Significado pronóstico y evolución a largo plazo de la frecuencia cardiaca en los pacientes con trasplante cardiaco / Prognostic significance of heart rate and its long-term trend in cardiac transplant patients

Introducción y objetivos. Estudiar la evolución y el significado pronóstico de la frecuencia cardiaca tras el trasplante cardiaco. Métodos. Estudio observacional de 170 pacientes que recibieron un trasplante cardiaco bicavo entre 1995 y 2005; todos estaban en ritmo sinusal. La frecuencia cardiaca en reposo se determinó a partir de electrocardiogramas al final del primer año tras el trasplante y anualmente hasta el décimo año. Mediante análisis de Cox, se evaluó la incidencia de eventos adversos en un seguimiento medio de 8,9 ± 3,1 años. El evento principal del estudio fue la variable combinada muerte o disfunción del injerto. Resultados. La frecuencia cardiaca en reposo, medida al final del primer año tras el trasplante, fue un predictor independiente del evento combinado principal (hazard ratio = 1,054; intervalo de confianza del 95%, 1,028-1,080; p < 0,001). Se observó una asociación estadísticamente significativa con la mortalidad total (hazard ratio = 1,058; intervalo de confianza del 95%, 1,030-1,087; p < 0,001) y con la mortalidad por causas cardiacas (hazard ratio = 1,069; intervalo de confianza del 95%, 1,026-1,113; p = 0,001), pero no con la disfunción del injerto (hazard ratio = 1,028; intervalo de confianza del 95%, 0,989-1,069; p = 0,161). Para los pacientes con frecuencia cardiaca ≥ 105 y < 90 lpm frente a aquellos con 90-104 lpm, las hazard ratio del evento principal fueron, respectivamente, 2,233 (intervalo de confianza del 95%, 1,250-3,989, p = 0,007) y 0,380 (intervalo de confianza del 95%, 0,161-0,895; p = 0,027). Este parámetro presentó una tendencia decreciente en los primeros 10 años del trasplante (p = 0,001). Los pacientes con incremento neto de frecuencia cardiaca en el seguimiento mostraron mayor incidencia de eventos adversos. Conclusiones. La frecuencia cardiaca elevada es un marcador pronóstico adverso tras el trasplante cardiaco (AU)

Introduction and objectives. The aim of the present study was to examine the prognostic significance of heart rate and its trend in heart transplantation. Methods. This observational study enrolled 170 patients who received a bicaval heart transplant between 1995 and 2005; all were in sinus rhythm. The resting heart rate was determined via electrocardiography at the end of the first posttransplant year and annually until the tenth year. Cox analysis was used to evaluate the incidence of adverse events with a mean (standard deviation) follow-up of 8.9 (3.1) years. The primary study end point was the composite outcome of death or graft dysfunction. Results. The resting heart rate at the end of the first posttransplant year was an independent predictor of the primary composite end point (hazard ratio = 1.054; 95% confidence interval, 1.028-1.080; P < .001) and was significantly associated with total mortality (hazard ratio = 1.058; 95% confidence interval, 1.030-1.087; P < .001) and mortality from cardiac causes (hazard ratio = 1.069; 95% confidence interval, 1.026-1.113; P = .001), but not with graft dysfunction (hazard ratio = 1.028; 95% confidence interval, 0.989-1.069; P = .161). For patients with a heart rate ≥ 105 or < 90 bpm vs those with 90-104 bpm, the hazard ratios of the primary end point were 2.233 (95% confidence interval, 1.250-3.989; P = .007) and 0.380 (95% confidence interval, 0.161-0.895; P = .027), respectively. Heart rate tended to decrease in the first 10 years after transplantation (P = .001). Patients with a net increase in heart rate during follow-up showed a higher incidence of adverse events. Conclusions. An elevated heart rate is an adverse prognostic marker after heart transplantation (AU)

A MicroRNA-Transcription Factor Blueprint for Early Atrial Arrhythmogenic Remodeling.

Spontaneous self-terminating atrial fibrillation (AF) is one of the most common heart rhythm disorders, yet the regulatory molecular mechanisms underlying this syndrome are rather unclear. MicroRNA (miRNA) transcriptome and expression of candidate transcription factors (TFs) with potential roles in arrhythmogenesis, such as Pitx2, Tbx5, and myocardin (Myocd), were analyzed by microarray, qRT-PCR, and Western blotting in left atrial (LA) samples from pigs with transitory AF established by right atrial tachypacing. Induced ectopic tachyarrhythmia caused rapid and substantial miRNA remodeling associated with a marked downregulation of Pitx2, Tbx5, and Myocd expression in atrial myocardium. The downregulation of Pitx2, Tbx5, and Myocd was inversely correlated with upregulation of the corresponding targeting miRNAs (miR-21, miR-10a/10b, and miR-1, resp.) in the LA of paced animals. Through in vitro transient transfections of HL-1 atrial myocytes, we further showed that upregulation of miR-21 did result in downregulation of Pitx2 in cardiomyocyte background. The results suggest that immediate-early miRNA remodeling coupled with deregulation of TF expression underlies the onset of AF.

Organización de la atención a la insuficiencia cardiaca en España: unidades existentes y características / Organization of heart failure care in Spain: characteristics of heart failure units

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Prognostic Significance of Heart Rate and its Long-term Trend in Cardiac Transplant Patients.

INTRODUCTION AND OBJECTIVES: The aim of the present study was to examine the prognostic significance of heart rate and its trend in heart transplantation. METHODS: This observational study enrolled 170 patients who received a bicaval heart transplant between 1995 and 2005; all were in sinus rhythm. The resting heart rate was determined via electrocardiography at the end of the first posttransplant year and annually until the tenth year. Cox analysis was used to evaluate the incidence of adverse events with a mean (standard deviation) follow-up of 8.9 (3.1) years. The primary study end point was the composite outcome of death or graft dysfunction. RESULTS: The resting heart rate at the end of the first posttransplant year was an independent predictor of the primary composite end point (hazard ratio=1.054; 95% confidence interval, 1.028-1.080; P<.001) and was significantly associated with total mortality (hazard ratio=1.058; 95% confidence interval, 1.030-1.087; P<.001) and mortality from cardiac causes (hazard ratio=1.069; 95% confidence interval, 1.026-1.113; P=.001), but not with graft dysfunction (hazard ratio=1.028; 95% confidence interval, 0.989-1.069; P=.161). For patients with a heart rate ≥ 105 or<90 bpm vs those with 90-104 bpm, the hazard ratios of the primary end point were 2.233 (95% confidence interval, 1.250-3.989; P=.007) and 0.380 (95% confidence interval, 0.161-0.895; P=.027), respectively. Heart rate tended to decrease in the first 10 years after transplantation (P=.001). Patients with a net increase in heart rate during follow-up showed a higher incidence of adverse events. CONCLUSIONS: An elevated heart rate is an adverse prognostic marker after heart transplantation.

Valor pronóstico de la disfunción ventricular izquierda inducida por el ejercicio en pacientes hipertensos sin enfermedad arterial coronaria / Prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients without coronary artery disease

Introducción y objetivos El propósito de este estudio es evaluar el valor pronóstico de la disfunción sistólica ventricular izquierda inducida por el ejercicio en pacientes hipertensos con ecocardiograma en reposo normal y sin enfermedad arterial coronaria. Métodos De nuestra base de datos de pacientes referidos a ecocardiografía de ejercicio, se identificó a 93 pacientes hipertensos, con fracción de eyección del ventrículo izquierdo en reposo normal (≥ 50%), sin cardiopatía estructural ni evidencia de enfermedad arterial coronaria en la angiografía. Del total, 39 pacientes desarrollaron disfunción sistólica ventricular izquierda inducida por el ejercicio (definida como caída de la fracción de eyección del ventrículo izquierdo por debajo de 50% en el máximo ejercicio) y 54 mostraron una respuesta normal de la fracción de eyección del ventrículo izquierdo al ejercicio. El seguimiento medio fue 6,1 ± 3,7 años. Los objetivos primarios fueron muerte por cualquier causa, muerte cardiaca, aparición de insuficiencia cardiaca y el evento combinado de muerte cardiaca o insuficiencia cardiaca. Resultados La aparición de disfunción sistólica ventricular izquierda inducida por el ejercicio se asoció con mayor riesgo de muerte por cualquier causa (hazard ratio = 3,4; intervalo de confianza del 95%, 1,1-10,3), muerte cardiaca (hazard ratio = 5,6; intervalo de confianza del 95%, 1,1-29,4), insuficiencia cardiaca (hazard ratio=8,9; intervalo de confianza del 95%, 1,8-44,2) y del evento combinado (hazard ratio=5,7; intervalo de confianza del 95%, 1,7-19,0). En un análisis multivariable, la disfunción sistólica ventricular izquierda inducida por el ejercicio continuó asociándose de manera independiente con mayor riesgo de insuficiencia cardiaca (hazard ratio = 6,9; intervalo de confianza del 95%, 1,3-37,4) y del evento combinado de muerte cardiaca o insuficiencia cardiaca (hazard ratio = 4,5; intervalo de confianza del 95%, 1,2-16,0). Conclusiones: La aparición de disfunción sistólica ventricular izquierda inducida por el ejercicio en pacientes hipertensos con fracción de eyección del ventrículo izquierdo normal en reposo y ausencia de enfermedad arterial coronaria es un potente predictor de eventos cardiacos y podría ser un marcador precoz de cardiopatía hipertensiva

Introduction and objectives We sought to assess the prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients with normal resting echocardiography and absence of coronary artery disease. Methods From our database of patients referred for treadmill exercise echocardiography, we identified 93 hypertensive patients with preserved resting left ventricular ejection fraction (≥ 50%), no evidence of structural heart disease, and absence of coronary artery disease on angiography. Overall, 39 patients developed exercise-induced left ventricular systolic dysfunction (defined as a decrease in left ventricular ejection fraction below 50% at peak exercise) and 54 exhibited a normal left ventricular ejection fraction response to exercise. The mean follow-up was 6.1 (3.7) years. End points were all-cause mortality, cardiac death, heart failure, and the composite event of cardiac death or heart failure. Results Patients who developed exercise-induced left ventricular systolic dysfunction were at higher risk of death from any cause (hazard ratio = 3.4; 95% confidence interval, 1.1-10.3), cardiac death (hazard ratio = 5.6; 95%CI, 1.1-29.4), heart failure (hazard ratio = 8.9; 95% confidence interval, 1.8-44.2), and the composite end point (hazard ratio = 5.7; 95% confidence interval, 1.7-19.0). In the multivariate analysis, exercise-induced left ventricular systolic dysfunction remained an independent predictor of both heart failure (hazard ratio = 6.9; 95% CI, 1.3-37.4) and the composite event of cardiac death or heart failure (hazard ratio = 4.5; 95% confidence interval, 1.2-16.0).Conclusions In hypertensive patients with preserved resting left ventricular ejection fraction and absence of coronary artery disease, exercise-induced left ventricular systolic dysfunction is a strong predictor of cardiac events and may represent early hypertensive heart disease (AU)

Venous thromboembolism in heart transplant recipients: incidence, recurrence and predisposing factors.

BACKGROUND: A high frequency of venous thromboembolism (VTE) has been observed after lung, kidney, and liver transplantation. However, data about the incidence of this complication among heart transplant (HT) recipients are lacking. METHODS: We analyzed the incidence, recurrence, and predisposing factors of VTE in a single-center cohort of 635 patients who underwent HT from April 1991 to April 2013. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were considered as VTE episodes. RESULTS: During a median post-transplant follow-up of 8.4 years, 62 VTE episodes occurred in 54 patients (8.5%). Incidence rates of VTE, DVT, and PE were, respectively, 12.7 (95% confidence interval [CI], 9.7-16.3), 8.4 (95% CI, 6.0-11.4), and 7.0 (95% CI 4.8-9.7) episodes per 1,000 patient-years. Incidence rates of VTE during the first post-transplant year and beyond were, respectively, 45.1 (95% CI, 28.9-67.1) and 8.7 (95% CI 6.2-11.2) episodes per 1,000 patient-years. The incidence rate of VTE recurrence after a first VTE episode was 30.5 (95% CI, 13.2-60.2) episodes per 1,000 patient-years. By means of multivariable Cox regression, chronic renal dysfunction, older age, obesity, and the use of mammalian target of rapamycin inhibitors were identified as independent risk factors for VTE among HT recipients. CONCLUSIONS: VTE is a frequent complication after HT, mainly during the first post-operative year. In view of a high recurrence rate, long-term anti-coagulation should be considered in HT recipients who experience a first VTE episode.

Exercise echocardiography and cardiac magnetic resonance imaging to predict outcome in patients with hypertrophic cardiomyopathy.

AIMS: We have observed that wall motion abnormalities (WMAs) during exercise echocardiography (ExE) are associated to events in hypertrophic cardiomyopathy (HCM). Our objective was to evaluate ExE and cardiac magnetic resonance (CMR) to predict outcome in HCM. METHODS AND RESULTS: ExE and CMR were performed in 148 patients with HCM. During follow-up (7.1 ± 2.7 years), there were 7 hard events (Hard-E) and 26 combined events (Comb-E). Exercise WMAs were observed in 13 patients (8.8%), perfusion defects in 10 (6.8%), and late gadolinium enhancement (LGE) in 48 (32.4%). WMAs were seen in 57% of patients with Hard-E vs. 6% without (P = 0.001) and in 23 and 6% with and without Comb-E (P = 0.005). Perfusion defects were also more frequent in patients with Hard-E than without (43 vs. 5%, P = 0.007) and in patients with Comb-E than without (23 vs. 5%, P = 0.002). LGE (g) was greater in patients with Comb-E than without [median (25th-75th percentile) 0 (0-21.1) vs. 0 (0-9.3) g P = 0.04]. Univariable predictors of Comb-E included NYHA class ≥2, peak double product, ΔWMSI, and CMR data. Peak double product [Hazard ratios (HR) = 0.99, confidence intervals (CI) 95% 0.99-0.99, P = 0.02] and ΔWMSI (HR = 404, CI 95% 12-13681, P = 0.001) remained independent predictors. Peak WMSI correlated with myocardial mass with LGE (r = 0.20, P = 0.02) and with perfusion defect area (r = 0.40, P < 0.001). LGE affecting ≥15% of the left ventricle was observed in 38% of patients with exercise WMAs vs. 12% without (P = 0.009). CONCLUSION: CMR data are associated to exercise WMAs in patients with HCM. ExE and CMR may help to predict outcome in them.

Prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients without coronary artery disease.

INTRODUCTION AND OBJECTIVES: We sought to assess the prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients with normal resting echocardiography and absence of coronary artery disease. METHODS: From our database of patients referred for treadmill exercise echocardiography, we identified 93 hypertensive patients with preserved resting left ventricular ejection fraction (≥ 50%), no evidence of structural heart disease, and absence of coronary artery disease on angiography. Overall, 39 patients developed exercise-induced left ventricular systolic dysfunction (defined as a decrease in left ventricular ejection fraction below 50% at peak exercise) and 54 exhibited a normal left ventricular ejection fraction response to exercise. The mean follow-up was 6.1 (3.7) years. End points were all-cause mortality, cardiac death, heart failure, and the composite event of cardiac death or heart failure. RESULTS: Patients who developed exercise-induced left ventricular systolic dysfunction were at higher risk of death from any cause (hazard ratio=3.4; 95% confidence interval, 1.1-10.3), cardiac death (hazard ratio=5.6; 95%CI, 1.1-29.4), heart failure (hazard ratio=8.9; 95% confidence interval, 1.8-44.2), and the composite end point (hazard ratio=5.7; 95% confidence interval, 1.7-19.0). In the multivariate analysis, exercise-induced left ventricular systolic dysfunction remained an independent predictor of both heart failure (hazard ratio=6.9; 95% CI, 1.3-37.4) and the composite event of cardiac death or heart failure (hazard ratio=4.5; 95% confidence interval, 1.2-16.0). CONCLUSIONS: In hypertensive patients with preserved resting left ventricular ejection fraction and absence of coronary artery disease, exercise-induced left ventricular systolic dysfunction is a strong predictor of cardiac events and may represent early hypertensive heart disease.

Genetics of cardiomyopathies: novel perspectives with next generation sequencing.

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium usually of genetic origin and with familial presentation. The identification of multiple genetic causes for these diseases has opened a new window for early diagnosis, understanding of their natural history and improvement in risk stratification and management. However, in the past years, the clinical application of genetics has been limited by the prohibiting cost and restricted yield of the available genotyping technologies. The emergence of Next Generation Sequencing (NGS) has completely changed this scenario. This group of sequencing technologies allow the evaluation of hundreds or even thousands of genes in parallel at an affordable cost. Now the challenge is not genotyping per se but the interpretation of the complex results that NGS generates. In this paper we review the main aspects related to the application and impact of Next Generation Sequencing in the study of cardiomyopathies: technology, analysis procedures, bioinformatics, clinical validation and interpretation of results.

Torsión ventricular izquierda durante el ejercicio en pacientes con y sin respuesta isquémica a la ecocardiografía de ejercicio / Left Ventricular Torsion During Exercise in Patients With and Without Ischemic Response to Exercise Echocardiography

Introducción y objetivos La torsión ventricular izquierda disminuye durante la isquemia miocárdica transmural, pero el efecto del ejercicio en aquella no se ha estudiado de manera detallada. Nuestra hipótesis era que la isquemia inducida por el ejercicio puede deteriorar la torsión ventricular izquierda. Por consiguiente, nuestro objetivo fue estudiar los efectos del ejercicio en la torsión ventricular izquierda en pacientes con una respuesta normal a la ecocardiografía de ejercicio y en pacientes con una respuesta normal. Métodos Se llevó a cabo un análisis retrospectivo de 172 pacientes con fracción de eyección Métodos: Se llevó a cabo un análisis retrospectivo de 172 pacientes con fracción de eyección ≥ 50% remitidos a ecocardiografía de ejercicio, a los que se examinó mediante speckle tracking en reposo, en ejercicio máximo y después del ejercicio. La torsión se definió como rotación apical - rotación basal (en grados) / longitud del ventrículo izquierdo (en centímetros). Un total de 114 pacientes presentaron una ecocardiografía de esfuerzo normal y 58 mostraron respuesta isquémica a la ecocardiografía de ejercicio. RESULTADOS: Los pacientes con respuesta isquémica a la prueba presentaron menor rotación basal en el ejercicio máximo (+0,30 ± 2,39° frente a -0,65 ± 2,61° en el grupo de respuesta normal; p = 0,03), mientras que la rotación máxima apical fue similar (respuesta isquémica a la prueba, 7,80 ± 3,51°; respuesta normal, 7,27 ± 3,28°; p = 0,36). La torsión en el ejercicio máximo fue también similar (1,07 ± 0,60° en el grupo de respuesta isquémica frente a 1,16 ± 0,57° en el grupo de respuesta normal; p = 0,37). Se observó mayor deterioro de la rotación basal máxima en los pacientes con afección anterior o anterior + posterior (respuesta isquémica anterior, +1,22 ± 2,45°; respuesta isquémica anterior + posterior, -0,20 ± 2,25°; respuesta isquémica posterior, -0,71 ± 1,96°; respuesta normal, -0,65 ± 2,60°; p = 0,02). CONCLUSIONES: La rotación basal en el ejercicio máximo está deteriorada en los pacientes con respuesta isquémica a la ecocardiografía de ejercicio, en especial la de quienes presentan afección anterior. La rotación apical y la torsión son similares a las de los pacientes con una ecocardiografía de ejercicio normal

Introduction and objectives Left ventricular torsion decreases during transmural myocardial ischemia, but the effect of exercise on left ventricular torsion has not been widely studied. We hypothesized that exercise-induced ischemia may impair left ventricular torsion. Therefore, our aim was to study the effects of exercise on left ventricular torsion in patients with an ischemic response to exercise echocardiography and in patients with a normal response. Methods A retrospective analysis was performed in 172 patients with ejection fraction patients with ejection fraction ≥ 50% who were referred for exercise-echocardiography and studied by speckle imaging at rest, peak and postexercise. Torsion was defined as apical rotation - basal rotation (in degrees) / left ventricular length (in centimeters). A total of 114 patients had a normal exercise echocardiography and 58 patients had an ischemic response to exercise echocardiography. Results: Patients with ischemic response to the test exhibited less basal rotation at peak exercise (+0.30° [2.39°] vs –0.65° [2.61°] in the normal group; P = .03), whereas peak apical rotation was similar (ischemic response to the test, 7.80° [3.51°]; normal response, 7.27° [3.28°]; P =.36). Torsion at peak exercise was also similar (1.07° [0.60°] in the ischemic response to the test group vs 1.16° [0.57°] in normal group; P =.37). A more impaired peak basal rotation was found in patients with anterior or anterior+posterior involvement (anterior ischemic response, +1.22° [2.45°]; anterior + posterior ischemic response, –0.20° [2.25°]; posterior ischemic response, –0.71° [1.96°]; normal response, –0.65° [2.60°]; P =.02). Conclusions: Basal rotation at peak exercise is impaired in patients with an ischemic response to exercise echocardiography, particularly in those with anterior involvement. Apical rotation and torsion are similar to those in patients with normal exercise echocardiography

Left ventricular torsion during exercise in patients with and without ischemic response to exercise echocardiography.

INTRODUCTION AND OBJECTIVES: Left ventricular torsion decreases during transmural myocardial ischemia, but the effect of exercise on left ventricular torsion has not been widely studied. We hypothesized that exercise-induced ischemia may impair left ventricular torsion. Therefore, our aim was to study the effects of exercise on left ventricular torsion in patients with an ischemic response to exercise echocardiography and in patients with a normal response. METHODS: A retrospective analysis was performed in 172 patients with ejection fraction ≥ 50% who were referred for exercise-echocardiography and studied by speckle imaging at rest, peak and postexercise. Torsion was defined as apical rotation - basal rotation (in degrees) / left ventricular length (in centimeters). A total of 114 patients had a normal exercise echocardiography and 58 patients had an ischemic response to exercise echocardiography. RESULTS: Patients with ischemic response to the test exhibited less basal rotation at peak exercise (+0.30° [2.39°] vs -0.65° [2.61°] in the normal group; P = .03), whereas peak apical rotation was similar (ischemic response to the test, 7.80° [3.51°]; normal response, 7.27° [3.28°]; P =.36). Torsion at peak exercise was also similar (1.07° [0.60°] in the ischemic response to the test group vs 1.16° [0.57°] in normal group; P =.37). A more impaired peak basal rotation was found in patients with anterior or anterior+posterior involvement (anterior ischemic response, +1.22° [2.45°]; anterior + posterior ischemic response, -0.20° [2.25°]; posterior ischemic response, -0.71° [1.96°]; normal response, -0.65° [2.60°]; P =.02). CONCLUSIONS: Basal rotation at peak exercise is impaired in patients with an ischemic response to exercise echocardiography, particularly in those with anterior involvement. Apical rotation and torsion are similar to those in patients with normal exercise echocardiography.

Exaggerated exercise blood pressure response and risk of stroke in patients referred for stress testing.

BACKGROUND/OBJECTIVES: There is some evidence to suggest that exercise systolic blood pressure (SBP) may be associated with future risk of stroke in subjects without a history of coronary artery disease (CAD). However, the value of an exaggerated exercise SBP response (EESBPR) for predicting stroke in patients referred for stress testing for clinical reasons has not been investigated. METHODS: We evaluated a community-based sample of 10,047 patients with known or suspected CAD who underwent treadmill exercise echocardiography. An EESBPR was defined as a peak exercise SBP of >220mmHg. The ratio of the increase in SBP during exercise to exercise workload (ΔSBPeEW) was also estimated. The endpoints were stroke of any type, ischemic stroke and hemorrhagic stroke. Median follow-up was 3.5years. RESULTS: Annualized rates of stroke of any type, ischemic stroke and hemorrhagic stroke were 0.6% (95% CI 0.53-0.67), 0.49% (95% CI 0.42-0.56) and 0.12% (95% CI 0.09-0.15) in patients without EESBPR vs. 0.69% (95% CI 0.37-1), 0.49% (95% CI 0.23-0.76) and 0.19% (95% CI 0.02-0.35) in those with EESBPR (p=0.68, 0.90 and 0.39, respectively). Similarly, there was no significant univariate association between ΔSBPeEW and the occurrence of any endpoint. In multivariate analysis, hypertension, male sex, age, diabetes mellitus and resting SBP remained predictors of stroke of any type. EESBPR and ΔSBPeEW were not predictors of any of the endpoints evaluated. CONCLUSION: We did not observe any significant association between exercise SBP and the future occurrence of stroke in patients with known or suspected CAD referred for exercise echocardiography.

Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes.

BACKGROUND: Pitx2 (paired-like homeodomain 2 transcription factor) is crucial for heart development, but its role in heart failure (HF) remains uncertain. The present study lays the groundwork implicating Pitx2 signalling in different modalities of HF. METHODOLOGY/PRINCIPAL FINDINGS: A variety of molecular, cell-based, biochemical, and immunochemical assays were used to evaluate: (1) Pitx2c expression in the porcine model of diastolic HF (DHF) and in patients with systolic HF (SHF) due to dilated and ischemic cardiomyopathy, and (2) molecular consequences of Pitx2c expression manipulation in cardiomyocytes in vitro. In pigs, the expression of Pitx2c, physiologically downregulated in the postnatal heart, is significantly re-activated in left ventricular (LV) failing myocardium which, in turn, is associated with increased expression of a restrictive set of Pitx2 target genes. Among these, Myf5 was identified as the top upregulated gene. In vitro, forced expression of Pitx2c in cardiomyocytes, but not in skeletal myoblasts, activates Myf5 in dose-dependent manner. In addition, we demonstrate that the level of Pitx2c is upregulated in the LV-myocardium of SHF patients. CONCLUSIONS/SIGNIFICANCE: The results provide previously unrecognized evidence that Pitx2c is similarly reactivated in postnatal/adult heart at distinct HF phenotypes and suggest that Pitx2c is involved, directly or indirectly, in the regulation of Myf5 expression in cardiomyocytes.

Long-term prognostic value of mitral regurgitation in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention.

The presence of mitral regurgitation (MR) is associated with an impaired prognosis in patients with ischemic heart disease. However, data with regard to the impact of this condition in patients with ST-segment elevation myocardial infarction (STEMI) treated by means of primary percutaneous coronary intervention (PPCI) are lacking. Our aim was to assess the effect of MR in the long-term prognosis of patients with STEMI after PPCI. We analyzed a prospective registry of 1,868 patients (mean age 62 ± 13 years, 79.9% men) with STEMI treated by PPCI in our center from January 2006 to December 2010. Our primary outcome was the composite end point of all-cause mortality or admission due to heart failure during follow-up. After exclusions, 1,036 patients remained for the final analysis. Moderate or severe MR was detected in 119 patients (11.5%). Those with more severe MR were more frequently women (p <0.001), older (p <0.001), and with lower ejection fraction (p <0.001). After a median follow-up of 2.8 years (1.7 to 4.3), a total of 139 patients (13.4%) experienced our primary end point. There was an association between the unfavorable combined event and the degree of MR (p <0.001). After adjustment for relevant confounders, moderate or severe MR remained as an independent predictor of the combined primary end point (adjusted hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.57 to 6.27) and each event separately (adjusted HR death 3.1, 95% CI 1.34 to 7.2; adjusted HR heart failure 3.3, 95% CI 1.16 to 9.4). In conclusion, moderate or severe MR detected early with echocardiography was independently associated with a worse long-term prognosis in patients with STEMI treated with PPCI.

Value of an exercise workload ≥10 metabolic equivalents for predicting inducible myocardial ischemia.

BACKGROUND: We sought to identify extensive ischemia on exercise echocardiography (ExE) relative to workload in patients without known coronary artery disease and to investigate whether ExE is useful in predicting outcomes in those with high exercise capacity (≥10 metabolic equivalents [METs]) plus a maximal test (≥85% of their maximal age-predicted heart rate [MAPHR]). METHODS AND RESULTS: The analysis was performed on 4269 patients who underwent ExE, of whom 3995 achieved ≥85% of their MAPHR. These patients were divided according to the reached workload (<7, 7-9, or ≥10 METs) and compared for ExE results. Outcomes in the group achieving ≥10 METs plus ≥85% of their MAPHR (n=2221) were specifically assessed. Ischemia was defined as new/worsening wall motion abnormalities with exercise. ExE results were different between groups because the METs were lower. Still, among patients achieving ≥10 METs plus ≥85% of their MAPHR, 9.3% had extensive ischemia and 6% multiterritory disease. During follow-up in this subgroup, 108 patients died and 42 had a major cardiac event. Annualized mortality and major cardiac event rates were 0.84% and 0.32% in patients without ischemia versus 2.26% and 0.84% in those with ischemia, respectively (P<0.001 and P=0.002, respectively). Ischemia was an independent predictor of mortality (hazard ratio, 1.88; 95% confidence interval, 1.23-2.89; P=0.004) and major cardiac event (hazard ratio, 2.39; 95% confidence interval, 1.22-4.71; P=0.01). CONCLUSIONS: Patients without known coronary artery disease achieving ≥10 METs plus ≥85% of their MAPHR may still have ischemia. However, the low event rates even in those with ischemia limit the usefulness of imaging for assessing outcomes in this group.

Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. METHODS AND RESULTS: We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. CONCLUSIONS: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.