Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance.

BACKGROUND: Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives. AIMS: We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020. RESULTS: Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively. CONCLUSION: Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.

Correlation of aortic valve annular plane assessment by on-table three-dimensional rotational angiography and preprocedural computed tomography.

OBJECTIVES: To assess the correlation between the aortic valve annular plane (AVAP) obtained by preprocedural computed tomography (CT) with on-table three-dimensional rotational angiography (3DRA), in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Accurate assessment of the AVAP is critical during TAVR procedures to enable optimal positioning and minimize complications. Most commonly, preprocedural CT has been used to determine the AVAP. However, this can differ from the actual AVAP obtained during the TAVR procedure. METHODS: Consecutive TAVR patients at a single center undergoing both preprocedural CT and 3DRA were included in the study. The AVAP assessment by CT was performed using 3mensio software (Pie Medical Imaging). 3DRA assessment was performed using DynaCT (Siemens). RESULTS: A total of 100 patients were included in the analysis. A difference of ≥5° and ≥10° in both the LAO/RAO and cranial/caudal components of the AVAP projection angle as assessed by CT and 3DRA was recorded in 39% and 10% of patients, respectively. The concordance correlation coefficient for the LAO/RAO and cranial/caudal implantation angles was 0.519 (95% CI: 0.377-0.661) and 0.558 (95% CI: 0.432-0.684), respectively. CONCLUSION: Correlation between preprocedural CT and on-table 3DRA in the prediction of the actual AVAP at the time of TAVR implantation is moderate.

Safety of Conscious Sedation for Transcatheter Aortic Valve Replacement Without an Anesthetist.

OBJECTIVES: To compare the safety of performing transfemoral transcatheter aortic valve replacement (TAVR) under conscious sedation without an anesthetist present (TAVR-NA) vs TAVR performed with an anesthetist supervising sedation (TAVR-A). BACKGROUND: In almost all United States and European centers, TAVR-A represents the standard of care. There are limited data on the safety of TAVR-NA. METHODS: The prospective Mater TAVR database was analyzed. Patients undergoing transfemoral TAVR under conscious sedation were identified and divided into 2 groups, ie, TAVR-NA and TAVR-A. Demographics, procedural characteristics, and clinical outcomes for each group were assessed and compared. RESULTS: From a cohort of 300 patients who underwent transfemoral TAVR under conscious sedation, TAVR-NA and TAVR-A were performed in 85 patients and 215 patients, respectively. Baseline variables were similar except for a higher median Society of Thoracic Surgeons score in the TAVR-NA group vs the TAVR-A group (5.1% vs 4.4% in the TAVR-A group; P=.05). TAVR-A patients had a higher rate of conversion to general anesthesia (4.2% vs 1.2% in the TAVR-NA group; P=.29), with 1 patient in each group requiring conversion to emergency surgery. In-lab and in-hospital complication rates were similar in the TAVR-NA and TAVR-A groups (7.1% vs 6.5% [P=.86] and 8.2% vs 12.1% [P=.34], respectively). The Kaplan-Meier estimate of freedom from mortality and/or stroke at 1 month was comparable between both groups (96.5% vs 97.7%; P=.57). CONCLUSIONS: In this modest-sized transfemoral TAVR cohort with a low conversion rate to emergency surgery, TAVR-NA was associated with safety outcomes that were equivalent to TAVR-A. In healthcare systems where access to TAVR may be limited by anesthetic resources, TAVR-NA appears to be a reasonable option to enable the application of this therapy.

Clinical experience with trans-catheter aortic valve implantation at a tertiary hospital in the Republic of Ireland.

INTRODUCTION: There is a paucity of published data on the clinical experience with trans-catheter aortic valve implantation (TAVI) in the Republic of Ireland. We sought to examine the clinical outcomes of patients with medium-term follow-up treated with TAVI at our institution. METHODS: A prospective TAVI registry was used to assess the baseline demographics, procedural variables and clinical outcomes of patients treated with TAVI between the inception of the programme in 2008 and November 2017. RESULTS: A total of 354 patients (mean age 80.9 ± 8.1 years, 58% male, mean STS score 6.1 ± 4.3%) were treated during the study period. Major in-hospital outcomes included in-lab death (n = 2, 0.6%), stroke (n = 8, 2.2%), device embolisation (n = 4, 1.2%), permanent pacemaker implantation (n = 22, 6.2%) and major vascular complication (n = 2, 0.6%). The median length of hospital stay was 4 days (IQR 2-8 days). The Kaplan-Meier estimate of freedom from death at 30 days and 1 year for the entire cohort was 97 ± 1% and 85.4 ± 2.3%, respectively. Trans-femoral access was associated with a significantly lower rate of death and/or stroke at 1 year compared to trans-apical access (84.9 ± 2.4% versus 60 ± 8.9%, p = 0.0005). There was no significant difference in freedom from death and/or stroke at 1 year between balloon-expandable and self-expanding valves (81.6 ± 2.6% versus 84.4 ± 7.4%, p = 0.63). CONCLUSION: This study documents low complication rates and favourable rates of survival following TAVI in a consecutive series of patients undergoing TAVI at a tertiary referral centre in the Republic of Ireland. These data support the application of this therapy in the Irish context.

MiR-93-5p is a novel predictor of coronary in-stent restenosis.

AIMS: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of multiple phases of atherothrombosis, and some reports have suggested altered levels in coronary artery in-stent restenosis (ISR). We recently demonstrated that miR-93-5 p was able to discriminate between patients with stable coronary artery disease (CAD) and those with no CAD, after adjusting for traditional risk factors (RFs). Thus, we wanted to determine if circulating miRNAs could predict coronary ISR. OBJECTIVE: To determine if circulating miRNAs have diagnostic capability for determining ISR in a cohort of matched patients with and without ISR. APPROACH AND RESULTS: To determine if miRNA plasma levels are elevated in coronary ISR, we conducted a study comprising 78 patients (39 with no ISR and 39 with ISR) and measured plasma miRNAs in each. We then determined the predictive ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) RFs, and stent length and diameter, to discriminate between ISR and no ISR. After correction for multiple testing, two miRNAs-miR425-5p and miR-93-5 p-were differential between patients with ISR and patients without ISR. Only miR-93-5 p remained a strong independent predictor of ISR after correction for FHS RFs (OR 6.30, p=0.008) and FHS RFs plus stent length and diameter (OR 4.80, p=0.02) and improved discriminatory power for ISR over FHS RFs alone in receiver operator characteristic curve analysis. CONCLUSION: This novel finding that miR-93-5 p independently predicts ISR extends our recent observation that miR-93-5 p predicted CAD after adjustment for traditional CAD RFs. These data suggest further potential diagnostic utility.

Young Adults and Adverse Childhood Events: A Potent Measure of Cardiovascular Risk.

INTRODUCTION: While cardiovascular disease is the leading cause of death, its determinants include unhealthy behaviors and clinical risk factors and are recognized as the "actual causes" of death. Risk likely accumulates over the life course, and adverse childhood experiences may increase the risk of "actual causes" of death. The objectives of the study are to determine the prevalence and test the association of adverse childhood experiences among unhealthy behaviors and risk factors as a primordial risk factor among young adults. METHODS: Data were extracted from the 2009 and 2011 Behavioural Risk Factor Surveillance System. Individuals ages 18-99 years provided complete information on adverse childhood experiences, health behaviors, and risk factors. Adverse childhood experiences were categorized and evaluated as cumulative burden. Multivariable logistic models, including stratified analysis for young adults, tested the association of adverse childhood experiences burden with unhealthy behaviors and risk factors. RESULTS: Among 45,482 study participants, 52% report one adverse childhood experience and 25% report 2 adverse childhood experience categories. Among the total study population, 37% report violence/emotional abuse, 34% report neglect, and 12% report sexual abuse. Even one adverse childhood experience is strongly associated with hypertension, dyslipidemia, and diabetes, and while the association increases in a dose-response (P trend < .001) for all, it is especially more pronounced among the younger adults, with minimal attenuation of effects in the fully adjusted models. CONCLUSION: The prevalence of adverse childhood experiences in this study population is high. Even one adverse childhood experience is strongly and independently associated with cardiovascular risk factors, with implications for primordial prevention. Future studies are needed to develop screening and treatment strategies targeted to this high-risk group, especially among young adults.

miRNA-93-5p and other miRNAs as predictors of coronary artery disease and STEMI.

BACKGROUND: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of all mediators of atherosclerosis, and some reports have suggested increased levels in coronary artery disease (CAD) and acute myocardial infarction (AMI). However, the potential of miRNAs as biomarkers or predictors of disease remains to be established. METHODS: We designed a study comprising 150 patients (50 Control, 50 Stable CAD, and 50 ST Elevation Myocardial Infarction (STEMI)), and measured plasma miRNAs in each. We then determined the ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) risk factors, to discriminate between CAD vs Control, and STEMI vs Control. RESULTS: Three miRNAs (miR15a-5p, miR16-5p, and miR93-5p) were significantly increased in Stable CAD vs Control groups and one (miR146a-5p) was significantly decreased in Stable CAD vs Control. One miRNA - miR499a-5p - was significantly increased in the STEMI group compared to Controls. After adjustment for FHS risk factors, miR93-5p levels remained an independent predictor of the presence of CAD (Odds Ratio [OR]=8.76, P=0.002). All 4 miRNAs improved discriminatory power for CAD over FHS alone in ROC analysis. Similarly, after adjustment for risk factors miR499-5p remained an independent predictor of STEMI (OR=3.03, P=0.001) and improved discriminatory power for STEMI in ROC analyses. CONCLUSION: We identified 4 miRNAs that were differentially expressed among stable CAD and control patients, and 1 miRNA that was elevated in STEMI patients vs controls. MiR93-5p was the strongest predictor of CAD after adjustment for traditional risk factors, suggesting potential diagnostic utility.

Transitioning high sensitivity cardiac troponin I (hs-cTnI) into routine diagnostic use: More than just a sensitivity issue.

OBJECTIVES: High sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI) assays show analytical, diagnostic and prognostic improvement over contemporary sensitive cTn assays. However, given the importance of troponin in the diagnosis of myocardial infarction, implementing this test requires rigorous analytical and clinical verification across the total testing pathway. This was the aim of this study. DESIGN AND METHODS: Analytical verification included assessment of critical outlier frequency, for hs-cTnI and cTnI assays. Concordance for paired cTnI and hs-cTnI measurements (n=1096) was verified using 99th percentiles for both genders (cTnI: 30 ng/L, hs-cTnI: 25 ng/L) and for men and women separately (hs-cTnI: M: 34;F: 16 ng/L). Discordant data was correlated with clinical and laboratory information. Diagnosis of Acute Coronary Syndrome (ACS) or Non-ACS was adjudicated by two cardiologists independently. RESULTS: The hs-cTnI assay showed a lower (10-fold) critical outlier rate (0.091%) and more detectable results above the limit of detection (LOD) (23.4%) and 99th percentile (2.4%), compared to cTnI. Analytical concordance between the two assays was high (94.5%) but decreased (91.7%) when gender-specific hs-cTnI cut-offs were used. The hs-cTnI assay gave fewer false negatives (up to 1.0%) but disproportionately more false positives (up to 6.7%) overall, which improved (3.9%) for serial measurements. CONCLUSIONS: Laboratories should analytically and clinically verify hs-cTn assays before use, with attention to performance and the clinical and diagnostic algorithms that support appropriate testing and result interpretation. Work in the pre- and post-analytical phases is necessary to augment the analytical improvement in the new era of troponin testing.

NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.

We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.

Antithrombotic treatment at onset of stroke with atrial fibrillation, functional outcome, and fatality: a systematic review and meta-analysis.

BACKGROUND: In atrial fibrillation-associated stroke, conflicting data exist regarding association between therapeutic vitamin K-antagonist anticoagulation (International Normalized Ratio 2-3) and early death and functional outcome, and few data exist relating to late outcome in ischemic and haemorrhagic atrial fibrillation-stroke. AIM: We performed a systematic review and meta-analysis of oral anticoagulation at stroke onset, death and functional outcome. METHODS: We performed a systematic review, searching multiple sources. Studies were included if outcomes in atrial fibrillation-associated stroke were reported stratified by pre-stroke antithrombotic status, with documented International Normalized Ratio at onset. Outcomes were survival and good functional outcome (modified Rankin score 0-2) at discharge/30 days, and at one-year. RESULTS: Of eight studies (3552 patients) in ischemic stroke, International Normalized Ratio ≥ 2 compared with other treatments (International Normalized Ratio < 2, antiplatelet, or no antithrombotic) was associated with good outcome [pooled odds ratio 1·9 (95% confidence interval) 1·5-2·5, P < 0·001] and improved survival at 30 days discharge (pooled odds ratio for death 0·4, confidence interval 0·2-0·5, P < 0·001). The net benefit remained after inclusion of haemorrhagic stroke (odds ratio for good outcome 1·89, confidence interval 1·45-2·46, P < 0·001). At one-year, improved functional outcome for International Normalized Ratio ≥ 2 (pooled odds ratio 1·7, confidence interval 1·0-2·7, P = 0·04) and survival (odds ratio for death 0·5, confidence interval 0·4-0·8, P = 0·001) were also observed. CONCLUSIONS: Therapeutic International Normalized Ratio at stroke onset was associated with early and late improved survival and functional recovery suggesting sustained benefit for warfarin anticoagulation for stroke outcome in atrial fibrillation patients. Long-term outcome data following stroke in patients taking new oral anticoagulants is required.

A brief cookery skills intervention is no more effective than written information alone in reducing body mass index in overweight cardiac rehabilitation patients [corrected].

Overweight and obesity are common health risks, but it can be difficult to effect weight change. This randomized controlled trial examined the effects of a novel Cookery skills intervention on body mass index (BMI) in overweight and obese patients with cardiovascular disease, who had previously attended a cardiac rehabilitation programme. Patients with BMI >27 kg/m(2) were randomized to either a 5-week cookery skills course with written educational materials, or to written materials only. Questionnaires on lifestyle risk factors and food frequencies were administered at baseline, 6 and 24 months. The primary outcome in an intention-to-treat analysis was a change in BMI at 6 months. Secondary outcome was a change in BMI at 24 months. Changes in macronutrient consumption were examined in both analysis of covariance and repeated measures ANOVA models. Of the 172 patients, 116 (67.4%) patients consented to participate in the study. The intervention was found to be well accepted and attended by the patients (70.5% of patients in the intervention group attended the sessions). Whilst both intervention and control groups were noted to have a small reduction in BMI, there was no significant difference between the groups. There was no significant group effect noted for any change in macronutrient consumption at 6- or 24-month follow-up. This pilot study of a novel cookery skills project was well accepted amongst this population. Although the majority of participants had a net loss in BMI, the cookery skills intervention was not associated with any change in BMI beyond that achieved by written information alone.

MicroRNA Expression in Coronary Artery Disease.

The pathogenesis of atherosclerosis involves the interplay of inflammation, altered cellular activity, angiogenesis, and neointima formation. The main cellular participants in atherosclerosis include vascular endothelial cells, smooth muscle cells, and monocytes. The recent discovery of small, non-coding RNAs, microRNAs (miRNAs), and their influence on these processes has provided a greater molecular insight into atherosclerosis. This in turn has led to increase focus on the potential utility of miRNA subtypes as biomarkers for coronary artery disease. Furthermore miRNAs could potentially provide therapeutic targets for the treatment of atherosclerosis and its complications. In this review, we discuss the experimental and clinical evidence for the role of miRNAs in the pathogenesis of coronary artery disease, the limitations of the data and challenges facing the field.

Detection of high-sensitivity troponin in outpatients with stable pulmonary hypertension identifies a subgroup at higher risk of adverse outcomes.

BACKGROUND: The detection of elevations in cardiorenal biomarkers, such as troponins, B-type natriuretic peptides (BNPs), and neutrophil gelatinase-associated lipocalins, are associated with poor outcomes in patients hospitalized with acute heart failure. Less is known about the association of these markers with adverse events in chronic right ventricular dysfunction due to pulmonary hypertension, or whether their measurement may improve risk assessment in the outpatient setting. METHODS AND RESULTS: We performed a cohort study of 108 patients attending the National Pulmonary Hypertension Unit in Dublin, Ireland, from 2007 to 2009. Cox proportional hazards analysis and receiver operating characteristic curves were used to determine predictors of mortality and hospitalization. Death or hospitalization occurred in 50 patients (46.3%) during the median study period of 4.1 years. Independent predictors of mortality were: 1) decreasing 6-minute walk test (6MWT; hazard ratio [HR] 12.8; P < .001); 2) BNP (HR 6.68; P < .001); and 3) highly sensitive troponin (hsTnT; HR 5.48; P < .001). Adjusted hazard analyses remained significant when hsTnT was added to a model with BNP and 6MWT (HR 9.26, 95% CI 3.61-23.79), as did the predictive ability of the model for death and rehospitalization (area under the receiver operating characteristic curve 0.81, 95% CI 0.73-0.90). CONCLUSIONS: Detection of troponin using a highly sensitive assay identifies a pulmonary hypertension subgroup with a poorer prognosis. hsTnT may also be used in a risk prediction model to identify patients at higher risk who may require escalation of targeted pulmonary vasodilator therapies and closer clinical surveillance.

The Brady Bunch? New evidence for nominative determinism in patients' health: retrospective, population based cohort study.

OBJECTIVE: To ascertain whether a name can influence a person's health, by assessing whether people with the surname "Brady" have an increased prevalence of bradycardia. DESIGN: Retrospective, population based cohort study. SETTING: One university teaching hospital in Dublin, Ireland. PARTICIPANTS: People with the surname "Brady" in Dublin, determined through use of an online telephone directory. MAIN OUTCOME MEASURE: Prevalence of participants who had pacemakers inserted for bradycardia between 1 January 2007 and 28 February 2013. RESULTS: 579 (0.36%) of 161,967 people who were listed on the Dublin telephone listings had the surname "Brady." The proportion of pacemaker recipients was significantly higher among Bradys (n=8, 1.38%) than among non-Bradys (n=991, 0.61%; P=0.03). The unadjusted odds ratio (95% confidence interval) for pacemaker implantation among individuals with the surname Brady compared with individuals with other surnames was 2.27 (1.13 to 4.57). CONCLUSIONS: Patients named Brady are at increased risk of needing pacemaker implantation compared with the general population. This finding shows a potential role for nominative determinism in health.

Frequent mental distress (FMD) in Irish Travellers: discrimination and bereavement negatively influence mental health in the All Ireland Traveller Health Study.

Travellers are an indigenous minority group in Ireland, with poorer life expectancy and health status than the general population. Recent data have shown that Travellers are at increased risk of poor mental health and sequelae from same. We aimed to examine the associations between sociodemographic and lifestyle factors with poor mental health in Irish Travellers. A census survey of all Travellers was undertaken, with 8,492 enumerated families (80% response rate). A random subset of 1,796 adults completed an adult health survey. Traveller peer researchers employed a novel oral-visual computer-aided data collection tool. Frequent mental distress (FMD) was defined as 14 or more days of poor mental health in the preceding 1 month. Prevalence ratios for typical associates of FMD were estimated using a Poisson regression model, adjusted for age and sex. FMD was present in 11.9% of Traveller respondents, and prevalence increased with age. After age and sex adjustment, FMD was more prevalent in those whose quality of life was impaired by physical health, by those who were recently bereaved of a friend or family member, and by those who had greater experiences of discrimination. This study shows that Travellers experience discrimination and bereavement, which negatively influence their mental health. The findings have implications for the mental healthcare needs of indigenous ethnic minorities worldwide.

Use of a highly-sensitive cardiac troponin I assay in a screening population for hypertrophic cardiomyopathy: a case-referent study.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic condition, and relatives of affected persons may be at risk. Cardiac troponin biomarkers have previously been shown to be elevated in HCM. This study examines the new highly-sensitive cardiac troponin I (hsTnI) assay in a HCM screening population. METHODS: Nested case-control study of consecutive HCM sufferers and their relatives recruited from May 2010 to September 2011. After informed consent, participants provided venous blood samples and clinical and echocardiographic features were recorded. Associations between the natural log (ln) of the contemporary troponin I (cTnI) and hsTnI assays and markers of cardiac hypertrophy were examined. Multiple regression models were fitted to examine the predictive ability of hsTnI for borderline or definite HCM. RESULTS: Of 107 patients, 24 had borderline and 19 had definite changes of HCM. Both TnI assays showed significant, positive correlations with measures of cardiac muscle mass. After age and sex adjustment, the area under the receiver operator characteristic (AUROC) curve for the outcome of HCM was 0.78, 95% CI [0.65, 0.90], for ln(hsTnI), and 0.66, 95% CI [0.51, 0.82], for ln(cTnI) (p=0.11). Including the hsTnI assay in a multiple-adjusted "screening" model for HCM resulted in a non-significant improvement in both the AUROC and integrated discrimination index. CONCLUSIONS: Both cTnI and hsTnI show a graded, positive association with measures of cardiac muscle mass in persons at risk of HCM. Further studies will be required to evaluate the utility of these assays in ECG- and symptom-based identification of HCM in at-risk families.

Subclinical myocardial dysfunction in multiple sclerosis patients remotely treated with mitoxantrone: evidence of persistent diastolic dysfunction.

BACKGROUND: Mitoxantrone is an effective disease-modifying therapy in multiple sclerosis (MS), but its use is limited by cardiotoxicity. We evaluated global myocardial function, including myocardial performance index (MPI), on echocardiography in MS patients after remote mitoxantrone treatment. METHODS AND RESULTS: Consecutive patients (n = 50) treated with standard-protocol mitoxantrone from 2002 to 2010 in our center were identified. After exclusion of those who had died (n = 4; all noncardiac) or had developed interim cardiovascular disease or risk factors (n = 3), 33 (mean age 49 ± 11 years, 45% male, median follow-up 77 months, mean cumulative dose 72 mg/m(2)) of the remaining patients (77%) underwent 2-dimensional echocardiography. A comparison group of 17 age- and sex-matched control subjects were included. No significant differences occurred in standard echocardiographic parameters between groups. However, mean MPI (defined as isovolumic contraction time plus isovolumic relaxation time (IVRT) divided by ejection time) was significantly higher in patients (0.51 ± 0.12 vs 0.39 ± 0.06; P = .02) owing to a significantly prolonged IVRT (81 ± 25 vs 60 ± 9 ms; P = .04). Overall MPI was >0.5 in 18 patients compared with none of the control subjects (54.5% vs 0%; P < .001). CONCLUSIONS: A subclinical form of global myocardial dysfunction reflecting primarily diastolic dysfunction may be present in MS patients after remote standard-dose mitoxantrone treatment.