Catherine Klersy

Independent and additive prognostic value of Right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure

OBJECTIVES We sought a better understanding of the coupling between right ventricular ejection fraction (RVEF) and pulmonary artery pressure (PAP), as it might improve the accuracy of the prognostic stratification of patients with heart failure. BACKGROUND Despite the long-standing view that systolic function of the right ventricle (RV) is almost exclusively dependent on the afterload that this cardiac chamber must confront, recent studies claim that RV function is an independent prognostic factor in patients with chronic heart failure. METHODS Right heart catheterization was performed in 377 consecutive patients with heart failure. RESULTS During a median follow-up period of 17 +/- 9 months, 105 patients died and 35 underwent urgent heart transplantation. Pulmonary artery pressure and thermodilution-derived RVEF were inversely related (r = 0.66, p < 0.001). However, on Cox multivariate survival analysis, no interaction between such variables was found, and both turned out to be independent prognostic predictors (p < 0.001). It was found that RVEF was preserved in some patients with pulmonary hypertension, and that the prognosis of these patients was similar to that of the patients with normal PAP. In contrast, when PAP was normal, reduced RV function did not carry an additional risk. CONCLUSIONS These observations emphasize the necessity of combining the right heart hemodynamic variables with a functional evaluation of the RV when trying to define the individual risk of patients with heart failure.

Left Cardiac Sympathetic Denervation in the Management of High-Risk Patients Affected by the Long-QT Syndrome

Background—The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite β-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. Methods and Results—We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543±65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with β-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P <0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P <0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P =0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. Conclusions—LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite β-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.

Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy.

The prognostic value of ultrasound evaluation of right ventricular (RV) performance in patients with congestive heart failure (CHF) is still a matter of investigation. We studied 140 consecutive patients with chronic CHF and a left ventricular ejection fraction <35%. All patients underwent a complete echocardiographic evaluation that systematically included the measurement of the tricuspid annular plane systolic excursion (TAPSE). During a follow-up period of 24 +/- 14 months, 45 patients died and 7 underwent emergency heart transplantation. At the multivariate survival analysis (Cox regression model) backward stepwise selection identified a prognostic model with 2 parameters: New York Heart Association (NYHA) class III or IV and TAPSE < or =14 mm (p <000). In a subgroup of 97 patients in sinus rhythm in whom mitral inflow Doppler variables could be measured, survival was further analyzed according to a model in which the significant parameters were included in the same order as usually used in routine clinical practice: clinical variables first, left ventricular function data second, mitral Doppler variables third, and indexes of right ventricular (RV) function last. TAPSE < or =14 mm added significant (p <0.03) prognostic information to NYHA class III or IV, left ventricular ejection fraction of <20%, and mitral deceleration time of < 125 ms. In conclusion, in patients with CHF, TAPSE adds significant prognostic information to the NYHA clinical classification, to the echocardiographic evaluation of left ventricular function, and to mitral Doppler variables. Furthermore, the measurement of TAPSE is easy to obtain in all patients, irrespective of heart rate and rhythm.

Serum N-Terminal Pro–Brain Natriuretic Peptide Is a Sensitive Marker of Myocardial Dysfunction in AL Amyloidosis

Background—Brain natriuretic peptide (BNP) is a marker of ventricular dysfunction and can be used to assess prognosis in heart failure and after myocardial infarction. Heart involvement is the most important prognostic factor and causes death in almost all patients with light-chain amyloidosis (AL). We investigated the prognostic value of NT-proBNP and its utility in monitoring amyloid heart dysfunction. Methods and Results—NT-proBNP was quantified at diagnosis in 152 consecutive patients seen at the coordinating center of the Italian Amyloidosis Study Group (Pavia) from 1999 throughout 2001. Heart involvement was estimated on the basis of clinical signs, electrocardiography, and echocardiography. NT-proBNP concentrations differed in patients with (n=90, 59%) and without (n=62, 41%) heart involvement (median: 507.8 pmol/L versus 22.1 pmol/L, P =10−7). The best cutoff for heart involvement was at 152 pmol/L (sensitivity: 93.33%, specificity: 90.16%, accuracy: 92.05%) and distinguished two groups with different survival (P <0.001). The Cox multivariate model including NT-proBNP was better than models including echocardiographic and clinical signs of heart involvement. NT-proBNP appeared to be more sensitive than conventional echocardiographic parameters in detecting clinical improvement or worsening of amyloid cardiomyopathy during follow-up. Conclusions—NT-proBNP appeared to be the most sensitive index of myocardial dysfunction and the most powerful prognostic determinant in AL amyloidosis. It adds prognostic information for newly diagnosed patients and can be useful in designing therapeutic strategies and monitoring response. NT-proBNP is a sensitive marker of heart toxicity caused by amyloidogenic light chains.

ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: Prognostic evaluation by pathological analysis

BACKGROUND & AIMS Gastric endocrine tumors show a wide spectrum of clinical behavior, and prognostic assessement of individual tumors is difficult. The aims of this work were to identify predictors of tumor malignancy and patient outcome and to provide a rationale for treatment guidelines. METHODS Gastric endocrine tumors (86 enterochromaffin-like cell carcinoids and 16 poorly differentiated carcinomas) were investigated for 15 clinicopathologic variables and for expression of Ki67, P53, and BCL-2 proteins. Data were analyzed by univariate and multivariate statistics for evidence of tumor malignancy and patient survival. RESULTS Histological grades 2 and 3, size >/=3 cm, 9 or more mitoses, or >/=300 Ki67-positive cells per 10 high-power fields identified 26 of 33 (79%) malignant (metastatic or deeply invasive) tumors, and size <1 cm and/or growth restricted to the mucosa characterized 46 of 69 (67%) tumors with benign behavior during a median follow-up of 39 months. Malignancy-predictive models were developed using angioinvasion, size, clinicopathologic type, mitotic index, and Ki67 index. The same variables, in addition to deep gastric wall invasion and histological grade, predicted patient outcome. CONCLUSIONS Criteria for the assessment of malignancy risk and patient outcome were developed for the different tumors, providing a basis for treatment guidelines.

Langerhans cell histiocytosis in adults Report from the International Registry of the Histiocyte Society

Langerhans cell histiocytosis (LCH), characterised by the infiltration of one or more organs by large mononuclear cells, can develop in persons of any age. Although the features of this disease are well described in children, they remain poorly defined in adults. From January 2000 to June 2001, 274 adults from 13 countries, with biopsy-proven adult LCH, were registered with the International Histiocyte Society Registry. Information was collected about clinical presentation, family history, associated conditions, cigarette smoking and treatment, to assist in future management decisions in patients aged 18 years and older. There were slightly more males than females (143:126), and the mean ages at the onset and diagnosis of disease were 33 years (standard deviation (S.D.) 15 years) and 35 years (S.D. 14 years), respectively. 2 patients had consanguineous parents, and 1 had a family history of LCH; 129 reported smoking (47.1%); 17 (6.2%) had been diagnosed with different types of cancer. Single-system LCH, found in 86 patients (31.4%), included isolated pulmonary involvement in 44 cases; 188 patients (68.6%) had multisystem disease; 81 (29.6%) had diabetes insipidus. Initial treatment consisted of vinblastine administered with or without steroids, to 82 patients (29.9%), including 9 who had received it with etoposide, which was the sole agent given to 19 patients. 236 patients were considered evaluable for survival. At a median follow-up of 28 months from diagnosis, 15 patients (6.4%) had died (death rate, 1.5/100 person years, 95% Confidence Interval (95% CI) 0.9-2.4). The probability of survival at 5 years postdiagnosis was 92.3% (95% CI 85.6-95.9) overall, 100% for patients with single-system disease (n=37), 87.8% (95% CI 54.9-97.2) for isolated pulmonary disease (n=34), and 91.7% (95% CI 83.6-95.9) for multisystem disease (n=163). Survival did not differ significantly among patients with multisystem disease, with or without liver or lung involvement) 5-year survival 93.6% (95% CI 84.7-97.4) versus 87.5% (95% CI 65.5-95.9), respectively; P value 0.1). LCH in adults is most often a multisystem disease with the highest mortality seen in patients with isolated pulmonary involvement. It should be included in the differential diagnosis of disseminated or localised disease of the bone, skin and mucosa, as well as the lung and the endocrine and central nervous system, regardless of the age of the patient. A prospective international therapeutic study is warranted.

New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival Outcomes

PURPOSE To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population. PATIENTS AND METHODS We gathered for analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed. RESULTS There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation. CONCLUSION This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.

A meta-analysis of remote monitoring of heart failure patients

OBJECTIVES The purpose of this study was to assess the effect of remote patient monitoring (RPM) on the outcome of chronic heart failure (HF) patients. BACKGROUND RPM via regularly scheduled structured telephone contact between patients and health care providers or electronic transfer of physiological data using remote access technology via remote external, wearable, or implantable electronic devices is a growing modality to manage patients with chronic HF. METHODS After a review of the literature published between January 2000 and October 2008 on a multidisciplinary heart failure approach by either usual care (in-person visit) or RPM, 96 full-text articles were retrieved: 20 articles reporting randomized controlled trials (RCTs) and 12 reporting cohort studies qualified for a meta-analysis. RESULTS Respectively, 6,258 patients and 2,354 patients were included in RCTs and cohort studies. Median follow-up duration was 6 months for RCTs and 12 months for cohort studies. Both RCTs and cohort studies showed that RPM was associated with a significantly lower number of deaths (RCTs: relative risk [RR]: 0.83, 95% confidence interval [CI]: 0.73 to 0.95, p = 0.006; cohort studies: RR: 0.53, 95% CI: 0.29 to 0.96, p < 0.001) and hospitalizations (RCTs: RR: 0.93, 95% CI: 0.87 to 0.99, p = 0.030; cohort studies: RR: 0.52, 95% CI: 0.28 to 0.96, p < 0.001). The decrease in events was greater in cohort studies than in RCTs. CONCLUSIONS RPM confers a significant protective clinical effect in patients with chronic HF compared with usual care.

TNM Staging of Neoplasms of the Endocrine Pancreas: Results From a Large International Cohort Study

BACKGROUND Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.

Effect of Long-Detection Interval vs Standard-Detection Interval for Implantable Cardioverter-Defibrillators on Antitachycardia Pacing and Shock Delivery: The ADVANCE III Randomized Clinical Trial

IMPORTANCE Using more intervals to detect ventricular tachyarrhythmias has been associated with reducing unnecessary implantable cardioverter-defibrillator (ICD) therapies. OBJECTIVE To determine whether using 30 of 40 intervals to detect ventricular arrhythmias (VT) (long detection) during spontaneous fast VT episodes reduces antitachycardia pacing (ATP) and shock delivery more than 18 of 24 intervals (standard detection). DESIGN, SETTING, AND PARTICIPANTS Randomized, single-blind, parallel-group trial that enrolled 1902 primary and secondary prevention patients (mean [SD] age, 65 [11] years; 84% men; 75% primary prevention ICD) with ischemic and nonischemic etiology undergoing first ICD implant at 1 of 94 international centers (March 2008-December 2010). INTERVENTIONS Patients were randomized 1:1 to programming with long- (n = 948) or standard-detection (n = 954) intervals. MAIN OUTCOMES AND MEASURES Total number of ATPs and shocks delivered for all episodes (primary outcomes) and inappropriate shocks, mortality, and syncopal rate (secondary outcomes). RESULTS During a median follow-up of 12 months (interquartile range, 11-13), long-detection group had 346 delivered therapies (42 therapies per 100 person-years, 95% CI, 38-47) vs 557 in the standard-detection group (67 therapies per 100 person-years [95% CI, 62-73]; incident rate ratio [IRR], 0.63 [95% CI, 0.51-0.78]; P < .001). The long- vs the standard-detection group experienced 23 ATPs per 100 person-years (95% CI, 20-27) vs 37 ATPs per 100 person-years (95% CI, 33-41; IRR, 0.58 [95% CI, 0.47-0.72]; P < .001); 19 shocks per 100 person-years (95% CI, 16-22) vs 30 shocks per 100 person-years (95% CI, 26-34; IRR, 0.77 [95% CI, 0.59-1.01]; P = .06), with a significant difference in the probability of therapy occurrence (P < .001); and a reduction in first occurrence of inappropriate shock (5.1 per 100 patient-years [95% CI, 3.7-6.9] vs 11.6 [95% CI, 9.4-14.1]; IRR, 0.55 [95% CI, 0.36-0.85]; P = .008). Mortality (5.5 [95% CI, 4.0-7.2] vs 6.3 [95% CI, 4.8-8.2] per 100 patient-years; HR, 0.87; P = .50) and arrhythmic syncope rates (3.1 [95% CI, 2.6-4.6] vs 1.9 [95% CI, 1.1-3.1] per 100 patient-years; IRR, 1.60 [95% CI, 0.76-3.41]; P = .22) did not differ significantly between groups. CONCLUSIONS AND RELEVANCE Among patients receiving an ICD, the use of a long- vs standard-detection interval resulted in a lower rate of ATP and shocks, and inappropriate shocks. This programming strategy may be an appropriate alternative. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00617175.