Negative lusitropic property of nifekalant identified using ventricular pressure-volume loop analyses in anesthetized monkeys.

The present study was conducted to clarify multiple cardiohemodynamic and electrophysiological properties including inotropic/lusitropic effects of nifekalant, a class III antiarrhythmic drug, in an isoflurane-anesthetized monkey. Nifekalant was administered intravenously at the therapeutic dose of 0.3 mg/kg over 10 min to male cynomolgus monkeys (n=4), followed by higher dose of 1 (n=3) or 3 mg/kg (n=1) that was limited due to arrythmogenicity. Left ventricular (LV) pressure-volume (PV) analysis revealed that the 0.3 mg/kg dose of nifekalant induced a negative lusitropic effect, recognized as a decrease in maximal rate of reduction in LV pressure and a prolonged isovolumic relaxation time. Nifekalant also decreased heart rate and increased LV end-diastolic pressure, but had no effects on the other cardiohemodynamic parameters examined. Electrophysiological analysis showed nifekalant at 0.3 mg/kg prolonged QT/QTc intervals with no evidence of arrhythmia. Higher doses of nifekalant induced ventricular arrhythmia in 3 out of 4 animals, in which both the short-term and long-term variability of the QT interval increased just before the occurrence of arrhythmia. In conclusion, a therapeutic dose of nifekalant had no effect on inotropic activity or cardiac compliance, whereas it showed negative lusitropic properties and QT/QTc prolongation in isoflurane-anesthetized monkeys. In addition, higher doses of nifekalant showed remarkable QT/QTc prolongation leading to arrhythmogenicity, which showed good accordance with clinical findings. Caution should be paid to negative lusitropic properties as well as arrhythmogenisity for the safe use of nifekalant.

The role of irradiated heart and left ventricular volumes in heart failure occurrence after childhood cancer.

BACKGROUND: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk. METHODS AND RESULTS: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline. CONCLUSIONS: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice.

Frequency of Left Ventricular End-Diastolic Volume-Mediated Declines in Ejection Fraction in Patients Receiving Potentially Cardiotoxic Cancer Treatment.

We sought to determine the frequency by which decreases in left ventricular (LV) end-diastolic volume (LVEDV) with and without increases in end-systolic volume (LVESV) influenced early cancer treatment-associated declines in LV ejection fraction (LVEF) or LV mass. One hundred twelve consecutively recruited subjects (aged 52 ± 14 years) with cancer underwent blinded cardiovascular magnetic resonance measurements of LV volumes, mass, and LVEF before and 3 months after initiating potentially cardiotoxic chemotherapy (72% of participants received anthracyclines). Twenty-six participants developed important declines in LVEF of >10% or to values <50% at 3 months, in whom 19% versus 60%, respectively, experienced their decline in LVEF due to isolated declines in LVEDV versus an increase in LVESV; participants who dropped their LVEF due to decreases in LVEDV lost more LV mass than those who dropped their LVEF due to an increase in LVESV (p = 0.03). Nearly one fifth of subjects experience marked LVEF declines due to an isolated decline in LVEDV after initiating potentially cardiotoxic chemotherapy. Because reductions in intravascular volume (which could be treated by volume repletion) may account for LVEDV-related declines in LVEF, these data indicate that LV volumes should be reviewed along with LVEF when acquiring imaging studies for cardiotoxicity during the treatment for cancer.

Cardiac Effects of Echinocandins in Endotoxemic Rats.

Echinocandins are known as effective and safe agents for the prophylaxis and treatment of different cohorts of patients with fungal infections. Recent studies revealed that certain pharmacokinetics of echinocandin antifungals might impact clinical efficacy and safety in special patient populations. The aim of our study was to evaluate echinocandin-induced aggravation of cardiac impairment in septic shock. Using an in vivo endotoxemic shock model in rats, we assessed hemodynamic parameters and time to hemodynamic failure (THF) after additional central-venous application of anidulafungin (2.5 mg/kg of body weight [BW]), caspofungin (0.875 mg/kg BW), micafungin (3 mg/kg BW), and control (0.9% sodium chloride). In addition, echinocandin-induced cytotoxicity was evaluated in isolated rat cardiac myocytes. THF of the animals in the caspofungin group (n = 7) was significantly reduced compared to that in the control (n = 6) (136 min versus 180 min; P = 0.0209). The anidulafungin group (n = 7) also showed a trend of reduced THF (136 min versus 180 min; log-rank test P = 0.0578). Animals in the micafungin group (n = 7) did not show significant differences in THF compared to those in the control. Control group animals and also micafungin group animals did not show altered cardiac output (CO) during our experiments. In contrast, administration of anidulafungin or caspofungin induced a decrease in CO. We also revealed a dose-dependent increase of cytotoxicity in anidulafungin- and caspofungin-treated cardiac myocytes. Treatment with micafungin did not cause significantly increased cytotoxicity. Further studies are needed to explore the underlying mechanism.

[INFLUENCE OF INTERMITTENT NORMOBARIC HYPOXIA ON CARDIOVASCULAR SYSTEM AND HEMODYNAMIC PARAMETERS OF CHILDREN LIVED AT RADIATION CONTAMINATED TERRITORIES.]

The effect of intermittent normobaric hypoxia (INH) of sanogenic level on the state of the cardiovascular system in 120 children aged from 12 to 17 years was studied. Children were divided into 3 groups. The 1st control group consisted of 20 persons (practically healthy ones), the 2nd group, a group of comparison, included 50 persons, and there were 50 persons in the 3rd group - a main group. Examined patients of two studied groups received the standard therapy, and those of the 3rd group - the seances of intermittent, normobaric hypoxia additionally to standard therapy. Systolic arterial pressure was significantly decreased in the rest from 108,2±1,9 to 103,8±1,1 mm Hg in children of the main group. Comparing the heart rate, systolic arterial pressure and diastolic arterial pressure their statistically decreased values by 9,3 min(-1), 8,36 and 7,84 mm Hg were revealed at 10 minutes of orthostatic, respectively. Autonomic supplying the activity of cardiovascular system with normal type of reaction was 34 % higher than that of the comparison group. It indicates an the improvement in hemodynamics and an increase in adaptation capabilities of the autonomic nervous system.

Upregulation of the kappa opioidergic system in left ventricular rat myocardium in response to volume overload: Adaptive changes of the cardiac kappa opioid system in heart failure.

Opioids have long been known for their analgesic effects and are therefore widely used in anesthesia and intensive care medicine. However, in the last decade research has focused on the opioidergic influence on cardiovascular function. This project thus aimed to detect the precise cellular localization of kappa opioid receptors (KOR) in left ventricular cardiomyocytes and to investigate putative changes in KOR and its endogenous ligand precursor peptide prodynorphin (PDYN) in response to heart failure. After IRB approval, heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. All rats of the control and ACF group were characterized by their morphometrics and hemodynamics. In addition, the existence and localization as well as adaptive changes of KOR and PDYN were investigated using radioligand binding, double immunofluorescence confocal analysis, RT-PCR and Western blot. Similar to the brain and spinal cord, [(3)H]U-69593 KOR selective binding sites were detected the left ventricle (LV). KOR colocalized with Cav1.2 of the outer plasma membrane and invaginated T-tubules and intracellular with the ryanodine receptor of the sarcoplasmatic reticulum. Interestingly, KOR could also be detected in mitochondria of rat LV cardiomyocytes. As a consequence of heart failure, KOR and PDYN were up-regulated on the mRNA and protein level in the LV. These findings suggest that the cardiac kappa opioidergic system might modulate rat cardiomyocyte function during heart failure.

Time Trends of Left Ventricular Ejection Fraction and Myocardial Deformation Indices in a Cohort of Women with Breast Cancer Treated with Anthracyclines, Taxanes, and Trastuzumab.

BACKGROUND: Trastuzumab, a HER2 monoclonal antibody, has transformed the prognosis of patients with the aggressive HER2-positive breast cancer type. Trastuzumab augments the cardiotoxic effects of anthracyclines, but its effect is thought to be at least partially reversible. The objective of this study was to examine the time trends of left ventricular (LV) size and function in a cohort of women treated with anthracyclines and trastuzumab. METHODS: Twenty-nine patients >18 years of age with first-time breast cancer treated with anthracyclines and trastuzumab were monitored using echocardiography before, at the completion of, and at a median follow-up of 24.7 months (interquartile range, 15.9-34 months) after the end of their cancer treatment. LV volume, LV ejection fraction, and global peak systolic longitudinal strain and strain rate were measured in the apical four- and two-chamber views. Left ventricular ejection fraction was measured using a modified Simpson's biplane method. RESULTS: LV end-diastolic and end-systolic volumes increased at the end of treatment compared with baseline and did not recover during follow-up. Left ventricular ejection fraction, strain, and strain rate decreased at the end of treatment compared with baseline (from 64 ± 6% to 59 ± 8%, from -20.0 ± 2.5% to -17.6 ± 2.6%, and from -1.26 ± 0.23 to -1.13 ± 0.16 sec(-1), respectively; P < .05 for all parameters) and remained decreased at follow-up. CONCLUSIONS: LV dilation and subclinical impairment in cardiac function persists >2 years after the end of anthracycline and trastuzumab treatment, without significant recovery after trastuzumab cessation, suggestive of long-term underlying cardiac damage and remodeling.

Reduction of heart volume during neoadjuvant chemoradiation in patients with resectable esophageal cancer.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiation (nCRT) followed by surgery is considered curative intent treatment for patients with resectable esophageal cancer. The aim was to establish hemodynamic aspects of changes in heart volume and to explore whether changes in heart volume resulted in clinically relevant changes in the dose distribution of radiotherapy. METHODS: A prospective study was conducted in patients who were treated with nCRT consisting of carboplatin and paclitaxel concomitant with radiotherapy (41.4 Gy/1.8 Gy per fraction). Physical parameters, cardiac volume on CT and Cone beam CT, cardiac blood markers and cardiac ultrasound were obtained. RESULTS: In 23 patients a significant decrease of 55.3 ml in heart volume was detected (95% CI 36.7-73.8 ml, p<0.001). There was a decrease in both systolic (mean decrease 18 mmHg, 95% CI 11-26 mmHg, p<0.001) and diastolic blood pressure (mean decrease 8 mmHg, 95% CI 2-14 mmHg, p=0.008) and an increase in heart rate with 6 beats/min (95% CI 1-11 beats/min, p=0.021). Except for Troponin T, no change in other cardiac markers and echocardiography parameters were observed. The change in heart volume did not result in a clinically relevant change in radiation dose distribution. CONCLUSION: Heart volume was significantly reduced, but was not accompanied by overt cardiac dysfunction. All observed changes in hemodynamic parameters are consistent with volume depletion. Adaptation of the treatment plan during the course of radiotherapy is not advocated.

Oral Coenzyme Q10 supplementation does not prevent cardiac alterations during a high altitude trek to everest base cAMP.

Exposure to high altitude is associated with sustained, but reversible, changes in cardiac mass, diastolic function, and high-energy phosphate metabolism. Whilst the underlying mechanisms remain elusive, tissue hypoxia increases generation of reactive oxygen species (ROS), which can stabilize hypoxia-inducible factor (HIF) transcription factors, bringing about transcriptional changes that suppress oxidative phosphorylation and activate autophagy. We therefore investigated whether oral supplementation with an antioxidant, Coenzyme Q10, prevented the cardiac perturbations associated with altitude exposure. Twenty-three volunteers (10 male, 13 female, 46±3 years) were recruited from the 2009 Caudwell Xtreme Everest Research Treks and studied before, and within 48 h of return from, a 17-day trek to Everest Base Camp, with subjects receiving either no intervention (controls) or 300 mg Coenzyme Q10 per day throughout altitude exposure. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac morphology and function. Following altitude exposure, body mass fell by 3 kg in all subjects (p<0.001), associated with a loss of body fat and a fall in BMI. Post-trek, left ventricular mass had decreased by 11% in controls (p<0.05) and by 16% in Coenzyme Q10-treated subjects (p<0.001), whereas mitral inflow E/A had decreased by 18% in controls (p<0.05) and by 21% in Coenzyme Q10-treated subjects (p<0.05). Coenzyme Q10 supplementation did not, therefore, prevent the loss of left ventricular mass or change in diastolic function that occurred following a trek to Everest Base Camp.

Right ventricular and right atrial function and deformation in patients with subclinical hypothyroidism: a two- and three-dimensional echocardiographic study.

BACKGROUND: We sought to investigate right ventricular (RV) function and deformation assessed by three-dimensional echocardiography (3DE) and speckle tracking in patients with subclinical hypothyroidism (SHT), and to evaluate the influence of levothyroxine (L-T4) therapy on RV remodeling. METHODS: We included 50 untreated women with SHT and 45 healthy control women matched by age. The L-T4 therapy was prescribed to all SHT patients who were followed 1 year after euthyroid status was achieved. All study participants underwent laboratory analyses which included thyroid hormone levels, and complete two-dimensional echocardiography (2DE) and 3DE examinations. RESULTS: 3DE RV end-diastolic volume and ejection fraction were significantly reduced in the SHT patients before therapy in comparison with the healthy controls and treated SHT subjects. RV longitudinal strain, systolic, and early diastolic strain rates (SRs) were significantly decreased, whereas RV late diastolic SR was increased in the SHT patients before therapy when comparing with the controls. 2DE speckle tracking imaging revealed that L-T4 substitution therapy significantly improved RV systolic mechanics, whereas RV diastolic deformation was not completely recovered. Right atrial (RA) function and deformation were significantly impacted by SHT. Replacement L-T4 treatment improved but did not completely restore RA mechanics in the SHT patients. CONCLUSION: RV and RA function and mechanics are significantly affected by SHT. L-T4 therapy and 1-year maintenance of euthyroid status improved but did not completely recover RV and RA function and deformation in the SHT patients, which implies that right heart remodeling caused by SHT is not reversible in a 1-year period.

Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice.

Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg(+/-)) mice, but not in mice defective for ligand binding (Pparg(P465L/+)). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity.

Reduction in cardiac volume during chemoradiotherapy for patients with esophageal cancer.

We investigated the change in cardiac volume over the course of chemoradiotherapy in 26 patients treated for esophageal cancer, using cone beam CT imaging. The cardiac volume reduced significantly, with a median reduction of 8%. A significant relationship with planned cardiac dose was not found.

Validation of admittance computed left ventricular volumes against real-time three-dimensional echocardiography in the porcine heart.

The admittance and Wei's equation is a new technique for ventricular volumetry to determine pressure-volume relations that addresses traditional conductance-related issues of parallel conductance and field correction factor. These issues with conductance have prevented researchers from obtaining real-time absolute ventricular volumes. Moreover, the time-consuming steps involved in processing conductance catheter data warrant the need for a better catheter-based technique for ventricular volumetry. We aimed to compare the accuracy of left ventricular (LV) volumetry between the new admittance catheterization technique and transoesophageal real-time three-dimensional echocardiography (RT3DE) in a large-animal model. Eight anaesthetized pigs were used. A 7 French admittance catheter was positioned in the LV via the right carotid artery. The catheter was connected to an admittance control unit (ADVantage; Transonic Scisense Inc.), and data were recorded on a four-channel acquisition system (FA404; iWorx Systems). Admittance catheterization data and transoesophageal RT3DE (X7-2; Philips) data were simultaneously obtained with the animal ventilated, under neuromuscular blockade and monitored in baseline conditions and during dobutamine infusion. Left ventricular volumes measured from admittance catheterization (Labscribe; iWorx Systems) and RT3DE (Qlab; Philips) were compared. In a subset of four animals, admittance volumes were compared with those obtained from traditional conductance catheterization (MPVS Ultra; Millar Instruments). Of 37 sets of measurements compared, admittance- and RT3DE-derived LV volumes and ejection fractions at baseline and in the presence of dobutamine exhibited general agreement, with mean percentage intermethod differences of 10% for end-diastolic volumes, 14% for end-systolic volumes and 9% for ejection fraction; the respective intermethod differences between admittance and conductance in eight data sets compared were 11, 11 and 12%. Admittance volumes were generally higher than those obtained by RT3DE, especially among the larger ventricles. It is concluded that it is feasible to derive pressure-volume relations using admittance catheterization in large animals. This study demonstrated agreements between admittance and RT3DE to within 10-14% mean intermethod difference in the estimation of LV volumes. Further investigation will be required to examine the accuracy of volumes in largest ventricles, where intermethod divergence is greatest.

Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease.

BACKGROUND: Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS: One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 µg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS: Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Selective serotonin reuptake inhibitor use is associated with right ventricular structure and function: the MESA-right ventricle study.

PURPOSE: Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114). METHODS: SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex. RESULTS: After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48-5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19-1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02-12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes. CONCLUSIONS: SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study.