Carmen Muñoz-Esparza

β-trace protein and cystatin C as predictors of long-term outcomes in patients with acute heart failure.

OBJECTIVES The purpose of this study was to evaluate the prognostic importance of novel markers of renal dysfunction among patients with acutely destabilized heart failure (ADHF). BACKGROUND β-trace protein (BTP) and cystatin C are newer biomarkers for renal dysfunction; the prognostic importance of these tests, particularly BTP, relative to standard measures of renal function remains unclear. METHODS A total of 220 consecutive hospitalized patients with ADHF were prospectively studied. Blood samples were collected on presentation. In-hospital worsening renal function, as well as mortality and/or heart failure (HF) hospitalization, over a median follow-up period of 500 days was examined as a function of BTP or cystatin C concentrations; results were compared with creatinine, estimated glomerular filtration rate, and blood urea nitrogen. RESULTS Neither BTP nor cystatin C was associated with worsening renal function during the index hospitalization. A total of 116 patients (53%) either died or were hospitalized for HF during follow-up. Those with adverse outcomes had higher BTP (1.04 mg/l [range 0.80 to 1.49 mg/l] vs. 0.88 mg/l [range 0.68 to 1.17 mg/l], p = 0.003) and cystatin C (1.29 mg/l [range 1.00 to 1.71 mg/l] vs. 1.03 mg/l [range 0.86 to 1.43 mg/l], p = 0.001). After multivariable adjustment, both BTP (hazard ratio: 1.41, 95% confidence interval: 1.06 to 1.88; p = 0.018) and cystatin C (hazard ratio: 1.50, 95% confidence interval: 1.13 to 2.01; p = 0.006) were significant predictors of death/HF hospitalization, whereas serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were no longer significant. In patients with an estimated glomerular filtration rate >60 ml/min/1.73 m(2), elevated concentrations of BTP and cystatin C were still associated with significantly higher risk of adverse clinical events (p < 0.05). Net reclassification index analysis suggested cystatin C and BTP deliver comparable information regarding prognosis. CONCLUSIONS Among patients hospitalized with ADHF, BTP and cystatin C predict risk of death and/or HF hospitalization and are superior to standard measures of renal function for this indication.

Highly sensitive troponin T for risk stratification of acutely destabilized heart failure

BACKGROUND A highly sensitive assay for troponin T (hsTnT) has been recently developed, which allows for the detection of even minor myocardial necrosis with high precision. It remains unexplored whether hsTnT provides incremental prognostic accuracy beyond conventional (c)TnT in patients with acutely decompensated heart failure (ADHF). METHODS A total of 202 consecutive patients admitted with ADHF and without criteria for acute myocardial infarction were studied. Troponin T was measured using the highly sensitive assay and compared with the conventional method. Patients were clinically followed up at a median of 406 days, with a primary outcome measure of all-cause mortality. RESULTS The high-sensitive assay detected measurable TnT in 98% of patients vs 56% for cTnT; 81% had an hsTnT above the 99th percentile for a healthy reference population, and it reclassified 60% of those with undetectable cTnT. Both TnT methods predicted the risk of death in adjusted multivariable Cox regression analyses, without a superiority of hsTnT over cTnT in the entire population (area under the curve 0.67 vs 0.71, P = .2). Among patients with a cTnT below 0.03 ng/mL (the lowest cut-point with <10% imprecision; n = 134), solely hsTnT improved the prediction of death over clinical risk factors (relative integrated discrimination improvement +36%, P = .01) and hsTnT above 20 pg/mL identified a significant higher risk of death (hazard ratio 4.7, 95% CI 1.6-13.8, P = .005). CONCLUSION Among patients with ADHF, myocardial necrosis (as detected with the hsTnT assay) was nearly ubiquitous. The highly sensitive assay for TnT provides comparable prognostic information to cTnT overall, but among those in whom the cTnT method was less precise or frankly negative, the hsTnT assay provided prognostic information.

El ancho de distribución eritrocitaria aporta valor pronóstico adicional en pacientes ambulatorios con insuficiencia cardiaca crónica

INTRODUCTION AND OBJECTIVES Red blood cell distribution width has emerged as a new prognostic biomarker in cardiovascular diseases. Its additional value in risk stratification of patients with chronic heart failure has not yet been established. METHODS A total of 698 consecutive outpatients with chronic heart failure were studied (median age 71 years [interquartile range, 62-77], 63% male, left ventricular ejection fraction 40 [14]%). On inclusion, the red cell distribution width was measured and clinical, biochemical, and echocardiographic variables were recorded. The median follow-up period was 2.5 years [interquartile range 1.2-3.7]. RESULTS A total of 211 patients died and 206 required hospitalization for decompensated heart failure. Kaplan-Meier analysis showed an increase in the probability of death and hospitalization for heart failure with red cell distribution width quartiles (log rank, P<.001). A ROC analysis identified a red cell distribution width of 15.4% as the optimal cut-off point for a significantly higher risk of death (P<.001; hazard ratio=2.63; 95% confidence interval, 2.01-3.45) and hospitalization for heart failure (P<.001; hazard ratio=2.37; 95% confidence interval, 1.80-3.13). This predictive value was independent of other covariates, and regardless of the presence or not of anaemia. Importantly, the addition of red cell distribution width to the clinical risk model for the prediction of death or hospitalization for heart failure at 1 year had a significant integrated discrimination improvement of 33% (P<.001) and a net reclassification improvement of 10.3% (P=.001). CONCLUSIONS Red cell distribution width is an independent risk marker and adds prognostic information in outpatients with chronic heart failure. These findings suggest that this biological measurement should be included in the management of these patients. Full English text available from:www.revespcardiol.org.

Utilidad de la prueba de troponina T de alta sensibilidad en la detección de rechazo agudo en trasplante cardiaco

INTRODUCTION AND OBJECTIVES Detection of acute allograft rejection in heart transplant recipients by noninvasive methods is a challenge in the management of these patients. In this study, the usefulness of a new highly sensitive method for the measurement of troponin T is evaluated. METHODS We designed a case-crossover study, in which each patient served as his or her own control, by selecting samples from treated acute rejection episodes (29 cases) and samples obtained immediately before and/or after rejection (38 controls). The highly sensitive troponin T was measured by a new pre-commercial test (Elecsys Troponin T HS). RESULTS In all samples, highly sensitive troponin T was detectable, with a median of 0.068 ng/L (IQR, 0.030-0.300 ng/L). The levels correlated with right atrial pressure (r=0.37; P=.002), N-terminal pro-brain natriuretic peptide concentration (r=0.67; P<.001), and time since transplantation (r=-0.81; P<.001). The highly sensitive troponin T concentrations were higher in patients with rejection (0.155 ng/mL vs 0.047 ng/mL; P=.006). In the receiver operating characteristic analysis, the area under the curve was 0.67 (95% confidence interval, 0.53-0.77) and the best cutoff was 0.035 ng/mL, which was associated with rejection (odds ratio=3.7; 95% confidence interval, 1.2-11.9; P=.02). By restricting the analysis to the first 2 months, the area under the curve increased to 0.86 (95% confidence interval 0.66-0.97), with an optimal cutoff of 1.10 ng/mL (S=58% [28%-85%]; E=100% [74%-100%]). CONCLUSIONS Troponin T was detectable in all samples when a new highly sensitive assay was used, and at higher concentrations in the presence of acute rejection; however, the usefulness of this test in patient management is limited to support for clinical or histological suspicion of rejection, especially in the early post-transplant period.

Valor pronóstico comparativo del pro-péptido natriurético tipo B aminoterminal urinario en pacientes con insuficiencia cardiaca aguda descompensada

INTRODUCTION AND OBJECTIVES Urinary concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP) may be prognostically meaningful; however, direct comparison to plasma concentrations of this marker have not been performed in patients with acutely decompensated heart failure (ADHF). The aims of this study were to compare the prognostic value of plasma versus urinary NT-proBNP concentration for the risk stratification of patients with ADHF. METHODS Consecutive hospitalized patients with ADHF were prospectively studied. Blood and urine samples were simultaneously collected on hospital arrival to determine NT-proBNP concentrations. Clinical follow-up was obtained, and the occurrence of mortality and heart failure hospitalization was registered. RESULTS The study included 138 patients (median, 74 years [interquartile range, 67-80]; 54% men). During a median follow-up period of 387 days [interquartile range, 161-559], 65 patients (47%) suffered adverse clinical events. Plasma NT-proBNP concentration was higher among patients who presented adverse events (4561 pg/mL [2191-8631] vs 2906 pg/mL [1643-5823]; P=.03), whereas urinary NT-proBNP was similar in both groups (P=.62). After multivariable Cox regression analyses, plasma NT-proBNP concentration was associated with a higher risk of adverse events, whether considered continuously (per 100 pg/mL; hazard ratio [HR]=1.004; 95% confidence interval [CI], 1.001-1.007; P=.003) or categorically (≥3345 pg/mL; HR=2.35; 95%CI, 1.41-3.93; P=.001). In contrast, urinary NT-proBNP concentration was not associated with adverse outcomes. CONCLUSIONS Plasma NT-proBNP concentration is superior to urinary NT-proBNP concentration for the prediction of adverse clinical outcomes among unselected patients with ADHF.

'Management multiple myeloma during pregnancy: a case report and review'.

Multiple myeloma (MM) is a hematologic neoplasm characterized by plasma tumor cell proliferation in the bone marrow. Its a rare malignancy before a 40‐year‐old and it is extremely uncommon during pregnancy. We report the case of a 37‐year‐old woman with a newly diagnosed IgG λ MM (Durie–Salmon stage IIIA, International Staging System II and good prognosis cytogenetic) at the 27th week of her pregnancy. Our management during pregnancy, the delivery, and initiation of anti‐myeloma treatment with bortezomib, lenalidomide, and dexamethasone are published. There are a few reviews reporting the most common features and management of MM during pregnancy. We perform a comprehensive review of all 32 cases reported between 1965 and 2014 in which a MM was diagnosed during pregnancy including score, cytogenetic results, labor characteristics, and response to therapy. About 53% of pregnant women did not start treatment before partum. Cesarean section was the most common form of delivery (82%). About 88% of newborns were healthy, although most of them were premature (73%). Management of a MM diagnosed during pregnancy should be based on the presence of myeloma‐related organ damage to secure survival of the mother without fetal adverse effects related to treatment. Serial fetal ultrasound may be helpful in order to avoid complications. The cesarean section may be preferred depending on maternal and fetus prognosis. Whole‐body diffusion‐weighted imaging minimal response could be an appropriate technique to discard plasmacytomas during pregnancy in critical situations such as the appearance of symptoms of spinal cord compression. Therapeutic choices should be agreed with the pregnant after a thorough discussion of the prognostic factors of the disease and the potential risk for the fetus and the patient. While awaiting partum, dexamethasone is a non‐toxic treatment. Triple therapy including a proteasome inhibitor should be started quickly after delivery. Copyright

Severe aortic valve stenosis with low-gradient and preserved ejection fraction: a misclassification issue?

INTRODUCTION AND OBJECTIVES Low-gradient severe aortic stenosis with preserved ejection fraction is a controversial entity. Misclassification of valvulopathy severity could explain the inconsistencies reported in the prognosis of these patients. Planimetry of the aortic area using three-dimensional transesophageal echocardiography could clear up these doubts. The objectives were to assess the agreement between measurements of the valvular aortic area by continuity equation in transthoracic echocardiography and that obtained through planimetry with three-dimensional transesophageal echocardiography in low-gradient severe aortic stenosis patients. METHODS Cross-sectional descriptive study of consecutive patients referred due to severe aortic stenosis. Patients underwent transthoracic echocardiography and three-dimensional transesophageal echocardiography. Paradoxical low-gradient severe aortic stenosis was defined by the presence in the transthoracic echocardiography of aortic valve area<1 cm(2), mean ventricular gradient<40 mmHg, and ejection fraction ≥ 50%. Concordance between the two techniques was evaluated. RESULTS Of 212 consecutive severe aortic stenosis patients evaluated, 63 cases (29.7%) fulfilled the paradoxical low-gradient inclusion criteria. We obtained three-dimensional aortic valve planimetry in 61 (96.8%) of those patients. In 52 patients (85.2%), aortic valve area by transesophageal echocardiography was <1 cm(2). The intraclass correlation coefficient between the two methods was 0.505 (95% confidence interval, 0.290-0.671; P<.001). CONCLUSIONS Paradoxical low-gradient severe aortic stenosis is an actual entity, confirmed in 85% of cases evaluated by three-dimensional transesophageal echocardiography.

Factors Influencing the Phenotypic Expression of Hypertrophic Cardiomyopathy in Genetic Carriers

INTRODUCTION AND OBJECTIVES Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. METHODS We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. RESULTS The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. CONCLUSIONS Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations.

Value of the “Standing Test” in the Diagnosis and Evaluation of Beta-blocker Therapy Response in Long QT Syndrome

INTRODUCTION AND OBJECTIVES Patients with congenital long QT syndrome (LQTS) have an abnormal QT adaptation to sudden changes in heart rate provoked by standing. The present study sought to evaluate the standing test in a cohort of LQTS patients and to assess if this QT maladaptation phenomenon is ameliorated by beta-blocker therapy. METHODS Electrographic assessments were performed at baseline and immediately after standing in 36 LQTS patients (6 LQT1 [17%], 20 LQT2 [56%], 3 LQT7 [8%], 7 unidentified-genotype patients [19%]) and 41 controls. The corrected QT interval (QTc) was measured at baseline (QTcsupine) and immediately after standing (QTcstanding); the QTc change from baseline (ΔQTc) was calculated as QTcstanding - QTcsupine. The test was repeated in 26 patients receiving beta-blocker therapy. RESULTS Both QTcstanding and ΔQTc were significantly higher in the LQTS group than in controls (QTcstanding, 528 ± 46ms vs 420 ± 15ms, P < .0001; ΔQTc, 78 ± 40ms vs 8 ± 13ms, P < .0001). No significant differences were noted between LQT1 and LQT2 patients. Typical ST-T wave patterns appeared after standing in LQTS patients. Receiver operating characteristic curves of QTcstanding and ΔQTc showed a significant increase in diagnostic value compared with the QTcsupine (area under the curve for both, 0.99 vs 0.85; P < .001). Beta-blockers attenuated the response to standing in LQTS patients (QTcstanding, 440 ± 32ms, P < .0001; ΔQTc, 14 ± 16ms, P < .0001). CONCLUSIONS Evaluation of the QTc after the simple maneuver of standing shows a high diagnostic performance and could be important for monitoring the effects of beta-blocker therapy in LQTS patients.

Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing.

INTRODUCTION AND OBJECTIVES Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. METHODS We identified the KCNH2-H562R mutation in a 65-year-old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. RESULTS The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. CONCLUSIONS Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment.