Nuno Cortez-Dias

Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy.

Background— Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy. Methods and Results— A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19; P <0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32; P =0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation. Conclusions— Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.Background— Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy. Methods and Results— A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19; P<0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32; P=0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation. Conclusions— Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.

Cystatin C as Prognostic Biomarker in ST-Segment Elevation Acute Myocardial Infarction

Cystatin C is a marker of renal dysfunction, and preliminary studies have suggested it might have a role as a prognostic marker in patients with coronary artery disease. The aim of the present study was to evaluate the usefulness of cystatin C for risk stratification of patients with ST-segment elevation myocardial infarction, regarding in-hospital and long-term outcomes. We included 153 consecutive patients with ST-segment elevation myocardial infarction treated by primary angioplasty. The baseline cystatin C level was measured at coronary angiography. The in-hospital outcome was determined as progression to cardiogenic shock or in-hospital death, and the long-term outcome was assessed, considering the following end points: (1) death and (2) death or reinfarction. Of the 153 patients evaluated (age 61 ± 12 years; 75.6% men), 15 (14.4%) progressed to cardiogenic shock and 4 (2.7%) died during hospitalization. The patients who progressed to cardiogenic shock or died during hospitalization had significantly greater cystatin C levels (1.02 ± 0.44 vs 0.69 ± 0.24 mg/L; p = 0.001). Long-term follow-up was available for 130 patients (583 ± 163 days). Among them, 11 patients died and 7 had reinfarction. A high baseline cystatin C level was associated with an increased risk of death (hazard ratio 8.5; p = 0.009) and death or reinfarction (hazard ratio 3.89; p = 0.021). Furthermore, only high baseline cystatin C levels and left ventricular ejection fraction ≤40% were independent predictors of the long-term risk of death, with synergistic interaction between the 2. In conclusion, cystatin C is a new biomarker with significant added prognostic value for patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, predicting both short- and long-term outcomes.

Circulating miR-122-5p/miR-133b Ratio Is a Specific Early Prognostic Biomarker in Acute Myocardial Infarction

BACKGROUND MicroRNAs (miRNAs) are key players in cardiovascular development and disease. However, not only miRNAs of a cardiac origin have a critical role in heart function. Recent studies have demonstrated that miR-122-5p, a hepatic miRNA, increases in the bloodstream during ischemic cardiogenic shock and it is upregulated in the infarcted myocardium. The aim of the present study was to determine the potential of circulating miR-122-5p as a biomarker for early prognostic stratification of ST-segment elevation acute myocardial infarction (STEMI) patients. METHODSANDRESULTS One hundred and forty-two consecutive STEMI patients treated with primary angioplasty were included in the study. Serum levels of miR-1-3p, -122-5p, -133a-3p, -133b, -208b-3p and -499a-5p were measured at the time of cardiac catheterization by quantitative polymerase chain reaction and related to in-hospital and long-term outcome. During a follow up of 20.8 months, 9 patients died, 6 had recurrence of myocardial infarction, and 26 patients suffered an adverse cardiovascular event. Event-free survival was significantly worse in patients with a higher miR-122-5p/133b ratio (3rd tertile distribution, above 1.42 Log(10)), having almost a 9-fold higher risk of death or myocardial infarction and a 4-fold higher risk of adverse cardiovascular events. CONCLUSIONS This study showed that the miR-122-5p/133b ratio is a new prognostic biomarker for the early identification of STEMI patients at a higher risk of developing major adverse events after undergoing primary percutaneous coronary intervention. (Circ J 2016; 80: 2183-2191).

Association of metabolic risk factors with uncontrolled hypertension: comparison of the several definitions of metabolic syndrome

Aims: To evaluate the influence of metabolic syndrome in the effectiveness of antihypertensive treatment and to compare it using the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (2001 and 2004), International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung and Blood Institute (AHA-NHLBI) definitions. Methods: The VALSIM (Estudo de Prevalência da Síndrome Metabólica) survey was designed as an observational cross-sectional study performed in a primary healthcare setting in Portugal. The first two adult patients scheduled for an appointment on a given day were invited to participate. The treatment effectiveness was evaluated by the occurrence of uncontrolled hypertension (≥140/90 mmHg) in patients taking antihypertensive drugs. Logistic regression analysis was used to determine the association between uncontrolled hypertension and metabolic risk factors, with adjustments for age, sex, and pattern of antihypertensive treatment. Results: Among the 16 856 individuals evaluated, 8925-treated hypertensive patients were identified. Only 35.8% of them had controlled hypertension. The risk of poor blood pressure control increased with age, waist circumference, serum levels of triglycerides and HDL-cholesterol. Among treatable risk factors, metabolic syndrome as defined by NCEP-ATP III 2001 diagnostic criteria was the strongest independent predictor of uncontrolled hypertension (odds ratio: 1.23; 95% CI: 1.08–1.41; P = 0.002). In opposition, the IDF or AHA-NHLBI definitions of metabolic syndrome failed to identify patients at risk of poor blood pressure control. Conclusion: Metabolic syndrome is associated with lower effectiveness of antihypertensive therapy and the NCEP-ATP III 2001 definition of metabolic syndrome is the one that better identifies patients at risk of poor blood pressure control.

Triple-site pacing for cardiac resynchronization in permanent atrial fibrillation – Acute phase results from a prospective observational study

INTRODUCTION AND AIM Multi-site pacing is emerging as a new method for improving response to cardiac resynchronization therapy (CRT), but has been little studied, especially in patients with atrial fibrillation. We aimed to assess the effects of triple-site (Tri-V) vs. biventricular (Bi-V) pacing on hemodynamics and QRS duration. METHODS This was a prospective observational study of patients with permanent atrial fibrillation and ejection fraction <40% undergoing CRT implantation (n=40). One right ventricular (RV) lead was implanted in the apex and another in the right ventricular outflow tract (RVOT) septal wall. A left ventricular (LV) lead was implanted in a conventional venous epicardial position. Cardiac output (using the FloTrac™ Vigileo™ system), mean QRS and ejection fraction were calculated. RESULTS Mean cardiac output was 4.81±0.97 l/min with Tri-V, 4.68±0.94 l/min with RVOT septal and LV pacing, and 4.68±0.94 l/min with RV apical and LV pacing (p<0.001 for Tri-V vs. both BiV). Mean pre-implantation QRS was 170±25 ms, 123±18 ms with Tri-V, 141±25 ms with RVOT septal pacing and LV pacing and 145±19 with RV apical and LV pacing (p<0.001 for Tri-V vs. both BiV and pre-implantation). Mean ejection fraction was significantly higher with Tri-V (30±11%) vs. Bi-V pacing (28±12% with RVOT septal and LV pacing and 28±11 with RV apical and LV pacing) and pre-implantation (25±8%). CONCLUSION Tri-V pacing produced higher cardiac output and shorter QRS duration than Bi-V pacing. This may have a significant impact on the future of CRT.

Reduced Myocardial 123-Iodine Meta-iodobenzylguanidine Uptake: A Prognostic Marker in Familial Amyloid Polyneuropathy

Background— Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy. Methods and Results— A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19; P <0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32; P =0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation. Conclusions— Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.Background— Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy. Methods and Results— A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19; P<0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32; P=0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation. Conclusions— Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.

Triple-site pacing for cardiac resynchronization in permanent atrial fibrillation: follow-up results from a prospective observational study

Aims Cardiac Resynchronization Therapy (CRT) is associated with a particularly high non-response rate in patients with atrial fibrillation (AF). We aimed to assess the effectiveness of triple-site (Tri-V) pacing CRT in this population. Methods and results Prospective observational study of patients with permanent AF who underwent CRT implantation with an additional right ventricle lead in the outflow tract septal wall. After implantation, programming mode (Tri-V or biventricular pacing) was selected based on cardiac output determination. Patients were classified as responders if NYHA class was reduced by at least one level and echocardiographic ejection fraction (EF) increased ≥ 10%, and as super-responders if in NYHA class I and EF ≥ 50%. Forty patients (93% male, mean age 72 ± 10 years) were included. Thirty-three were programmed in Tri-V. The following results pertain to this subgroup. At baseline, 58% were in NYHA class III and 36% NYHA class II. At 1 year follow-up, Minnesota QoL score was reduced (36 ± 23 vs. 8 ± 6; P = 0.001) and the 6MWT distance improved (384 ± 120 m to 462 ± 87 m, P = 0.003). Mean EF increased (26% ± 8 vs. 39 ± 10; P < 0.001 at 6 months and 41 ± 10; P < 0.001 at 12 months). Responder rate was 59% at 6 months and 79% at 12 months. Super-responder rate was 9% at 6 months and 16% at 12 months. One year survival free from heart failure hospitalization was 87.9%. Conclusion Tri-V CRT yielded higher response and super-response rates than usually reported for CRT in patients with permanent AF using clinical and remodeling criteria.

The circulating non-coding RNA landscape for biomarker research: lessons and prospects from cardiovascular diseases

Pervasive transcription of the human genome is responsible for the production of a myriad of non-coding RNA molecules (ncRNAs) some of them with regulatory functions. The pivotal role of ncRNAs in cardiovascular biology has been unveiled in the last decade, starting from the characterization of the involvement of micro-RNAs in cardiovascular development and function, and followed by the use of circulating ncRNAs as biomarkers of cardiovascular diseases. The human non-coding secretome is composed by several RNA species that circulate in body fluids and could be used as biomarkers for diagnosis and outcome prediction. In cardiovascular diseases, secreted ncRNAs have been described as biomarkers of several conditions including myocardial infarction, cardiac failure, and atrial fibrillation. Among circulating ncRNAs, micro-RNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been proposed as biomarkers in different cardiovascular diseases. In comparison with standard biomarkers, the biochemical nature of ncRNAs offers better stability and flexible storage conditions of the samples, and increased sensitivity and specificity. In this review we describe the current trends and future prospects of the use of the ncRNA secretome components as biomarkers of cardiovascular diseases, including the opening questions related with their secretion mechanisms and regulatory actions.

Progressão da desnervação simpática cardíaca avaliada por cintigrafia com MIBG‐I123 na polineuropatia amiloidótica familiar e o impacto da transplantação hepática

INTRODUCTION Familial amyloid polyneuropathy (FAP) is a rare disease caused by systemic deposition of amyloidogenic variants of the transthyretin (TTR) protein. The TTR-V30M mutation is caused by the substitution of valine by methionine at position 30 and mainly affects the peripheral and autonomic nervous systems. Cardiovascular manifestations are common and are due to autonomic denervation and to amyloid deposition in the heart. Cardiac sympathetic denervation detected by iodine-123 labeled metaiodobenzylguanidine (MIBG) is an important prognostic marker in TTR-V30M FAP. Liver transplantation, widely used to halt neurological involvement, appears to have a varying effect on the progression of amyloid cardiomyopathy. Its effect on the progression of cardiac denervation remains unknown. METHODS In this observational study, patients with the TTR-V30M mutation underwent annual cardiac assessment and serial MIBG imaging with quantification of the late heart-to-mediastinum (H/M) ratio. RESULTS We studied 232 patients (median age 40 years, 54.7% female, 37.9% asymptomatic at the time of inclusion) who were followed for a median of 4.5 years and underwent a total of 558 MIBG scans. During follow-up, 47 patients (20.3%) died. MIBG scintigraphy at inclusion was a strong predictor of prognosis, with the risk of death increasing by 27.8% for each one-tenth reduction in the late H/M ratio. The late H/M ratio decreased with age (0.082/year, p<0.001), but progression of cardiac denervation was so slow that annual repetition of MIBG imaging did not increase its prognostic accuracy. During follow-up, 70 symptomatic patients underwent liver transplantation. The late H/M ratio decreased by 0.19/year until transplantation but no statistically significant differences were detected after the procedure. CONCLUSIONS Cardiac denervation is common during the progression of TTR-V30M FAP and quantification of the late H/M ratio on MIBG scintigraphy is valuable for prognostic stratification of these patients. Liver transplantation stabilizes cardiac denervation, without recovery or further deterioration in cardiac MIBG uptake after the procedure.

Ripple mapping: Initial multicenter experience of an intuitive approach to overcoming the limitations of 3D activation mapping

Ripple mapping (RM) displays electrograms as moving bars over a three‐dimensional surface displaying bipolar voltage, and has shown in a single‐center series to be effective for atrial tachycardia (AT) mapping without annotation of local activation time or window‐of‐interest assignment. We tested the reproducibility of these findings in operators naïve to RM, using it for the first time in postablation AT.