Right ventricle in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure. While previously neglected, the right ventricle (RV) has sparked interest in recent years as a means for better understanding this condition and as a potential therapeutic target.Right ventricular dysfunction (RVD) is present in 4%-50% of patients with HFpEF. The RV is intimately connected to the pulmonary circulation, and pulmonary hypertension is commonly implicated in the pathophysiology of RVD. The development of RVD in HFpEF may also be driven by comorbidities, such as chronic obstructive pulmonary disease, obesity, obstructive sleep apnoea and atrial fibrillation. The evaluation of RVD is particularly challenging due to anatomical and structural factors, as well as unique physiological characteristics of this chamber like load and interventricular dependency. Fractional area change, tricuspid annular plane systolic excursion and tricuspid annular systolic velocity are commonly used measurements of RV function. Speckle tracking echocardiography and cardiac magnetic resonance (CMR) are also gaining attention as important tools for the assessment of RV structure, fibre deformation and systolic performance. Further research is needed to confirm the utility and prognostic significance of RV [18F]fluorodeoxyglucose (FDG) positron emission tomography imaging as FDG accumulation is suggested to increase with progressive RVD. Targeted pharmacotherapy with phosphodiesterase inhibitors, guanylate-cyclase stimulators, nitrates and inhaled inorganic nitrites have yet to demonstrate improvement in RVD, compelling the need for evaluation and discovery of novel pharmacological interventions for this entity.

Assessment of spatial heterogeneity of ventricular repolarization after multi-channel blocker drugs in healthy subjects.

BACKGROUND AND OBJECTIVES: In contrast to potassium channel blockers, drugs affecting multiple channels seem to reduce torsadogenic risks. However, their effect on spatial heterogeneity of ventricular repolarization (SHVR) is still matter of investigation. Aim of this work is to assess the effect of four drugs blocking the human ether-à-go-go-related gene (hERG) potassium channel, alone or in combination with other ionic channel blocks, on SHVR, as estimated by the V-index on short triplicate 10 s ECG. METHODS: The V-index is an estimate of the standard deviation of the repolarization times of the myocytes across the entire myocardium, obtained from multi-lead surface electrocardiograms. Twenty-two healthy subjects received a pure hERG potassium channel blocker (dofetilide) and 3 other drugs with additional varying degrees of sodium and calcium (L-type) channel block (quinidine, ranolazine, and verapamil), as well as placebo. A one-way repeated-measures Friedman test was performed to compare the V-index over time. RESULTS: Computer simulations and Bland-Altman analysis supported the reliability of the estimates of V-index on triplicate 10 s ECG. Ranolazine, verapamil and placebo did not affect the V-index. On the contrary, after quinidine and dofetilide administration, an increase of V-index from predose to its peak value was observed (ΔΔV-index values were 19 ms and 27 ms, respectively, p < 0.05). CONCLUSIONS: High torsadogenic drugs (dofetilide and quinidine) affected significantly the SHVR, as quantified by the V-index. The metric has therefore a potential in assessing drug arrhythmogenicity.

Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer.

BACKGROUND: Anthracycline-induced cardiotoxicity is a major cause of morbidity and mortality in childhood cancer survivors (CCSs). Echocardiographic myocardial strain imaging is recommended in adult patients with cancer, but its role in pediatric CCSs has not been well established. Aims of this study were to determine the prevalence of abnormalities in left ventricular strain in pediatric CCSs, to compare strain with other echocardiographic measurements and blood biomarkers, and to explore risk factors for reduced strain. METHODS: CCSs ≥3 years from their last anthracycline treatment were enrolled in this multicenter study and underwent a standardized functional echocardiogram and biomarker collection. Regression analysis was used to identify factors associated with longitudinal strain (LS). RESULTS: Five hundred forty-six pediatric CCSs were compared with 134 healthy controls. Abnormal left ventricular ejection fraction (<50%) and mean LS (Z score, <-2) was found in 0.8% and 7.7% of the CCSs, respectively. LS was significantly lower in CCSs than in controls, but the absolute difference was small (0.7%). Lower LS in CCSs was associated with older current age and higher body surface area. Sex, cumulative anthracycline dose, radiotherapy, and biomarkers were not independently associated with LS. Circumferential strain, diastolic parameters, and biomarkers were not significantly different in pediatric CCSs. CONCLUSIONS: Global systolic function and LS are only mildly reduced in pediatric CCSs, and most LS values are within normal range. This makes single LS measurements of limited added value in identifying CCSs at risk for cardiac dysfunction. The utility of strain imaging in the long-term follow-up of CCS remains to be demonstrated.

Contractile performance of the Alaska blackfish (Dallia pectoralis) ventricle: Assessment of the effects of temperature, pacing frequency, the role of the sarcoplasmic reticulum in contraction and adrenergic stimulation.

The air-breathing Alaska blackfish (Dallia pectoralis) experiences aquatic hypoxia, but restricted air-access in winter due to ice-cover. To lend insight into its overwintering strategy, we examined the effects of thermal acclimation (15 °C vs. 5 °C), acute temperature change (to 10 °C), increased pacing frequency, inhibition of sarcoplasmic reticulum (SR) Ca2+ release and uptake and adrenaline (1000 nmol l-1) on the contractile performance of isometrically-contracting, electrically-paced ventricular strips. At routine pacing frequencies, maximal developed force (Fmax) was equivalent at 5 °C (2.1 ±â€¯0.2 mN mm-2) and 15 °C (2.2 ±â€¯0.3 mN mm-2), whereas contraction durations were 2.2- to 2.4-times longer and contraction rates 2.4- to 3.5-times slower at 5 °C. Maximum contraction frequency was reduced by decreased temperature, being 0.91 ±â€¯0.04 Hz at 15 °C, 0.35 ±â€¯0.02 Hz at 5 °C and equivalent between acclimation groups at 10 °C (~0.8 Hz). 15 °C and 5 °C strips were insensitive to SR inhibition at routine stimulation frequencies, but SR function supported high contraction rates at 10 °C and 15 °C. Adrenaline shortened T0.5R and increased relaxation rate by 18-40% at 15 °C, whereas at 5 °C, adrenaline augmented Fmax by 15-25%, in addition to increasing contraction kinetics by 22-82% and decreasing contraction duration by 20%. Overall, the results reveal that ventricular contractility is suppressed in cold-acclimated Alaska blackfish largely by acute and perhaps direct effects of decreased temperature, which effectively preconditions the tissue for low energy supply during winter hypoxia. Additionally, the level of cardiac performance associated with maintained activity in winter is supported by enhanced inotropic responsiveness to adrenaline at 5 °C.

Assessment of Prognostic Value of Left Ventricular Global Longitudinal Strain for Early Prediction of Chemotherapy-Induced Cardiotoxicity: A Systematic Review and Meta-analysis.

Importance: Echocardiographic left ventricular global longitudinal strain (GLS) detects early subclinical ventricular dysfunction and can be used in patients receiving potentially cardiotoxic chemotherapy. A meta-analysis of the prognostic value of GLS for cancer therapy-related cardiac dysfunction (CTRCD) has not been performed, to our knowledge. Objective: To explore the prognostic value of GLS for the prediction of CTRCD. Data Sources: Systematic search of the MEDLINE, Embase, Scopus, and the Cochrane Library databases from database inception to June 1, 2018. Study Selection: Cohort studies assessing the prognostic or discriminatory performance of GLS before or during chemotherapy for subsequent CTRCD. Data Extraction and Synthesis: Random-effects meta-analysis and hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the prognostic and discriminatory performance of different GLS indices. Publication bias was assessed using the Egger test, and meta-regression was performed to assess sources of heterogeneity. Main Outcomes and Measures: The primary outcome was CTRCD, defined as a clinically significant change in left ventricular ejection fraction with or without new-onset heart failure symptoms. Results: Analysis included 21 studies comprising 1782 patients with cancer, including breast cancer, hematologic malignancies, or sarcomas, treated with anthracyclines with or without trastuzumab. The incidence of CTRCD ranged from 9.3% to 43.8% over a mean follow-up of 4.2 to 23.0 months (pooled incidence, 21.0%). For active treatment absolute GLS (9 studies), the high-risk cutoff values ranged from -21.0% to -13.8%, with worse GLS associated with a higher CTRCD risk (odds ratio, 12.27; 95% CI, 7.73-19.47; area under the HSROC, 0.86; 95% CI, 0.83-0.89). For relative changes vs a baseline value (9 studies), cutoff values ranged from 2.3% to 15.9%, with a greater decrease linked to a 16-fold higher risk of CTRCD (odds ratio, 15.82; 95% CI, 5.84-42.85; area under the HSROC, 0.86; 95% CI, 0.83-0.89). Both indices showed significant publication bias. Meta-regression identified differences in sample size and CTRCD definition but not GLS cutoff value as significant sources of interstudy heterogeneity. Conclusions and Relevance: In this meta-analysis, measurement of GLS after initiation of potentially cardiotoxic chemotherapy with anthracyclines with or without trastuzumab had good prognostic performance for subsequent CTRCD. However, risk of bias in the original studies, publication bias, and limited data on the incremental value of GLS and its optimal cutoff values highlight the need for larger prospective multicenter studies.

QT Assessment in Early Drug Development: The Long and the Short of It.

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound's cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.

Biocompatibility assessment of titanium dioxide nanoparticles in mice fetoplacental unit.

As the applications of titanium dioxide nanomaterials (nTiO2 ) are growing with an ever-increasing speed, the hazardous risks of this material have become a major concern. Several recent studies have reported that nTiO2 can cross the placental barrier in pregnant mice and cause neurotoxicity in their offspring. However, the influence of these nanoparticles on the fetoplacental unit during the pregnancy is yet to be studied. The present study reports on the effects of nTiO2 on the anatomical structure of fetal brain and liver in a pregnant mice model. Moreover, changes in the size and weight of the fetus and placenta are investigated as markers of fetal growth. Lastly, the toxicity of nTiO2 in primary brain and liver is quantified. Animals treated with nTiO2 showed a disrupted anatomical structure of the fetal brain and liver. Furthermore, the fetus and placental unit in the mice treated with these nanoparticles were smaller compared to untreated controls. Toxicity analyses revealed that nTiO2 was toxic to the brain and liver cells and the mechanism of cell death was mostly necrosis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 580-589, 2018.

Early assessment of the left ventricular function by epirubicin-induced cardiotoxicity in postoperative breast cancer patients.

OBJECTIVE: Epirubicin (Epi) is a potent and effective drug for many malignant cancers with serious cardiotoxicity. Therefore, layer-specific two-dimensional speckle tracking echocardiography (2D-STE) was used to evaluate the longitudinal and circumferential systolic function of the left ventricular for the early detection of cardiotoxicity in this retrospective work. METHODS: Overall, 130 female patients with postoperative breast cancer who did not receive radiotherapy were classified into three groups: Group A (control group, n = 40) without any chemotherapy; Group B (n = 44) administered Epi at 180 ~ 240 mg/m2 ; and Group C (n = 46) administered Epi at ≥360 mg/m2 . Peak and global systolic longitudinal strains (GLS) in the total and endocardium, mid-myocardium, and epicardium were measured and calculated from apical four-chamber, apical two-chamber, and left ventricular long-axis views, respectively. Peak and global circumferential strains (GCS) in the total and endocardium, mid-myocardium, and epicardium were measured and calculated from mitral annulus, papillary muscle, and apical levels of the short-axis view, respectively. RESULTS: The total GLS and GLS of the endocardium in every view were significantly reduced in group C compared with both groups A and B (P < .05), but there was no significant difference between groups A and B (P > .05). The GLS of the epicardium and mid-myocardium in groups B and C were not significantly reduced (P > .05). There were no significant differences in the total GCS and layer-specific GCS of endocardium, mid-myocardium, and epicardium among the three groups (P > .05). CONCLUSIONS: Left ventricular longitudinal systolic dysfunction was detected. Moreover, an impaired endocardium was also detected in an early assessment by layer-specific 2DSTE.

In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles.

AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. METHODS: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. RESULTS: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. CONCLUSIONS: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.

Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study.

BACKGROUND: There are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab. METHODS: Prospective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters. RESULTS: Of the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p < 0.001 for both), but not at 18 months (p = 0.82 and 0.13 respectively). RV ejection fraction (RVEF), when compared to baseline (58.3%, 95% CI 57.1-59.5%), showed corresponding decreases at 6 months (53.9%, 95% CI 52.5-55.4%, p < 0.001) and 12 months (55%, 95% CI 53.8-56.2%, p < 0.001) that recovered at 18 months (56.6%, 95% CI 55.1-58.0%, p = 0.08). Although the temporal pattern of changes in LVEF and RVEF were similar, there was no significant correlation between RVEF and LVEF at baseline (r = 0.29, p = 0.07) or between their changes at 6 months (r = 0.24, p = 0.17). CONCLUSION: In patients receiving trastuzumab without overt cardiotoxicity, there is a subtle but significant deleterious effect on RV structure and function that recover at 18 months, which can be detected by CMR. Furthermore, monitoring of LVEF alone may not be sufficient in detecting early RV injury. These novel findings provide further support for CMR in monitoring early cardiotoxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01022086 . Date of registration: November 27, 2009.

Assessment of Longitudinal Reproducibility of Mice LV Function Parameters at 11.7 T Derived from Self-Gated CINE MRI.

The objective of this work was the assessment of the reproducibility of self-gated cardiac MRI in mice at ultra-high-field strength. A group of adult mice (n = 5) was followed over 360 days with a standardized MR protocol including reproducible animal position and standardized planning of the scan planes. From the resulting CINE MRI data, global left ventricular (LV) function parameters including end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and left ventricular mass (LVM) were quantified. The reproducibility of the self-gated technique as well as the intragroup variability and longitudinal changes of the investigated parameters was assessed. Self-gated cardiac MRI proved excellent reproducibility of the global LV function parameters, which was in the order of the intragroup variability. Longitudinal assessment did not reveal any significant variations for EDV, ESV, SV, and EF but an expected increase of the LVM with increasing age. In summary, self-gated MRI in combination with a standardized protocol for animal positioning and scan plane planning ensures reproducible assessment of global LV function parameters.

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept.

BACKGROUND AND PURPOSE: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. EXPERIMENTAL APPROACH: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. RESULTS: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). CONCLUSION AND IMPLICATIONS: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

Echocardiographic Assessment of Cardiotoxic Effects of Cancer Therapy.

Patients with cancer can present with difficult management issues, as the medicine can sometimes cause sequelae destructive to healthy tissue. As this population lives longer, cardiotoxic effects are beginning to emerge, but the early recognition of this signal can prove difficult, with too late a recognition leading to lifelong cardiac impairment and dysfunction. Cardio-oncology can bridge this difficulty, and echocardiography and its newer imaging abilities are proving efficacious in this population. This article will address common sequelae of cardiotoxic treatment regimens and offer recommendations for echocardiographic surveillance. We recommend echocardiography, preferably three-dimensional and strain imaging, to monitor for cardiotoxic myocardial effects before, during, and after chemotherapy with cardiotoxic drug regimens, particularly anthracycline derivatives. A reduction in left ventricular (LV) global longitudinal strain in all patients, or reduction in LV global circumferential strain or global radial strain in patients at intermediate to high risk for cardiotoxicity, despite normal LV ejection fraction warrants a clinical assessment on the benefits of continuing cardiotoxic chemotherapeutic agents. Lifelong surveillance using echocardiography for cardiotoxicity and radiation-related valvular, pericardial, and coronary artery disease is prudent.

Assessment of drug-induced proarrhythmia: The importance of study design in the rabbit left ventricular wedge model.

In the present study, we investigated an impact of the stimulation rate on the detection of the proarrhythmic potential of 10 reference compounds with effects on different cardiac ion channels in the isolated arterially-perfused rabbit left ventricular wedge preparation. The compounds were tested in the wedge model using two distinct protocols; including baseline stimulation at 1-Hz followed by a brief period at 0.5-Hz, either without an additional brief period of 2-Hz stimulation (i.e. Protocol 1) or with 2-Hz stimulation (i.e. Protocol 2). As expected, QT-prolonging drugs (ibutilide and quinidine) prolonged the QT interval, similarly increased the Torsades de Pointes (TdP) score, and elicited early afterdepolarizations (EADs) in both protocols. HMR1556 and JNJ-303 (IKs blockers) also prolonged the QT interval up to 1µM similarly in both protocols. Nifedipine (Ca(2+) antagonist) shortened the QT interval, and reduced force of contraction similarly in both protocols. However, Na(+) channel blockers (Ia, Ib, Ic) widened the QRS duration more in Protocol 2 than in Protocol 1. Furthermore, it was only possible to detect non-TdP-like ventricular tachycardia/fibrillation (VT/VF) induced by Na(+) blockers and by QT-shortening drugs (levcromakalim and mallotoxin) using the 2-Hz stimulation (Protocol 2). Our data suggest that the inclusion of a brief period of fast stimulation at 2Hz is critical for detecting drug-induced slowing of conduction (QRS widening), QT shortening and associated (non-TdP-like) VT/VF, which are distinct from the QT prolongation/TdP proarrhythmia in isolated, arterially-perfused rabbit left ventricular wedges.

The cross-bridge dynamics is determined by two length-independent kinetics: Implications on muscle economy and Frank-Starling Law.

The cellular mechanisms underlying the Frank-Starling Law of the heart and the skeletal muscle force-length relationship are not clear. This study tested the effects of sarcomere length (SL) on the average force per cross-bridge and on the rate of cross-bridge cycling in intact rat cardiac trabeculae (n=9). SL was measured by laser diffraction and controlled with a fast servomotor to produce varying initial SLs. Tetanic contractions were induced by addition of cyclopiazonic acid, to maintain a constant activation. Stress decline and redevelopment in response to identical ramp shortenings, starting at various initial SLs, was analyzed. Both stress decline and redevelopment responses revealed two distinct kinetics: a fast and a slower phase. The duration of the rapid phases (4.2 ± 0.1 msec) was SL-independent. The second slower phase depicted a linear dependence of the rate of stress change on the instantaneous stress level. Identical slopes (70.5 ± 1.6 [1/s], p=0.33) were obtained during ramp shortening at all initial SLs, indicating that the force per cross-bridge and cross-bridge cycling kinetics are length-independent. A decrease in the slope at longer SLs was obtained during stress redevelopment, due to internal shortening. The first phase is attributed to rapid changes in the average force per cross-bridge. The second phase is ascribed to both cross-bridge cycling between its strong and weak conformations and to changes in the number of strong cross-bridges. Cross-bridge cycling kinetics and muscle economy are length-independent and the Frank-Starling Law cannot be attributed to changes in the force per cross-bridge or in the single cross-bridge cycling rates.

Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance.

BACKGROUND: In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. METHODS AND RESULTS: In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51 ± 12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57 ± 6% to 54 ± 7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1 ± 5.1 to 15.9 ± 6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). CONCLUSIONS: Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects.

Assessment of early-onset chronic progressive anthracycline cardiotoxicity in children: different response patterns of right and left ventricles.

We aimed to assess early-onset chronic progressive cardiotoxicity in the left and right ventricles with increasing cumulative anthracycline doses. We evaluated 72 patients within the first year after doxorubicin and/or daunorubicin treatment (median 1.3 months; range 0.3-11.5) and 31 healthy controls. Pretreatment and posttreatment QT interval analyzes were performed in 27 newly diagnosed patients. The echocardiographic data of all examinations of 72 patients were classified into three groups according to instant cumulative anthracycline doses: treatment group (TG)-I (≤120 mg/m(2); n = 26), TG-II (120-240 mg/m(2); n = 39), and TG-III (≥240 mg/m(2); n = 40). Diastolic and systolic parameters were analyzed by conventional echocardiography and tissue Doppler imaging (TDI) and compared with those of healthy controls. The mean age for patients and controls was 8.2 ± 4.5 and 9.6 ± 4.2 years, respectively (p > 0.05). QTc dispersion significantly increased after anthracycline treatment (p = 0.02). TDI showed decreased E' velocity (p < 0.001) and E'/A' ratio (p < 0.001) at lateral tricuspid annulus segment in TG-I, and these findings continued in TG-II and -III. In addition, S' velocity decreased in TG-I, -II, and -III at lateral mitral annulus (10.5 ± 2.6 cm/s, p < 0.05; 9.9 ± 2.2 cm/s, p < 0.001; and 10.1 ± 2.3 cm/s, p < 0.01, respectively). However, decrease in left-ventricular ejection fraction was statistically significant in TG-II and -III (p < 0.001). Although myocardial performance index was significantly increased in all treatment groups in both segments, it was primarily due to significant increases in isovolumic relaxation time at the lateral tricuspid annulus and isovolumic contraction time at the lateral mitral annulus. Abnormalities in diastolic function in right ventricle and systolic function in the left ventricle were observed even with a cumulative anthracycline dose <120 mg/m(2) by TDI. In addition, anthracycline treatment led to an increase in QTc dispersion.

A translational assessment of preclinical versus clinical tools for the measurement of cardiac contractility: comparison of LV dP/dt(max) with echocardiography in telemetry implanted beagle dogs.

INTRODUCTION: Regarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements. METHODS: As a step towards translation of preclinical to clinical outcomes, this study in telemetered dogs was initiated to compare indexes of contractility, such as LV dP/dt(max) (contractility measured as the maximum raise of pressure in the left ventricle) and LV dP/dt(max)/P (contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure) (telemetry; both commonly preclinically used) and EF (ejection fraction) and FS (fractional shortening) (echocardiography; both commonly clinically used). Different inotropic states were induced by minoxidil, milrinone, isoprenaline, clonidine, atenolol and verapamil. RESULTS: Both techniques demonstrated reproducible changes in contractility which showed a clear linear association. A change in LV dP/dt(max) of 1000 mmHg/s (in the range of 2500 to 7500 mmHg/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of approximately 6%. A change of 10/s LV dP/dt(max)/P (in the range of 35 to 85/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of 7%. DISCUSSION: The correlation found in this study could potentially enable a better--translational--assessment of the clinical relevance of changes in contractility indices measured with telemetry devices in preclinical safety studies.

In silico assessment of drug safety in human heart applied to late sodium current blockers.

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I(NaL)) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K(+) current (I(Kr)). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I(Kr)/I(NaL) ratio of steady-state block of drug candidates on "torsadogenic" biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I(NaL) and I(Kr) were evaluated. "Safety plots" were developed to illustrate the value of the specific biomarker for selected combinations of IC(50)s for I(Kr) and I(NaL) of potential drugs. The reference biomarkers at baseline changed depending on the "drug" specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I(NaL)) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.

Clinical experience with low-dose continuous infusion of furosemide in acute heart failure: assessment of efficacy and safety.

INTRODUCTION: Clinical data are scarce for furosemide administered as a low-dose (<160 mg/24 hours) continuous intravenous infusion in acute heart failure (HF). Our purpose was to evaluate the efficacy and safety of low-dose continuous infusion of furosemide on diuretic response, renal function, and patient outcomes. METHODS: A retrospective study of patients with acute HF who received furosemide administered as a continuous infusion after initial therapy with intermittent boluses (usually 40-80 mg every 12 hours). End points included mean hourly urine output, incidence of acute renal injury, and outcome disparities of patients who developed acute renal injury. Comparison of patients with preserved and reduced left ventricular ejection fraction (LVEF) was also performed. RESULTS: The study included 150 patients (age 57 ± 13 years, male gender 61%, admission weight 87 ± 32 kg, LVEF 37 ± 15%, 28% preserved LVEF). Mean initial and maximum furosemide doses were 5.1 ± 1.1 mg/h and 6.2 ± 2.2 mg/h, respectively. Mean duration of therapy was 51.4 ± 67.5 hours. Continuous infusion of furosemide was associated with a significant increase in mean hourly urine output compared to baseline (150 ± 77 mL/h vs 116 ± 69 mL/h, P < .001). Acute renal injury developed in 19% of patients, with 70% of those occurring within the first 48 hours of therapy. Mean serum creatinine (baseline 1.55 ± 1.50 mg/dL vs at discharge 1.64 ± 1.61 mg/dL, P = .20) and estimated glomerular filtration rate (baseline 67 ± 39 mL/min vs at discharge 67 ± 43 mL/min, P = .89) did not significantly change over the course of the hospitalization. Development of acute renal injury was associated with poorer outcomes, higher furosemide dose, and longer duration of furosemide therapy. Diuretic response and safety were not different between patients with preserved or reduced LVEF. CONCLUSIONS: In patients with acute HF, furosemide administered as a low-dose continuous infusion was effective in achieving diuresis and was not associated with a detectable effect on renal function. This diuretic approach appeared to be similarly effective and safe in patients with preserved LVEF.