Prognostic Value of Heart Rate Reserve during Dipyridamole Stress Echocardiography in Patients With Abnormal Chronotropic Response to Exercise.

Heart rate reserve (HRR) during physical or pharmacological stress is a sign of cardiac autonomic function and sympathetic reserve, but it can be reduced during exercise for confounders such as poor motivation, drugs or physical fitness. In this study we sought to assess the prognostic meaning of HRR during dipyridamole stress echocardiography (DSE) in patients with abnormal chronotropic response to exercise. From 2004 to 2019, we prospectively acquired and retrospectively analyzed 379 patients (age 62 ± 11 years; ejection fraction 60 ± 5%) with suspected (n = 243) or known (n = 136) chronic coronary syndromes, referred to DSE for chronotropic incompetence during upright bicycle exercise-electrocardiography test defined as HRR used [(peak HR - rest HR) / (220 - age) - rest HR] ≤80% in patients off and ≤62% in patients on beta-blockers. All patients were in sinus rhythm and underwent DSE (0.84 mg/kg) within 3 months of exercise testing. During DSE, age-independent HRR (peak/rest HR) ≤1.22 was considered abnormal. All patients were followed-up. All-cause death was the only outcome measure. HRR during DSE was normal in 275 (73%) and abnormal in 104 patients (27%). During a follow-up of 9.0 ± 4.2 years, 67 patients (18%) died. The 15-year mortality rate was 23% in patients with normal and 61% in patients with abnormal HRR (p < 0.0001). At multivariable analysis a blunted HRR during DSE was an independent predictor of outcome (hazard ratio 2.01, 95% confidence intervals 1.23-3.29; p = 0.005) with age and diabetes, while neither inducible ischemia nor ongoing beta-blocker therapy were significant predictors. In conclusion, a blunted HRR during DSE predicts a worse survival in patients with chronotropic incompetence during exercise test. HRR during DSE is an appealingly simple biomarker of cardiac autonomic dysfunction independent of imaging, exercise and beta-blocker therapy.

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

PURPOSE: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork. METHODS: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured. RESULTS: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%. CONCLUSIONS: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.

Prognostic Value of Heart Rate Reserve in Patients with Permanent Atrial Fibrillation during Dipyridamole Stress Echocardiography.

In patients in sinus rhythm, a blunted heart rate reserve (HRR) during dipyridamole stress echocardiography (SE) is a prognostically unfavorable sign of cardiac autonomic dysfunction. In this study we sought to assess the prognostic meaning of HRR in patients with permanent atrial fibrillation (AF). The study population was made by 301 patients (176 men, age 73 ± 8 years) with suspected (n = 200) or known (n = 101) coronary artery disease and permanent AF who underwent high-dose dipyridamole SE. HRR was calculated on an average of 5 consecutive beats as the peak/rest ratio of HR from 12-lead EKG. During a median follow-up time of 77 months (first quartile 44, third quartile 115 months), 111 (37%) patients died. Receiver operating characteristics analysis identified HRR ≤1.17 as the best predictor of mortality. At multivariable analysis, HRR ≤1.17 (HR 1.75, 95% CI 1.17 to 2.62; p = 0.006) independently predicted mortality together with age (HR 1.09, 95% CI 1.06 to 1.13; p <0.0001), rest wall motion score index (HR 1.69, 95% CI 1.01 to 2.83; p = 0.04), and systemic hypertension (HR 1.76, 95% CI 1.06 to 3.00; p = 0.04). The annual mortality was 5.1% in the overall population, 7.0% in the 140 (46%) patients with abnormal HRR and 3.5% in the 161 (54%) patients with normal HRR. The 8-year mortality was 48% in patients with abnormal HRR and 18% in those with normal HRR (p <0.0001). In conclusion, patients with suspected or known coronary artery disease with permanent AF with a blunted HRR have an increased mortality. HRR outweighs inducible ischemia for prediction of survival. The assessment of HRR should become an integral part of dipyridamole SE reading also in AF.

Usefulness of Blunted Heart Rate Reserve as an Imaging-Independent Prognostic Predictor During Dipyridamole Stress Echocardiography.

A blunted heart rate (HR) response during dipyridamole myocardial perfusion imaging has been associated with a poor outcome. To assess the value of HR response in patients who underwent high-dose dipyridamole stress echocardiography (SE), we retrospectively selected a sample of 3,059 patients (none with pacemakers or atrial fibrillation; mean age 66 ± 11 years). All underwent high-dose (0.84 mg/kg) dipyridamole SE for evaluation of known or suspected coronary artery disease and/or heart failure in 2 laboratories of Pisa-IFC and Lucca. HR (with 12-lead ECG) was obtained each minute and recorded at rest and peak stress. HR reserve (HRR) was calculated as the peak/rest HR ratio. All patients were followed up. Patients were randomly divided into the modeling and validation group of equal size. During a median follow-up time of 1,004 days, 321 hard events occurred: 231 deaths and 90 nonfatal myocardial infarctions. HRR ≤ 1.22 identified by receiver operating characteristic analysis in the modeling group was an independent predictor of infarction-free survival in the modeling (hazard ratio 1.83, 95% confidence interval [CI] 1.30 to 2.60, p = 0.001), in the validation (hazard ratio 1.47, 95% CI 1.08 to 2.01, p = 0.02), and in the overall group (hazard ratio 1.60, 95% CI 1.27 to 2.02, p <0.0001), either off- or on-ß blockers. Five-year event rate increased from 8% to 24 % from the highest (≥1.41) to the lowest (≤1.14) HRR quartile. In conclusion, blunted HRR is a useful nonimaging predictor of adverse events during high-dose dipyridamole SE, independent of inducible ischemia, and beta-blocker therapy.

Efficacy of a remote web-based lung ultrasound training for nephrologists and cardiologists: a LUST trial sub-project.

Within the framework of the LUST trial (LUng water by Ultra-Sound guided Treatment to prevent death and cardiovascular events in high-risk end-stage renal disease patients), the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis Transplant Association established a central core lab aimed at training and certifying nephrologists and cardiologists participating in this trial. All participants were trained by an expert trainer with an entirely web-based programme. Thirty nephrologists and 14 cardiologists successfully completed the training. At the end of training, a set of 47 lung ultrasound (US) videos was provided to trainees who were asked to estimate the number of B-lines in each video. The intraclass correlation coefficient (ICC) for the whole series of 47 videos between each trainee and the expert trainer was high (average 0.81 ± 0.21) and >0.70 in all but five cases. After further training, the five underperforming trainees achieved satisfactory agreement with the expert trainer (average post-retraining ICC 0.74 ± 0.14). The Bland-Altman plot showed virtually no bias (difference between the mean 0.03) and strict 95% limits of agreement lines (-1.52 and 1.45 US B-lines). Only four cases overlapped but did not exceed the same limits. Likewise, the Spearman correlation coefficient applied to the same data series was very high (r = 0.979, P < 0.0001). Nephrologists and cardiologists can be effectively trained to measure lung congestion by an entirely web-based programme. This web-based training programme ensures high-quality standardization of US B-line measurements and represents a simple, costless and effective preparatory step for clinical trials targeting lung congestion.

Correction: How Reliable Are Current Data for Assessing the Actual Prevalence of Chronic Obstructive Pulmonary Disease?

[This corrects the article DOI: 10.1371/journal.pone.0149302.].

How Reliable Are Current Data for Assessing the Actual Prevalence of Chronic Obstructive Pulmonary Disease?

BACKGROUND: Estimating COPD occurrence is perceived by the scientific community as a matter of increasing interest because of the worldwide diffusion of the disease. We aimed to estimate COPD prevalence by using administrative databases from a city in central Italy for 2002-2006, improving both the sensitivity and the reliability of the estimate. METHODS: Multiple sources were used, integrating the hospital discharge register (HDR), clinical charts, spirometry and the cause-specific mortality register (CMR) in a longitudinal algorithm, to reduce underestimation of COPD prevalence. Prevalence was also estimated on the basis of COPD cases confirmed through spirometry, to correct misclassification. Estimating such prevalence relied on using coefficients of validation, derived as the positive predictive value (PPV) for being an actual COPD case from clinical and spirometric data at the Institute of Clinical Physiology of the National Research Council. RESULTS: We found that sensitivity of COPD prevalence increased by 37%. The highest estimate (4.43 per 100 residents) was observed in the 5-year period, using a 3-year longitudinal approach and combined data from three sources. We found that 17% of COPD cases were misclassified. The above estimate of COPD prevalence decreased (3.66 per 100 residents) when coefficients of validation were applied. The PPV was 80% for the HDR, 82% for clinical diagnoses and 91% for the CMR. CONCLUSIONS: Adjusting the COPD prevalence for both underestimation and misclassification of the cases makes administrative data more reliable for epidemiological purposes.

Prediction of mortality by stress echocardiography in 2835 diabetic and 11 305 nondiabetic patients.

BACKGROUND: To compare the capability by stress echocardiography results to predict overall mortality in a large unselected cohort of diabetic and nondiabetic patients. METHODS AND RESULTS: The study group comprised 14 140 patients (2835 diabetics and 11 305 nondiabetics) who underwent stress echocardiography for evaluation of known (n=5671) or suspected (n=8469) coronary artery disease. Ischemia at stress echocardiography was observed in 768 (27%) diabetics and 2644 (23%) nondiabetics. During a median follow-up of 30 months (first quartile, 9; third quartile, 63), 1213 patients died. In diabetics, multivariable indicators of mortality were age (hazard ratio [HR], 1.07, 95% confidence interval [CI], 1.06-1.09), rest wall motion abnormality (HR, 2.43; 95% CI, 1.83-3.22), and ischemia at stress echocardiography (HR, 1.71; 95% CI, 1.34-2.18). In nondiabetics, multivariable indicators of mortality were age (HR, 1.07; 95% CI, 1.06-1.08), rest wall motion abnormality (HR, 2.19; 95% CI, 1.86-2.57), male sex (HR, 1.65; 95% CI, 1.41-1.93), ischemia at stress echocardiography (HR, 1.54; 95% CI, 1.32-1.80), and antischemic therapy at the time of test (HR, 1.15; 95% CI, 1.00-1.32). In stress echo negative subjects for ischemia, antischemic therapy showed increased annual mortality in nondiabetic patients with (3.8% versus 3.1%; P=0.04) or without rest wall motion abnormality (1.6% versus 0.9%; P<0.0001); it failed to do so in diabetic patients with (5.7% versus 5.8%; P=0.89) or without rest wall motion abnormality (2.6% versus 1.9%; P=0.10). CONCLUSIONS: Ischemia at stress echocardiography is a strong and independent predictor of total mortality in diabetic as well as nondiabetic patients. Antischemic therapy markedly affects the negative predictive value of stress echocardiography in nondiabetic patients, whereas it is prognostically neutral in the diabetic population.

[Record-linkage procedures in epidemiology: an Italian multicentre study]. / Procedure di record linkage in epidemiologia: uno studio multicentrico italiano.

OBJECTIVE: To compare record linkage (RL) procedures adopted in several Italian settings and a standard probabilistic RL procedure for matching data from electronic health care databases. DESIGN: Two health care archives are matched: the hospital discharges (HD) archive and the population registry of four Italian areas. Exact deterministic, stepwise deterministic techniques and a standard probabilistic RL procedure are applied to match HD for acute myocardial infarction (AMI) and diabetes mellitus. Sensitivity and specificity for RL procedures are estimated after manual review. Age and gender standardized annual hospitalization rates for AMI and diabetes are computed using different RL procedures and compared. SETTING: Municipalities of Pisa and Roma, and Regions of Puglia and Piemonte. PARTICIPANTS: Residents in the considered areas on 31 December 2003 and corresponding episodes of hospitalization in the same areas during 2004. MAIN OUTCOME MEASURES: Measures of accuracy of RL procedures to match health care administrative databases. RESULTS: Data quality varies among archives and affects the decision rule of the probabilistic procedure. A unique decision rule was therefore adopted by means of choosing a positive predictive value of at least 98% for all the considered areas. The number of matched pairs identified with the probabilistic procedure is on average more then 11% greater than the number identified with the deterministic procedure. Sensitivity of probabilistic RL is similar or greater than that of other procedures. Differences between annual standardized hospitalization rates computed with stepwise deterministic RL and the standard probabilistic RL procedure vary among areas. CONCLUSION: Exact deterministic RL works well when unique identifiers and high quality data are available. The probabilistic procedure here proposed works as well as semi-deterministic RL when the latter implements a quality control of data or a manual review of final results. Otherwise, deterministic or semi-deterministic procedures imply classification errors of unknown size and direction.

Prognostic value of extravascular lung water assessed with ultrasound lung comets by chest sonography in patients with dyspnea and/or chest pain.

BACKGROUND: Ultrasound lung comets (ULCs) consist of multiple comet tails originating from water-thickened interlobular septa. They are a new echographic tool to assess the pathologic increase in extravascular lung water, which is a possible harbinger of impending acute heart failure. The objective was to assess the prognostic value of ULCs in patients with dyspnea and/or chest pain syndrome at hospital admission. METHODS AND RESULTS: A total of 290 consecutive in-hospital patients (aged 68 +/- 13 years) admitted for dyspnea and/or chest pain syndrome were evaluated on admission with a comprehensive two-dimensional and Doppler echocardiographic evaluation and chest sonography with ULC assessment. A patient ULC score was obtained by summing the number of comets from each of the scanning spaces in the anterior right and left hemithoraxes, from the second to fifth intercostal spaces. All patients were followed up for a median period of 16 months (interquartile range: 2.8-29.1 months). During the follow-up, 62 events occurred: 19 cardiac deaths, 3 nonfatal myocardial infarctions, 20 acute heart failures requiring hospitalization, and 20 noncardiac deaths. The 16-month event-free survival was highest in patients with no ULCs and lowest in patients with severe (>30) ULCs at entry (70% vs 19%, P = .0007). At univariate analysis, ULCs (hazard ratio [HR] 2.349; confidence interval [CI] 1.364-4.044) were more powerful predictors than other echocardiographic variables of recognized prognostic value, including ejection fraction (HR 0.974; 95% CI 0.958-0.99) and wall motion score index (HR 1.628; CI 1.15-2.304). On multivariable analysis, ULCs provided additional prognostic information (HR 1.9; 95% CI 1.1-3.4) on diabetes (HR 2.05; 95% CI 1.2-3.5) and New York Heart Association class (HR 1.3; 95% CI 1.0-1.6). CONCLUSION: ULCs are a simple user-friendly, radiation-free bedside sign of extravascular lung water. They provide useful information for the prognostic stratification of patients with dyspnea and/or chest pain syndrome.

Early assessment of heart rate variability is predictive of in-hospital death and major complications after acute myocardial infarction.

BACKGROUND: Depressed heart rate variability at acute myocardial infarction discharge is associated with poor long-term prognosis. However, its early (<48 h) predictive value has not been extensively investigated. Aim of this Multicenter Italian Study was to investigate, during acute myocardial infarction, in-hospital prognostic value of heart rate variability and its short-term evolution. METHODS: Twenty-four hour ECG monitoring was prospectively obtained on admission in 413 patients with new-onset acute myocardial infarction and repeated in 349 at discharge. Heart rate variability statistical and frequency domain indices, peak creatine kinase, echocardiographic wall motion score index and risk factors were obtained. The occurrence of cardiac death and resuscitated ventricular fibrillation were the primary end-points; cardiogenic shock, ventricular tachycardia, post-infarction angina and heart failure the secondary end-points. RESULTS: At admission, a marked reduction in heart rate variability indices was evident. Nine patients died during hospitalization and 13 were resuscitated from ventricular fibrillation. Secondary endpoints occurred in other 91 patients. At univariate analysis, low frequencies (LF), mean time interval between consecutive heart beats (RR), wall motion score index and family history of ischemic heart disease were predictive of combined primary and secondary end-points. At multivariate analysis, only LF and family history were predictive with a relative risk of 2.01 and 1.84, respectively (P<0.003). In survivors, heart rate variability indices significantly increased during hospitalization, still remaining below reference values. CONCLUSIONS: A depressed heart rate variability was present in the early phase of infarction and improved at discharge. LF power was an independent predictor of the combined unfavorable short-term events.

Prognostic value of pharmacological stress echocardiography is affected by concomitant antiischemic therapy at the time of testing.

BACKGROUND: The aim of this study was to determine whether antianginal medications affect the prognostic value of pharmacological stress echocardiography. METHODS AND RESULTS: From the EPIC-EDIC Data Bank, 7333 patients (5452 men; age; 59+/-10 years) underwent pharmacological stress echocardiography with either high-dose dipyridamole (0.84 mg/kg over 10 minutes; n=4984) or high-dose dobutamine (up to 40 microg x kg(-1) x min(-1); n=2349) (DET) for diagnostic purposes. At the time of testing, 1791 patients were on antiischemic therapy (nitrates and/or calcium antagonists and/or beta-blockers). Patients were followed up for a mean of 2.6 years (range, 1 to 206 months). DET was positive for myocardial ischemia in 2854 patients (39%) and negative in 4479 (61%). Total mortality was 336 (4.5%). Death was attributed to cardiac causes in 161 patients (2.1%). Survival was highest in patients with negative DET off therapy and lowest in patients with positive DET studied on therapy (95% versus 81%; P=0.0000). Survival was comparable in patients with a negative test on therapy and in patients with a positive test off therapy (88% versus 84%, P=NS). CONCLUSIONS: Ongoing antiischemic therapy at the time of testing heavily modulates the prognostic value of pharmacological stress echo. In the presence of concomitant antiischemic therapy, a positive test is more prognostically malignant, and a negative test less prognostically benign.

Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease.

BACKGROUND: Clinical and experimental data have suggested a potential negative impact of low-T3 state on the prognosis of cardiac diseases. The aim of the present prospective study was to assess the role of thyroid hormones in the prognosis of patient population with heart disease. METHODS AND RESULTS: A total of 573 consecutive cardiac patients underwent thyroid function profile evaluation. They were divided in two subgroups: group I, 173 patients with low T3, ie, with free T3 (fT3) <3.1 pmol/L, and group II, 400 patients with normal fT3 (>or=3.1 pmol/L). We considered cumulative and cardiac death events. During the 1-year follow-up, there were 25 cumulative deaths in group I and 12 in group II (14.4% versus 3%, P<0.0001); cardiac deaths were 13 in group I and 6 in group II (7.5% versus 1.5%, P=0.0006). According to the Cox model, fT3 was the most important predictor of cumulative death (hazard ratio [HR] 3.582, P<0.0001), followed by dyslipidemia (HR 2.955, P=0.023), age (HR 1.051, P<0.005), and left ventricular ejection fraction (HR 1.037, P=0.006). At the logistic multivariate analysis, fT3 was the highest independent predictor of death (HR 0.395, P=0.003). A prevalence of low fT3 levels was found in patients with NYHA class III-IV illness compared with patients with NYHA class I-II (chi(2) 5.65, P=0.019). CONCLUSIONS: Low-T3 syndrome is a strong predictor of death in cardiac patients and might be directly implicated in the poor prognosis of cardiac patients.