuspid gradient, central venous pressure, systolic pulmonary artery pressure, as well as some parameters of diastolic function. RESULTS: In univariate analysis RA larger than LA was associated with all-cause mortality (hazard ratio [HR] of 1.88, P<.001). The relation of RA larger than LA to all-cause mortality remained even after adjusting for age, heart rate, LVEF, atrial fibrillation, percutaneous coronary intervention, LVM index, LA volume index, SmRV, and the presence of severe TR (HR: 1.79, P=.04). CONCLUSION: RA larger than LA, independently of LVEF, is associated with all-cause mortality in elderly patients hospitalized due to HF.

Renal systolic time intervals derived from intra-renal artery Doppler as a novel predictor of adverse cardiac outcomes.

The aim of this study was to evaluate the use of renal systolic time intervals measured by electrocardiographic gated Doppler ultrasonography for predicting adverse cardiac events. This longitudinal observation study enrolled 205 patients. Renal systolic time intervals, including pre-ejection period (PEP) and ejection time (ET), and ratio of renal PEP to ET, were measured by electrocardiographic gated Doppler ultrasound. The 14 adverse cardiac events identified in this population included 9 cardiac deaths and 5 hospitalizations for heart failure during an average follow up of 30.9 months (25th-75th percentile: 30-33 months). Renal PEP (hazard ratio = 1.023, P = 0.001), renal ET (hazard ratio = 0.975, P = 0.001) and renal PEP/ET (per 0.01 unit increase, hazard ratio = 1.060, P < 0.001) were associated with poor cardiac outcomes. The addition of renal PEP/ET to a Cox model containing important clinical variables and renal resistive index further improved the value in predicting adverse cardiac events (Chi-square increase, 9.996; P = 0.002). This study showed that parameters of intra-renal hemodynamics were potential predictors of adverse cardiac outcomes. However, the generalizability of these indicators need to be investigated in future large-scale studies.

Incidence of right heart catheterization in patients initiated on pulmonary arterial hypertension therapies: A population-based study.

BACKGROUND: Pulmonary hypertension represents a heterogeneous collection of conditions classified into 5 groups according to pathology, pathophysiology and response to treatment. Right heart catheterization is required to classify patients and before initiation of specific therapy for treatment of pulmonary arterial hypertension. The aim of this study was to determine performance of right heart catheterization in patients prescribed pulmonary arterial hypertension (PAH)-specific medications. METHODS: A retrospective review of administrative claims was performed using the Clinformatics Data Mart database. Individuals with an encounter diagnosis of pulmonary hypertension were identified by ICD-9 codes. An initial encounter diagnosis was defined as continuous enrollment for 12 months without a previous ICD-9 diagnosis of pulmonary hypertension. These individuals were followed for 15 months after initial encounter diagnosis. Individuals prescribed PAH-specific medications were assessed for characteristics, comorbidities and performance of echocardiography and right heart catheterization. RESULTS: From 2002 to 2011, 15,772 patients had an outpatient visit with a diagnosis of pulmonary hypertension. From the initial group, 969 (6.1%) patients were prescribed PAH-specific medications within 1 year of encounter diagnosis. Oral PAH-specific medications were prescribed to 94.2% of patients. In patients prescribed PAH-specific medications, 91% had an echocardiogram within 1 year of encounter diagnosis. Cardiac catheterization was performed in 407 patients (42%) within 3 months of initial prescription and in 583 patients (60.2%) during the entire study period. CONCLUSION: Performance of right heart catheterization was low in this population-based study of patients with an ICD-9 diagnosis code of pulmonary hypertension and taking PAH-specific medications.

Combined Circumferential and Longitudinal Left Ventricular Systolic Dysfunction in Patients with Rheumatoid Arthritis without Overt Cardiac Disease.

BACKGROUND: Patients with rheumatoid arthritis have an increased risk for cardiovascular disease. Because of accelerated atherosclerosis and changes in left ventricular (LV) geometry, circumferential and longitudinal (C&L) LV systolic dysfunction (LVSD) may be impaired in these patients despite preserved LV ejection fraction. The aim of this study was to determine the prevalence of and factors associated with combined C&L LVSD in patients with rheumatoid arthritis. METHODS: One hundred ninety-eight outpatients with rheumatoid arthritis without overt cardiac disease were prospectively analyzed from January through June 2014 and compared with 198 matched control subjects. C&L systolic function was evaluated by stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S'). Combined C&L LVSD was defined if sc-MS was <86.5% and S' was <9.0 cm/sec (the 10th percentiles of sc-MS and S' derived in 132 healthy subjects). RESULTS: Combined C&L LVSD was detected in 56 patients (28%) and was associated with LV mass (odds ratio, 1.03; 95% CI, 1.01-1.06; P = .04) and concentric LV geometry (odds ratio, 2.76; 95% CI, 1.07-7.15; P = .03). By multiple logistic regression analysis, rheumatoid arthritis emerged as an independent predictor of combined C&L LVSD (odds ratio, 2.57; 95% CI, 1.06-6.25). The relationship between sc-MS and S' was statistically significant in the subgroup of 142 patients without combined C&L LVSD (r = 0.40, F < 0.001), having the best fitting by a linear function (sc-MS = 58.1 + 3.34 × peak S'; r(2) = 0.19, P < .0001), absent in patients with combined C&L LVSD. CONCLUSIONS: Combined C&L LVSD is detectable in about one fourth of patients with asymptomatic rheumatoid arthritis and is associated with LV concentric remodeling and hypertrophy. Rheumatoid arthritis predicts this worrisome condition, which may explain the increased risk for cardiovascular events in these patients. NOTICE OF CLARIFICATION: The aim of this "notice of clarification" is to analyze in brief the similarities and to underline the differences between the current article (defined as "paper J") and a separate article entitled "Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis" (defined as "paper E"), which was written several months before paper J, and recently accepted for publication by the journal "Echocardiography" (Cioffi et al. http://dx.doi.org/10.1111/echo.13186). We wish to explain more clearly how the manuscript described in "paper J" relates to the "paper E" and the context in which it ought to be considered. Data in both papers were derived from the same prospective database, so that it would appear questionable if the number of the enrolled patients and/or their clinical/laboratory/echocardiographic characteristics were different. Accordingly, both papers reported that 198 patients with rheumatoid arthritis (RA) were considered and their characteristics were identical, due to the fact that they were the same subjects (this circumstance is common and mandatory among all studies in which the patients were recruited from the same database). These are the similarities between the papers. In paper E, which was written several months before paper J, we focused on the prevalence and factors associated with impaired circumferential left ventricular (LV) systolic function measured as mid-wall shortening (corrected for circumferential end-systolic stress). We found that 110 patients (56% of the whole population) demonstrated this feature. Thus, these 110 patients were the object of the study described in paper E, in which we specifically analyzed the factors associated with the impairment of stress-corrected mid-wall shortening (sc-MS). The conclusions of that paper were: (i) subclinical LV systolic dysfunction (LVSD) is detectable in more than half RA population without overt cardiac disease as measured by sc-MS, (ii) RA per se is associated with LVSD, and (iii) in RA patients only LV relative wall thickness was associated with impaired sc-MS based upon multivariate logistic regression analysis. Differently, in the paper J, we focused on the prevalence and factors associated with combined impairment of circumferential and longitudinal shortening (C&L) in 198 asymptomatic patients with RA. We found that 56 patients (28% of the whole population) presented this feature. Thus, these 56 patients were analyzed in detail in this study, as well as the factors associated with the combined impairment of C&L shortening. In paper J, we evaluated sc-MS as an indicator of circumferential systolic LV shortening, and we also determined the average of tissue Doppler measures of maximal systolic mitral annular velocity at four different sampling sites ( S') as an indicator of longitudinal LV systolic shortening. This approach clearly demonstrates that in paper J, we analyzed data deriving from the tissue Doppler analysis, which were not taken into any consideration in paper E. The investigation described in paper J made evident several original and clinically relevant findings. In patients with RA: (i) the condition of combined C&L left ventricular systolic dysfunction (LVSD) is frequent; (ii) these patients have comparable clinical and laboratory characteristics with those without combined C&L LVSD, but exhibit remarkable concentric LV geometry and increased LV mass, a phenotype that can be consider a model of compensated asymptomatic chronic heart failure; (iii) RA is an independent factor associated with combined C&L LVSD; (iv) no relationship between indexes of circumferential and longitudinal function exists in patients with combined C&L LVSD, while it is statistically significant and positive when the subgroup of patients without combined C&L LVSD is considered, having the best fitting by a linear function. All these findings are unique to the paper J and are not presented (they could not have been) in paper E. It appears clear that, starting from the same 198 patients included in the database, different sub-groups of patients were selected and analyzed in the two papers (they had different echocardiographic characteristics) and, consequently, different factors emerged by the statistical analyses as covariates associated with the different phenotypes of LVSD considered. Importantly, both papers E and J had a very long gestation because all reviewers for the different journals found several and important issues that merited to be addressed: a lot of changes were proposed and much additional information was required, particularly by the reviewers of paper E. Considering this context, it emerges that although paper E was written well before paper J, the two manuscripts were accepted at the same time (we received the letters of acceptance within a couple of weeks). Thus, the uncertainty about the fate of both manuscripts made it very difficult (if not impossible) to cite either of them in the other one and, afterward, we just did not think about this point anymore. Of note, the idea to combine in the analysis longitudinal function came therefore well after the starting process of revision of the paper E and was, in some way inspired by a reviewer's comment. That is why we did not put both findings in the same paper. We think that our explanations provide the broad audience of your journal a perspective of transparency and our respect for the readers' right to understand how the work described in the paper J relates to other work by our research group. Giovanni Cioffi On behalf of all co-authors Ombretta Viapiana, Federica Ognibeni, Andrea Dalbeni, Davide Gatti, Carmine Mazzone, Giorgio Faganello, Andrea Di Lenarda, Silvano Adami, and Maurizio Rossini.

Echo-Doppler-derived indexes of ventricular stiffness and ventriculo-arterial interaction as predictors of new-onset atrial fibrillation in patients with heart failure.

BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure (HF) and worsens their prognosis. Vulnerability to changes in loading is an important factor in the development of AF and is strongly influenced by ventricular stiffness and ventriculo-arterial interaction. The aim of this study was to investigate predictors of AF development in patients with HF. METHODS: We studied 349 patients with stable HF. The following parameters of ventricular stiffness and ventriculo-arterial interaction were derived from echo-Doppler measurements: left ventricular (LV) diastolic elastance (Ed), effective arterial elastance (Ea), LV end-systolic elastance (Ees) and ventricular-vascular coupling index (VVI). RESULTS: AF occurred in 57 (16.3%) patients over a median follow up of 30.3 months. Echo-Doppler-derived parameters of ventricular stiffness and ventriculo-arterial interaction were closely associated with HF severity. Ed was independently associated with AF after adjustment for age, hypertension, diabetes mellitus, and left atrial volume index (hazard ratio [HR] 5.49, p = 0.018). Ea and VVI were also associated with new-onset AF (HR 1.66, p = 0.027, and HR 1.06, p = 0.001, respectively). CONCLUSIONS: Echo-Doppler indexes of ventricular stiffness are closely associated with HF severity. LV diastolic elastance (Ed) is the strongest predictor of new-onset AF in HF patients.

Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with clinical outcome.

BACKGROUND: Cirrhotic cardiomyopathy has been characterized by impaired contractile response to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease. However, the clinical significance of diastolic dysfunction (DDF) in cirrhotic patients has not been clarified. METHODS: We studied 84 cirrhotic patients with normal systolic function to evaluate the prevalence of DDF using tissue Doppler imaging, and to investigate the possible correlation of DDF with outcomes (hospitalization, death) and with the specific causes of death. RESULTS: The mean follow-up was 10±8months. DDF was diagnosed in 22 patients (26.2%). Patients with DDF more frequently had ascites (90.9% vs. 64.5 %; p=0.026), lower levels of albumin (OR: 5.39; p=0.004), higher NT-proBNP levels, and longer QTc interval (464±23ms vs. 452±30ms; p=0.039). At follow-up, patients with DDF did not have a higher incidence of adverse events in terms of hospitalization and death. CONCLUSIONS: The presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease.

Association between high-sensitivity troponin T, left ventricular hypertrophy, and myocardial performance index.

BACKGROUND: The prognostic importance of high-sensitivity cardiac troponin T (hs-cTnT) has recently been reported in patients with heart failure. The myocardial performance index (MPI), which combines parameters of both systolic and diastolic ventricular function, provides a better marker of left ventricular dysfunction in hypertensive patients with preserved left ventricular ejection fraction (LVEF). AIM: We aimed to investigate the relationship between hs-cTnT and tissue Doppler-derived MPI in newly diagnosed hypertensive patients with preserved LVEF. METHODS: We studied 306 patients with newly diagnosed hypertension. The patients were divided into two groups according to their median MPI values: MPIlo and MPIhigh groups. The MPI was calculated from the pulsed-wave Doppler recordings. Left ventricular mass index (LVMI) was determined according to the Devereux formula. hs-cTnT, uric acid, and high-sensitivity C-reactive protein (hs-CRP) levels were measured in all patients. RESULTS: Hs-cTnT, hs-CRP, and uric acid levels were higher in the MPIhigh group compared with the MPIlow group (p < 0.05, for all). The LVMI values in the MPIhigh group were higher than in the MPIlow group (p < 0.05). MPI was independently associated with age, uric acid, hs-cTnT, and LVMI in multivariate analysis. Multivariate logistic regression analysis showed that MPI and LVMI were independent predictors of high hs-cTnT level in newly diagnosed hypertensive patients with preserved LVEF. CONCLUSION: Hs-cTnT was independently associated with LV dysfunction and LV hypertrophy assessed with MPI in newly diagnosed hypertensive patients.

Prevalence and factors related to left ventricular systolic dysfunction in asymptomatic patients with rheumatoid arthritis. A prospective tissue Doppler echocardiography study.

BACKGROUND: Patients with rheumatoid arthritis (RA) have a high risk for cardiovascular disease due to a chronic inflammatory state, accelerated atherosclerosis, and changes in left ventricular (LV) geometry. These conditions predispose patients to LV systolic dysfunction (LVSD). In this study we assessed whether RA is a condition associated with LVSD, and analyzed the prevalence and factors associated with LVSD in patients with RA. PATIENTS AND METHODS: Echocardiographic and clinical data from 198 patients with RA without presence or history of symptoms of cardiac disease were compared with 198 non-RA controls matched for cardiovascular risk factors. LVSD was identified with tissue Doppler echocardiography (TDE) when mitral annular peak systolic velocity (S') was < 9.0 cm/s. RESULTS: Patients with RA were 61 ± 12 years old and 71 % were female (disease duration 14 ± 10 years). LVSD was found in 89 patients with RA (45 %). By multiple regression analysis including both RA patients and controls, RA emerged as an independent condition associated with LVSD (exp ß 3.89; CI: 1.87-8.08) together with higher E/E' ratio (index of LV diastolic function) and diabetes mellitus. For the 198 patients with RA, the variables associated with LVSD were higher E/E' ratio and systolic blood pressure. CONCLUSIONS: Almost half of asymptomatic RA patients without history of cardiac disease have subclinical LVSD easily detectable with TDE. RA is closely related to LVSD. A higher degree of LV diastolic dysfunction and systolic blood pressure are associated with LVSD in these patients, whose risk for cardiovascular events could be better defined using such information in the asymptomatic stage of cardiac disease.