Comprehensive and Safe Decongestion in Acutely Decompensated Heart Failure.

PURPOSE OF THE REVIEW: Progressive intravascular, interstitial, and alveolar fluid overload underlies the transition from compensated to acutely decompensated heart failure and loop diuretics are the mainstay of treatment. Adverse effects and resistance to loop diuretics received much attention while the contribution of a depressed cardiac output to diuretic resistance was downplayed. RECENT FINDINGS: Analysis of experience with positive inotropic agents, especially dobutamine, indicates that enhancement of cardiac output is not consistently associated with increased renal blood flow. However, urinary output and renal sodium excretion increase likely due to dobutamine-mediated decrease in renal and systemic reduced activation of sympathetic nervous- and renin-angiotensin-aldosterone system. Mechanical circulatory support with left ventricular assist devices ascertained the contribution of low cardiac output to diuretic resistance and the pathogenesis and progression of kidney disease in acutely decompensated heart failure. Diuretic resistance commonly occurs in acutely decompensated heart failure. However, failure to resolve fluid overload despite high doses of loop diuretics should alert to the presence of a low cardiac output state.

Detection of Profound Myocardial Damage by Cardiac MRI in a Patient with Severe Cardiotoxicity Induced by Anti-HER2 Therapy.

Anti-HER2 therapy has greatly improved the long-term prognosis of patients with HER2-positive breast cancer. Meanwhile, by interfering with the protective effects of neuregulin-1/HER2 signaling on stressed cardiomyocytes, anti-HER2 therapy occasionally induces reversible cancer therapeutics-related cardiac dysfunction (CTRCD). Cardiac magnetic resonance (CMR) parametric mapping or myocardial feature-tracking, in combination with late gadolinium enhancement (LGE) imaging, has the potential to detect changes in the myocardium in anti-HER2 therapy-related cardiac dysfunction. Here we report a breast cancer patient who experienced life-threatening CTRCD after treatment with trastuzumab plus pertuzumab. This case showed multiple transmural LGE-positive myocardial lesions in CMR imaging and high native T1 and T2 values in CMR parametric mapping, which was apparently more extensive than those observed in most patients with anti-HER2 therapy-related cardiac dysfunction. Consistent with profound myocardial damage indicated by CMR, her cardiac function was not fully restored despite intensive care and cardioprotective drug therapy. These findings suggest the potential usefulness of LGE imaging and parametric mapping by CMR for the assessment of myocardial injury to determine the clinical severity of anti-HER2 therapy-related cardiac dysfunction.

A sex-balanced rodent model for evaluating phosphine inhalation toxicity.

Exposure to phosphine (PH3 ), a common grain fumigant, is characterized by diverse nonspecific symptoms and a high mortality rate. Although PH3 poisoning is thought to target oxidative respiration, the exact mechanism of action remains largely unknown, resulting in limited treatment options. In our study, the effects of PH3 on female rats were assessed to elucidate potential sex-specific differences and obtain a more comprehensive understanding of PH3 toxicity. Lethality, physiology, and behavior were evaluated in female rats exposed to gaseous PH3 (13,200-26,400 ppm × min), and results were compared with corresponding findings in male rats. Median lethal concentration-time (LCt50 ) and time of death (tTOD ) did not differ significantly between the sexes. Cardiopulmonary changes induced by PH3 were also of comparable magnitude, although temporally, respiratory responses occurred earlier and cardiovascular variations manifested later in female rats. Behavioral observations corroborated physiological findings and indicated a response to hypoxic conditions and low cardiac output. Together, these results provided insights on the toxic mechanisms of PH3 , in particular, its potential interference with oxygen transport and circulation.

Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy.

BACKGROUND: This review update has been managed by both the Childhood Cancer and Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Groups.The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. To prevent this cardiotoxicity, different anthracycline dosage schedules have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules (that is peak doses and infusion durations) in people with cancer. SEARCH METHODS: We searched the databases of the Cochrane Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 11, 2015), MEDLINE (1966 to December 2015), and EMBASE (1980 to December 2015). We also searched reference lists of relevant articles, conference proceedings, experts in the field, and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in people with cancer (children and adults). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, the 'Risk of bias' assessment, and data extraction. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified 11 studies: 7 evaluated different infusion durations (803 participants), and 4 evaluated different peak doses (5280 participants). Seven studies were RCTs addressing different anthracycline infusion durations; we identified long-term follow-up data for one of the trials in this update. The meta-analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of six hours or longer as compared to a shorter infusion duration (risk ratio (RR) 0.27; 95% confidence interval 0.09 to 0.81; 5 studies; 557 participants). The majority of participants included in these studies were adults with different solid tumours. For different anthracycline peak doses, we identified two RCTs addressing a doxorubicin peak dose of less than 60 mg/m(2) versus 60 mg/m(2) or more, one RCT addressing a liposomal doxorubicin peak dose of 25 mg/m(2) versus 50 mg/m(2), and one RCT addressing an epirubicin peak dose of 83 mg/m(2) versus 110 mg/m(2). A significant difference in the occurrence of clinical heart failure was identified in none of the studies. The participants included in these studies were adults with different solid tumours. High or unclear 'Risk of bias' issues were present in all studies. AUTHORS' CONCLUSIONS: An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.We identified no significant difference in the occurrence of clinical heart failure in participants treated with a doxorubicin peak dose of less than 60 mg/m(2) or 60 mg/m(2) or more. Only one RCT was available for the other identified peak doses, so we can make no definitive conclusions about the occurrence of cardiotoxicity. More high-quality research is needed, both in children and adults and in leukaemias and solid tumours.

Ultrasound evaluation of the inferior vena cava collapsibility index in congestive heart failure patients treated with intravenous diuretics: new insights about its relationship with renal function: an observational study.

OBJECTIVE: In chronic heart failure (CHF), collapsibility index of the inferior vena cava (IVCCI) is used for noninvasive ultrasonographic appraisal of central venous pressure, but it also may be related both to estimated glomerular filtration rate (eGFR) and renal outcome. METHODS: On the basis of retrospective observational cohort study, we analyzed 49 patients with right or biventricular CHF in III NYHA class, who had undergone intravenous intensive treatment with furosemide. Aggravated renal dysfunction (ARD) was defined by serum creatinine (Cr) increase of ≥0.3 mg/dL from baseline. IVCCI was categorized in three layers (IVCCI ≤15%, IVCCI 16-40% and IVCCI >40%). The predictors of ARD were searched for as well as any relation between basal IVCCI and both eGFR at admission and occurrence of ARD. RESULTS: Overall, 15 cases and 34 controls were compared. Multivariate predictors of ARD were a lower basal eGFR (HR: 0.82 CI: 0.72-0.94 p=0.0045) and intravenous furosemide daily mean dose >80 mg (HR: 48.62 CI: 1.62-3841.5 p=0.0430). A very significant positive correlation was found between IVCCI at admission ≤ 15% and basal eGFR (r=0.96 p<0.0001), while a negative correlation with eGFR was detected in the IVCCI highest (>40%) range (r=-0.696 p=0.0013). Furthermore, the category with basal IVCCI >40% showed a higher rate of ARD compared to that with basal IVCCI 16-40% (p<0.05). CONCLUSION: On the basis of the demonstrated u-shaped relationship between IVCCI and eGFR both the stratum with the highest (>40%) and the one with the lowest (≤15%) basal IVCCI may be associated with increased risk of ARD.

Standardized preoperative corticosteroid treatment in neonates undergoing cardiac surgery: results from a randomized trial.

OBJECTIVE: A heightened inflammatory response occurs after cardiac surgery. The perioperative use of glucocorticoids has been advocated as a method to improve postoperative outcomes. Randomized prospective studies to quantify the effect of methylprednisolone on perioperative outcomes in neonatal cardiac surgery have not been performed. We sought to determine whether preoperative methylprednisolone would improve postoperative recovery in neonates requiring cardiac surgery. METHODS: Neonates scheduled for cardiac surgery were randomly assigned to receive either 2-dose (8 hours preoperatively and operatively, n = 39) or single-dose (operatively, n = 37) methylprednisolone (30 mg/kg per dose) in a prospective double-blind trial. The primary outcome was the incidence of low cardiac output syndrome (standardized score) or death 36 hours postoperatively. Secondary outcomes were death at 30 days, interleukin-6 levels, inotropic score, fluid balance, serum creatinine, and intensive care unit and hospital stay. RESULTS: Preoperative plasma levels of the inflammatory cytokine interleukin-6 were reduced by 2-fold (P < .001) in the 2-dose methylprednisolone group, consistent with the anti-inflammatory effects of methylprednisolone. However, the incidence of low cardiac output syndrome was 46% (17/37) in the single-dose and 38% (15/39) in the 2-dose methylprednisolone groups (P = .51). Two-dose methylprednisolone was associated with a higher serum creatinine (0.61 ± 0.18 mg/dL vs 0.53 ± 0.12 mg/dL, P = .03) and poorer postoperative diuresis (-96 ± 49 mL, P = .05). Inotropic requirement, duration of mechanical ventilation, intensive care unit, and hospital stay did not differ between the 2 groups. CONCLUSIONS: Combined preoperative and intraoperative use of glucocorticoids in neonatal cardiac surgery does not favorably affect early clinical outcomes and may exacerbate perioperative renal dysfunction.

Successful resuscitation following ropivacaine-induced systemic toxicity in a neonate.

A 5-week-old preterm infant was scheduled for inguinal hernia repair. Following induction of general anaesthesia, 10 mg.kg(-1) ropivacaine was injected, accidently, into the caudal space. The infant developed cardiac depression with bradycardia (minimum heart rate 50 beats.min(-1) ), elevated T waves and widening of QRS complexes. Resuscitation by means of external chest compression, intravenous adrenaline and fluid administration was successful. Ropivacaine serum concentrations were obtained at three time points yielding a peak level of 6 µg.ml(-1) 20 min after caudal injection.

Different anthracycline derivates for reducing cardiotoxicity in cancer patients.

BACKGROUND: The use of anthracyclines is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline derivates have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline derivates in cancer patients. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 to 29 May 2009) and EMBASE (1980 to 2 June 2009). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing-trials-databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline derivates were compared in cancer patients (children and adults). DATA COLLECTION AND ANALYSIS: Two authors independently performed study selection, assessment of risk of bias and data-extraction including adverse effects. MAIN RESULTS: We identified five RCTs of varying quality addressing epirubicin versus doxorubicin (1036 patients) with the same dose. The meta-analysis showed no evidence for a significant difference in the occurrence of clinical heart failure between the treatment groups (RR = 0.36, 95% CI 0.12 to 1.11). However, there is some suggestion of a lower rate of clinical heart failure in patients treated with epirubicin.We identified two RCTs with varying quality addressing liposomal-encapsulated doxorubicin versus conventional doxorubicin (521 patients). The meta-analysis showed a significantly lower rate of both clinical heart failure and clinical and subclinical heart failure combined in patients treated with liposomal-encapsulated doxorubicin (RR = 0.20, 95% CI 0.05 to 0.75 and RR = 0.38, 95% CI 0.24 to 0.59 respectively). It should be noted that in one of the studies patients in the liposomal-encapsulated doxorubicin group received a higher cumulative anthracycline dose than patients in the doxorubicin group.For the other possible combinations of different anthracycline derivates only one RCT (epirubicin versus liposomal-encapsulated doxorubicin) or no RCT was identified. AUTHORS' CONCLUSIONS: We are not able to favour either epirubicin or doxorubicin when given with the same dose. Based on the currently available evidence on heart failure, we conclude that in adults with a solid tumour liposomal-encapsulated doxorubicin should be favoured over doxorubicin. For both epirubicin versus doxorubicin and liposomal-encapsulated doxorubicin versus conventional doxorubicin no conclusions can be made about the effects of treatment in children treated with anthracyclines and also not in patients diagnosed with leukaemia. More research is needed. For other combinations of anthracycline derivates not enough evidence was available to make definitive conclusions about the occurrence of cardiotoxicity in patients treated with anthracyclines.

Different anthracycline derivates for reducing cardiotoxicity in cancer patients.

BACKGROUND: The use of anthracyclines is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline derivates have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline derivates in cancer patients. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 to 29 May 2009) and EMBASE (1980 to 2 June 2009). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing-trials-databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline derivates were compared in cancer patients (children and adults). DATA COLLECTION AND ANALYSIS: Two authors independently performed study selection, assessment of risk of bias and data-extraction including adverse effects. MAIN RESULTS: We identified five RCTs of varying quality addressing epirubicin versus doxorubicin (1036 patients) with the same dose. The meta-analysis showed no evidence for a significant difference in the occurrence of clinical heart failure between the treatment groups (RR = 0.36, 95% CI 0.12 to 1.11). However, there is some suggestion of a lower rate of clinical heart failure in patients treated with epirubicin.We identified two RCTs with varying quality addressing liposomal-encapsulated doxorubicin versus conventional doxorubicin (521 patients). The meta-analysis showed a significantly lower rate of both clinical heart failure and clinical and subclinical heart failure combined in patients treated with liposomal-encapsulated doxorubicin (RR = 0.20, 95% CI 0.05 to 0.75 and RR = 0.38, 95% CI 0.24 to 0.59 respectively). It should be noted that in one of the studies patients in the liposomal-encapsulated doxorubicin group received a higher cumulative anthracycline dose than patients in the doxorubicin group.For the other possible combinations of different anthracycline derivates only one RCT (epirubicin versus liposomal-encapsulated doxorubicin) or no RCT was identified. AUTHORS' CONCLUSIONS: We are not able to favour either epirubicin or doxorubicin when given with the same dose. Based on the currently available evidence on heart failure, we conclude that in adults with a solid tumour liposomal-encapsulated doxorubicin should be favoured over doxorubicin. For both epirubicin versus doxorubicin and liposomal-encapsulated doxorubicin versus conventional doxorubicin no conclusions can be made about the effects of treatment in children treated with anthracyclines and also not in patients diagnosed with leukaemia. More research is needed. For other combinations of anthracycline derivates not enough evidence was available to make definitive conclusions about the occurrence of cardiotoxicity in patients treated with anthracyclines.

Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy.

BACKGROUND: The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. To prevent this cardiotoxicity, different anthracycline dosage schedules have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules (i.e. peak doses and infusion durations) in cancer patients. SEARCH STRATEGY: We searched the databases of The Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2008), MEDLINE (1966 to November 2008) and EMBASE (1980 to November 2008). Also, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in cancer patients (children and adults). DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection, the risk of bias assessment and the data-extraction. MAIN RESULTS: We identified seven RCTs addressing different anthracycline infusion durations. The meta-analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of 6 hours or longer as compared to a shorter infusion duration (relative risk (RR) = 0.27; 95% confidence interval (CI) 0.09 to 0.81; 5 studies; 557 patients). The majority of patients included in these studies were adults with different solid tumours. For different anthracycline peak doses we identified two RCTs addressing a doxorubicin peak dose of less than 60 mg/m(2) versus 60 mg/m(2) or more, one RCT addressing a liposomal doxorubicin peak dose of 25 mg/m(2) versus 50 mg/m(2) and one RCT addressing an epirubicin peak dose of 83 mg/m(2) versus 110 mg/m(2). In none of the studies a significant difference in the occurrence of clinical heart failure was identified. All patients included in these studies were adults with different solid tumours. AUTHORS' CONCLUSIONS: An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure and it seems to reduce the risk of subclinical cardiac damage. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.No significant difference in the occurrence of clinical heart failure was identified in patients treated with a doxorubicin peak dose of less than 60 mg/m(2) or 60 mg/m(2) or more. For the other identified peak doses only one RCT was available, so no definitive conclusions can be made about the occurrence of cardiotoxicity. More high quality research is needed, both in children and adults and in leukaemias and solid tumours.

Autonomic consequences of kainic acid-induced limbic cortical seizures in rats: peripheral autonomic nerve activity, acute cardiovascular changes, and death.

PURPOSE: Autonomic consequences of seizures are common, but can be severe. We sought to define changes in autonomic activity from limbic cortical seizures and their impact on the heart. METHODS: We studied kainic acid (KA)-induced seizures in urethane-anesthetized rats using peripheral nerve, blood pressure (BP), and ECG recordings and echocardiography. RESULTS: Seizures were associated with massive increases in parasympathetic (vagus nerves) and sympathetic (cervical sympathetic ganglion >renal nerve >splanchnic nerve) activity. Seizure-associated activity increases were greater than activity changes induced by nitroprusside or phenylephrine (each producing BP changes of >50 mmHg). Increases in c-fos expression were found in both sympathetic and parasympathetic medullary regions (as well as hypothalamic areas). Baroreceptor reflex function (tested with nitroprusside and phenylephrine) was impaired during seizures. Finally, a significant fraction of the animals died and the mechanism of death was defined through ECG, BP, and echocardiographic measures to be profound cardiac dilatation and bradyarrhythmia leading to hypoperfusion of the brain and ultimately hypoperfusion of the heart. Cardiovascular changes occur within seconds (or less) of autonomic nerve activity changes and death by these mechanisms takes minutes. DISCUSSION: We propose that the massive parasympathetic and sympathetic outflow that occurs during a seizure gets compounded by respiratory distress (driving both autonomic nervous system divisions in the same direction) causing mechanical dysfunction, slowing the heart, and hypoperfusing the brain.

5-Fluorouracil cardiotoxicity complicating treatment of stage IIB cervical cancer--case report.

A 31-year-old female was found to have FIGO Stage IIB squamous cell carcinoma of the cervix. The patient began her prescribed radiation therapy and 5-fluorouracil radio-sensitizing chemotherapy. During the first day of infusion, she began having severe shortness of breath. Cardiac evaluation revealed acute congestive heart failure with a cardiac ejection fraction of 19%. Radiation was continued without chemotherapy. Four years later, the patient is alive and well with an ejection fraction of 53%.

Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure.

Cardiac myosin-binding protein-C (cMyBP-C) is an important regulator of cardiac contractility, and its phosphorylation by PKA is a mechanism that contributes to increased cardiac output in response to beta-adrenergic stimulation. It is presently unknown whether heart failure alters cMyBP-C phosphorylation. The present study determined the level of phosphorylated cMyBP-C in failing human hearts and in a canine model of pacing-induced heart failure. A polyclonal antibody directed against the major phosphorylation site of cMyBP-C (Ser-282) was generated and its specificity was confirmed by PKA phosphorylation with isoprenaline in cardiomyocytes and Langendorff-perfused mouse hearts. Left ventricular myocardial tissue from (i) patients with terminal heart failure (hHF; n=12) and nonfailing donor hearts (hNF; n=6) and (ii) dogs with rapid-pacing-induced end-stage heart failure (dHF; n=10) and sham-operated controls (dNF; n=10) were used for quantification of total cMyBP-C and phospho-cMyBP-C by Western blotting. Total cMyBP-C protein levels were similar in hHF and hNF as well as in dHF and dNF. In contrast, the ratio of phospho-cMyBP-C to total cMyBP-C levels were >50% reduced in hHF and >40% reduced in dHF. In summary, cMyBP-C phosphorylation levels are markedly decreased in human and experimental heart failure. Thus, the compromised contractile function of the failing heart might be in part attributable to reduced cMyBP-C phosphorylation levels.

Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium.

The positive force-frequency relation, one of the key factors modulating performance of healthy myocardium, has been attributed to an increased Ca(2+) influx per unit of time. In failing hearts, a blunted, flat or negative force-frequency relation has been found. In healthy and failing hearts frequency-dependent alterations in Ca(2+) sensitivity of the myofilaments, related to different phosphorylation levels of contractile proteins, could contribute to this process. Therefore, the frequency dependency of force, intracellular free Ca(2+) ([Ca(2+)](i)), Ca(2+) sensitivity and contractile protein phosphorylation were determined in control and monocrotaline-treated, failing rat hearts. An increase in frequency from 0.5 to 6 Hz resulted in an increase in force in control (14.3 +/- 3.0 mN mm(-2)) and a decrease in force in failing trabeculae (9.4 +/- 3.2 mN mm(-2)), whereas in both groups the amplitude of [Ca(2+)](i) transient increased. In permeabilized cardiomyocytes, isolated from control hearts paced at 0 and 9 Hz, Ca(2+) sensitivity remained constant with frequency (pCa(50): 5.55 +/- 0.02 and 5.58 +/- 0.01, respectively, P>0.05), whereas in cardiomyocytes from failing hearts Ca(2+) sensitivity decreased with frequency (pCa(50): 5.62 +/- 0.01 and 5.57 +/- 0.01, respectively, P<0.05). After incubation of the cardiomyocytes with protein kinase A (PKA) this frequency dependency of Ca(2+) sensitivity was abolished. Troponin I (TnI) and myosin light chain 2 (MLC2) phosphorylation remained constant in control hearts but both increased with frequency in failing hearts. In conclusion, in heart failure frequency-dependent myofilament Ca(2+) desensitization, through increased TnI phosphorylation, contributes to the negative force-frequency relation and is counteracted by a frequency-dependent MLC2 phosphorylation. We propose a novel role for PKC-mediated TnI phosphorylation in modulating the force-frequency relation.