Cardiac Left Ventricular Ejection Fraction Research Articles

A real-world experience of TCH (docetaxel/carboplatin/trastuzumab) regimen in early, locally advanced and oligometastatic HER2 positive breast cancer from tertiary care center in North India.

e12505 Background: In HER2 positive breast cancer, TCH is a safe and efficacious anthracycline free regimen used as both adjuvant and neoadjuvant modality. Three is scarcity of data regarding its long term safety and efficacy from India. Methods: This retrospective study comprised of 210HER2 positive breast cancer female patients treated with TCH [docetaxel (75mg/m2), carboplatin (AUC=6) and trastuzumab (8mg/kg loading followed by 6mg/kg) q 21 days with GSF prophylaxis] protocol for 6 cycles at our centre between Jan 2014 and Dec 2021. All eligible patients received maintenance trastuzumab, hormonal therapy and radiotherapy as per institutional protocol. The information regarding baseline clinico-demographic characteristics, treatment details, outcomes and toxicities were collected and evaluated. Results: The median age was 49 years (23-72), 113 (53.8%) were post-menopausal and 100 (47.6%) were Estrogen receptor/Progesterone receptor positive. Sixty-eight (32.4%) patients were stage I and II, 112 (53.3%) stage III and 30 (14.3%) were oligometastatic. TCH regimen was given as neoadjuvant chemotherapy (NACT) in 130 (61.9%) patients and as adjuvant chemotherapy in 80 (38.1%) patients. Of the patients receiving NACT, 114 (87.6%) patients underwent surgery. Twenty-two (19.3%) patients underwent breast conservation surgery and 92 (80.7%) underwent modified radical mastectomy. Over the study period, 62 (29.5%) patients had progression of the disease and 22 (10.5%) patients died. With a median follow up of 31.9 months, 3-year disease free survival (DFS) was 63.5% and overall survival (OS) was 90.8%. Median DFS was 31 months in patients with node positive disease and was not reached in patients with node positive disease. Of the patients who received NACT, pathologic complete response (pCR) was recorded in 42 (36.8%) patients. Three-year DFS was 59.1% in patients who achieved pCR and 44.8% in those who did not achieve pCR. Any grade 3/4 toxicity was seen in 26.7% patients which caused dose modification in 13.9% patients. The most common grade 3/4 hematological toxicity was anemia (15.1%) and thrombocytopenia (10.4%), while non-hematological toxicity was diarrhea (11.6%). Febrile neutropenia was seen in 4 (1.9%) patients. Four patients (1.9%) had reversible decrease in cardiac left ventricular ejection fraction. Conclusions: Anthracycline free TCH regimen is an effective and safe regimen for use in curative (adjuvant and neoadjuvant) setting for HER2 positive breast cancer in Indian women with outcomes comparable to the anthracycline based regimens reported in literature.

Cardiac dysfunction in Multisystem Inflammatory Syndrome in Children: An Italian single-center study

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a novel condition temporally associated with SARS-CoV2 infection. Cardiovascular involvement is mainly evident as acute myocardial dysfunction in MIS-C. The aim of this study was to describe the cardiac dysfunction in patients with MIS-C, defining the role of severity in the clinical presentations and outcomes in a single cohort of pediatric patients.MethodsA single-center retrospective study on patients diagnosed with MIS-C, according to the Center for Disease Control and Prevention (CDC) definition, and referred to Vittore Buzzi Children’s Hospital in Milan from November 2020 to February 2021. Patients were managed according to a local approved protocol. According to the admission cardiac left ventricular ejection fraction (LVEF), the patients were divided into group A (LVEF < 45%) and group B (LVEF ≥45%). Pre-existing, clinical, and laboratory factors were assessed for evaluating outcomes at discharge.ResultsThirty-two patients were considered. Cardiac manifestations of MIS-C were reported in 26 patients (81%). Group A included 10 patients (9 M/1F, aged 13 years [IQR 5–15]), and group B included 22 patients (15 M/7 M, aged 9 years [IQR 7–13]). Significant differences were noted among clinical presentations (shock, diarrhea, intensive care unit admission), laboratory markers (leucocytes, neutrophils, and protein C-reactive), and cardiac markers (troponin T and N-terminal pro B-type Natriuretic Peptide) between the groups, with higher compromission in Group A. We found electrocardiogram anomalies in 14 patients (44%) and rhythm alterations in 3 patients (9%), without differences between groups. Mitral regurgitation and coronary involvement were more prevalent in group A. Total length of hospital stay and cardiac recovery time were not statistically different between groups. A recovery of cardiac functioning was reached in all patients.ConclusionDespite significant differences in clinical presentations and need for intensive care, all of the MIS-C patients with significant cardiac involvement in this study completely recovered. This suggests that the heart is an involved organ and did not influence prognosis if properly treated and supported in the acute phase.

Cancer Therapy-Induced Cardiotoxicity-A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy.

Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented.

Water-soluble lectin (WSMoL) from Moringa oleifera seeds treatment recovers glycemic levels and improves left ventricular ejection fraction on Type-2 Diabetes mice model.

Moringa oleifera, a plant widely used in traditional medicine as well as for water purification, contains a lectin on its seeds named WSMoL which modulates several immune characteristics and has shown cardiac safe properties. Here, we tested the hypothesis that WSMoL is able to recover fasting glucose levels and to improve the cardiac left ventricular (LV) function in a type 2 diabetes mellitus (T2DM) mice model. T2DM was induced in adult C57BL/6 mice by combining a high fat diet and low doses of Streptozotocin. Mice were randomly divided in two groups: i. received WSMoL for 21 consecutive days by gavage (T2DM + WSMoL) and ii. received saline solution (T2DM). Metabolic parameters and LV function were assessed. WSMoL was able to reduce fasting blood glucose levels in T2DM mice after 2 weeks of treatment, when compared to T2DM untreated group. Regarding to cardiac LV function, the T2DM + WSMoL group depicted ejection fraction values comparable to non-diabetic group. Our results show: i. WSMoL treatment presented a potent hypoglycemic effect decreasing insulin resistance and ii. WSMoL was able to improve cardiac LV ejection fraction. Collectively, the results presented here show WSMoL as a potential hypoglycemic agent to be tested in T2DM patients.

Cardiac left ventricular ejection fraction in men and women with schizophrenia on long-term antipsychotic treatment

Patients with schizophrenia exhibit a higher cardiovascular mortality compared to the general population which has been attributed to life-style factors, genetic susceptibility and antipsychotic medication. Recent echocardiographic studies have pointed to an association between clozapine treatment and reduced left ventricular ejection fraction (LVEF), a measure that has been inversely associated with adverse outcomes including all-cause mortality. Cardiovascular magnetic resonance (CMR) is considered the reference method for LVEF measurement. The aim of the present study was to investigate the LVEF in patients with schizophrenia on long-term treatment with antipsychotics and healthy controls. Twenty-nine adult patients with schizophrenia on long-term medication with antipsychotics and 27 age-, sex- and body mass index-matched healthy controls (mean ages 44 and 45 years, respectively) were recruited from outpatient psychiatric clinics in Uppsala, Sweden. The participants were interviewed and underwent physical examination, biochemical analyses, electrocardiogram and CMR. Men with schizophrenia on long-term antipsychotic treatment showed significantly lower LVEF than controls (p = 0.0076), whereas no such difference was evident among women (p = 0.44). Specifically, clozapine-treated male patients had 10.6% lower LVEF than male controls (p = 0.0064), whereas the LVEF was 5.5% below that of controls among male patients treated with non-clozapine antipsychotics (p = 0.047). Among medicated men with schizophrenia, we found significantly lower LVEF compared to healthy individuals, suggesting the need of routine cardiac monitoring in this patient group. This is the first study showing a significant negative association between treatment with non-clozapine antipsychotics and LVEF.

Acute Cardiotoxicity With Concurrent Trastuzumab and Hypofractionated Radiation Therapy in Breast Cancer Patients.

Purpose: Radiotherapy for patients with non-metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer is commonly administered concurrently with adjuvant trastuzumab. However, there is limited data on the use of concurrent trastuzumab and hypofractionated radiotherapy (Hypo-RT), which is now standard of care for the majority of women receiving whole breast irradiation. In this study, we compared acute cardiotoxicity rates in HER2-positive breast cancer patients treated with concurrent trastuzumab and Hypo-RT or conventionally fractionated radiotherapy (Conv-RT).Methods: We performed a review of our institutional database to identify HER2-positive breast cancer patients treated with trastuzumab and Hypo-RT or Conv-RT from 2005 to 2018 who underwent serial cardiac Left Ventricular Ejection Fraction (LVEF) evaluation. Decrease in LVEF was assessed by either echocardiography (ECHO) or multiple gated acquisition (MUGA) scan performed at baseline and every 3 months during trastuzumab therapy. Significant LVEF decline was defined as an absolute decrease in LVEF of ≥10% below the lower limit of normal or ≥16% from baseline value.Results: We identified 41 patients treated with Hypo-RT and 100 patients treated with Conv-RT. Median follow-up was 32 months (range, 13–90 months). Baseline median LVEF was 62% (range, 50–81%) in Hypo-RT group and 64% (range, 51–76%) in Conv-RT group (p = 0.893). Final median LVEF was 60% (range, 50–75%) in both groups. Three patients (7%) in Hypo-RT and five (5%) in Conv-RT group developed significant asymptomatic LVEF decline (p = 0.203). There was no significant difference in mean heart dose in patients who developed significant asymptomatic LVEF decline vs. those who did not in Hypo-RT (p = 0.427) and Conv-RT (p = 0.354) groups. No symptomatic congestive heart failure was reported in either group.Conclusions: The rate of asymptomatic LVEF decline in patients receiving concurrent trastuzumab and Hypo-RT was low (7%) and was similar to the rate observed in patients receiving Conv-RT. Longer follow-up is warranted to assess late cardiotoxicity.

SAT-332 THE EFFECT OF SPIRONOLACTONE IN A RAT MODEL OF ESTABLISHED HYPERTENSION.

Hypertension is one of the leading contributors to cardiovascular and renal disease. Spironolactone (SP) improves cardiac outcomes following injury, but its impact on hypertension-induced kidney fibrosis is uncertain. We aimed to investigate the impact of sustained hypertension with and without daily administration of spironolactone (SP) on the function and injury progression in both heart and kidney, in a transgenic rat model of hypertension. Male, eight week old, Cyp1a1Ren2 rats were randomised to either normal chow or chow with the addition of 0.167% w/w Indol-3-carbinol to induce hypertension (systolic >150mmHg). Hypertensive rats were further divided into those receiving spironolactone daily (human equivalent dose of 50mg), or not, following the establishment of hypertension. Measurement of systolic blood pressure (SBP) and echocardiograms were performed regularly and tissue collected for analyses following termination (after three months). The extent of fibrosis was determined histologically using quantitative pixel count analysis while glomerulosclerosis was scored semi-quantitatively. Induction of chronic hypertension resulted in elevated SBP (196±21 vs 91±13 mmHg (controls)), proteinuria (60±19 vs 14±3 ml.kg-1.hr-1), cortical fibrosis (7±0.4% vs 0.2±0.1%) and glomerulosclerosis index scores (GSI: 2.6±0.3 vs 0.2±0.06) [all variables were significant at p<0.001]. Hypertension also reduced cardiac left ventricular ejection fraction (LVEF, 67±7 vs 80±3%, p<0.001) and myocardial global longitudinal strain (myoGLS, -11±2 vs -17±2%, p<0.001) compared to normotensive animals. Treatment of hypertensive animals with SP resulted in reduced SBP (184±15, p<0.01) and blunted the deterioration of LVEF (72±4, p<0.05) and myoGLS (-13±1, p<0.01) when compared to untreated animals. While SP had no impact on proteinuria, it did result in significant reductions in cortical fibrosis (3±1.3%, p<0.05) and GSI (2±0.1, p<0.05) when compared to untreated hypertensive animals. Prolonged elevation of untreated SBP caused significant and progressive cardiac and renal damage over three months. The addition of spironolactone to established hypertensive animals improved physiological measurements and significantly decreased fibrotic and sclerotic damage in the kidney. Further work aims to explore the relationship between hypertension and renal deterioration.

LEFT VENTRICULAR EJECTION FRACTION: COMPARISON BETWEEN TRUE VOLUME-BASED MEASUREMENTS AND AREA-BASED ESTIMATES.

Left ventricular ejection fraction (LVEF) is a critical measure of cardiac health commonly acquired in clinical practice, which serves as the basis for cardiovascular therapeutic treatment. Ultrasound (US) imaging of the heart is the most common, least expensive, reliable and non-invasive modality to assess LVEF. Cardiologists, in practice, persistently use 2D US images to provide visual estimates of LVEF, which are based on 2D information embedded in the US images by examining the area changes in LV blood pool between diastole and systole. There has been some anecdotal evidence that visual estimation of the LVEF based on the area changes of the LV blood pool significantly underestimate true LVEF. True LVEF should be calculated based on changes in LV volumes between diastole and systole. In this project, we utilized both idealized models of the LV geometry - a truncated prolate spheroid (TPS) and a paraboloid model - to represent the LV anatomy. Cross-sectional areas and volumes of simulated LV shapes using both models were calculated to compare the LVEF. Further, a LV reconstruction algorithm was employed to build the LV blood pool volume in both systole and diastole from multi-plane 2D US imaging data. Our mathematical models yielded an area-based LVEF of 41 4.7% and a volume-based LVEF of 55 ±5.7%, while the 3D recon-struction model showed an area-based LVEF of 35 11.9% and a volume-based LVEF of 48.0 ± 14.0%. In summary, the area-based LVEF using all three models ±underestimate the volume-based LVEF using corresponding models by 13% to 14%. This preliminary study confirms both mathematically and empirically that area-based LVEF estimates indeed underestimate the true volume-based LVEF measurements and suggests that true volumetric measurements of the LV blood pool must be computed to correctly assess cardiac LVEF.

A Randomized Comparison of Radiation Therapy Techniques in the Management of Node-Positive Breast Cancer: Primary Outcomes Analysis

Although inverse-planned intensity modulated radiotherapy (IMRT) and deep inspiration breath hold (DIBH) may allow for more conformal dose distributions, it is unknown whether using these technologies reduces cardiac or pulmonary toxicity of breast radiotherapy. A randomized controlled trial compared IMRT-DIBH versus standard, free-breathing, forward-planned, three-dimensional conformal radiotherapy in patients with left-sided, node-positive breast cancer in whom the internal mammary nodal region was targeted. Endpoints included dosimetric parameters and changes in pulmonary and cardiac perfusion and function, measured by single photon emission computed tomography (SPECT) scans and pulmonary function testing performed at baseline and 1year post treatment. Of 62 patients randomized, 54 who completed all follow-up procedures were analyzed. Mean doses to the ipsilateral lung, left ventricle, whole heart, and left anterior descending coronary artery were lower with IMRT-DIBH; the percent of left ventricle receiving ≥5Gy averaged 15.8% with standard radiotherapy and 5.6% with IMRT-DIBH (P<.001). SPECT revealed no differences in perfusion defects in the left anterior descending coronary artery territory, the study's primary endpoint, but did reveal statistically significant differences (P=.02) in left ventricular ejection fraction (LVEF), a secondary endpoint. No differences were found for lung perfusion or function. The small but statistically significant benefit in preservation of cardiac LVEF observed here should motivate future studies that include LVEF as a potentially meaningful endpoint. Future studies should disaggregate the impact of IMRT from that of DIBH. Clinical practice should recognize the importance of minimizing cardiac dose, even when already low in comparison to historical levels.

Combination Therapy With Coenzyme Q10 and Trimetazidine in Patients With Acute Viral Myocarditis

Acute viral myocarditis is an inflammatory disease with global impact. Although it may resolve spontaneously, its course is not easily predicted, and there is a paucity of specific treatment options available with proven efficacy. Coenzyme Q10 (CQ10) and trimetazidine possess antioxidant and antiinflammatory effects. We examined the therapeutic efficacy of these agents in acute viral myocarditis both individually and in combination. Patients were blinded and randomized to receive CQ10 (n = 42), trimetazidine (n = 39), or CQ10 + trimetazidine (n = 43) treatment. Serum inflammatory and oxidative stress marker and myocardial enzyme levels, and heart function were measured. Both CQ10 and trimetazidine decreased inflammatory and oxidative stress biomarker levels compared with baseline measurements. However, combination therapy with CQ10 and trimetazidine showed a significantly more powerful effect not only on markers of inflammation and oxidative stress, but also on left ventricular systolic function and troponin, compared with either treatment alone. This study confirmed the beneficial effect of CQ10 and trimetazidine individually, but demonstrated a superior effect of combining the therapies on cardiac left ventricular ejection fraction, and biochemical markers of myocardial damage in acute viral myocarditis.

A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy.

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%–12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition.

Phase I study of doxorubicin (D) plus anti-insulin-like growth factor 1 receptor (IGF-1R) antibody cixutumumab (IMC-A12) in advanced soft tissue sarcoma (STS).

10028 Background: IGF1R is overexpressed in many STS, but its exact role in the biology of the disease is unclear. Anti-IGF1R antibody cixutumumab (C) has shown acceptable toxicity in a single-agent phase 2 study of STS. Here we performed a dose escalation study of C with D in STS. Methods: Eligible pts had advanced STS, ECOG ≤2, age&gt;16, ≤1 prior chemotherapy, fasting glucose&lt;120 mg/dL and acceptable organ function. C was administered IV over 60 min on D1,8,15 at one of three dose levels and D as a 48 hr infusion on D1 of a 21-day cycle. After 6 cycles of combination rx, pts with SD or better continued on single agent C. The Time-to-Event Continual Reassessment Method (TITE-CRM) was used to estimate the probability of DLT at each dose level and to assign patients to the dose with the estimated probability of DLT closest to but not exceeding 30%. Results: 30 pts with STS were enrolled between 9/08-1/12. Median age was 64 (range 29-80); 17M/13 F, 7 pts received prior chemo. One pt withdrew prior to rx; 5 pts are on active rx. Reasons for discontinuation were: progression (18), toxicity (3), death (1), pt decision (2). DLTs observed were hyperglycemia and mucositis. Grade 3 decrease in cardiac left ventricular ejection fraction was observed in 2 pts at dose level 2 after 4 or more cycles. Common G1/2 nonhematologic AEs: nausea (73%), fatigue (68%), pain (59%), diarrhea (41%), constipation (36%), hyperglycemia (32%), mucositis (32%), nail changes (27%), weight loss (27%). Gr3/4 toxicities in &gt;10%: hyperglycemia (18%), lymphopenia (18%), anemia (14%), neutropenia (14%), thrombocytopenia (14%). Median PFS was 5.3 months, 95% CI 2.7 -7.9 months. Four of 22 pts (18%) evaluable for response achieved a PR. Conclusions: C and D is tolerable and the recommended phase II dosing is dose level 3. The potential of cardiotoxicity should be monitored and assessed further in ongoing studies of this regimen. [Table: see text]

Replacement of conventional doxorubicin by pegylated liposomal doxorubicin is a safe and effective alternative in the treatment of non-Hodgkin's lymphoma patients with cardiac risk factors

Anthracyclines are a major component in the therapy of non-Hodgkin's lymphoma. However, due to their cardiac toxicity potential, curative and palliative treatment is often limited in patients with preexisting cardiac dysfunction. Liposomal doxorubicin formulations have been described to be less cardiotoxic than conventional doxorubicin. In the current study, we analyzed the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) as constituent of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen replacing conventional doxorubicin in 21 patients with impaired cardiac left ventricular ejection fraction or preexisting cardiac risk factors and established diagnosis of diffuse large B cell lymphoma (n = 15), mantle cell lymphoma (n = 3), follicular lymphoma (n = 1), and T cell lymphoma (n = 2). Overall and complete response rate were 85% and 40%, respectively. Event-free survival and overall survival after 2years were 58%. One lethal event of acute cardiac death occurred during the first cycle in a patient with transposition of the big arteries, atrial flutter, and mitral valve regurgitation. In the remaining 20 patients, no deterioration of myocardial function was observed in echocardiography performed before and after treatment. Seven cases of grade III-IV hematological toxicity were observed as well as four episodes of neutropenic fever leading to hospitalization. No infection-related death occurred. However, 25% of patients developed a hand-foot syndrome (HFS) leading to discontinuation of treatment. Importantly, the incidence of HFS increased considerably when PLD doses of 15mg/m(2)/week were exceeded. We conclude that replacing conventional doxorubicin with PLD in polychemotherapy regimens such as CHOP is an efficient alternative in the treatment of patients with preexisting cardiac dysfunction. However, we recommend that PLD dose should not exceed 15mg/m(2)/week. The rationale for the use of non-pegylated liposomal doxorubicin formulations should be evaluated in further studies.

Characterization of a Transgenic Short Hairpin RNA-Induced Murine Model of Tafazzin Deficiency

Barth's syndrome (BTHS) is an X-linked mitochondrial disease that is due to a mutation in the Tafazzin (TAZ) gene. Based on sequence homology, TAZ has been characterized as an acyltransferase involved in the metabolism of cardiolipin (CL), a unique phospholipid almost exclusively located in the mitochondrial inner membrane. Yeast, Drosophila, and zebrafish models have been invaluable in elucidating the role of TAZ in BTHS, but until recently a mammalian model to study the disease has been lacking. Based on in vitro evidence of RNA-mediated TAZ depletion, an inducible short hairpin RNA (shRNA)-mediated TAZ knockdown (TAZKD) mouse model has been developed (TaconicArtemis GmbH, Cologne, Germany), and herein we describe the assessment of this mouse line as a model of BTHS. Upon induction of the TAZ-specific shRNA in vivo, transgenic mouse TAZ mRNA levels were reduced by >89% in cardiac and skeletal muscle. TAZ deficiency led to the absence of tetralineoyl-CL and accumulation of monolyso-CL in cardiac muscle. Furthermore, mitochondrial morphology from cardiac and skeletal muscle was altered. Skeletal muscle mitochondria demonstrated disrupted cristae, and cardiac mitochondria were significantly enlarged and displace neighboring myofibrils. Physiological measurements demonstrated a reduction in isometric contractile strength of the soleus and a reduction in cardiac left ventricular ejection fraction of TAZKD mice compared with control animals. Therefore, the inducible TAZ-deficient model exhibits some of the molecular and clinical characteristics of BTHS patients and may ultimately help to improve our understanding of BTHS-related cardioskeletal myopathy as well as serve as an important tool in developing therapeutic strategies for BTHS.

Exercise training improves cardiac function, quality of life and exercise capacity in patients with dilated cardiomyopathy

Objective To determine the effects of short term exercise training on cardiac metabolism and function, during rest and exercise, in patients with dilated cardiomyopathy (DCM). Background Exercise training may play a beneficial role in patients with DCM, however the effects on cardiac function at rest and during exercise have not been defined. Methods Patients with DCM (n = 15, age 58 ± 2 years), stable on medical therapy, were studied before and after 8 weeks of training for 20 minutes, 5 times per week on a home exercise bike. Cardiac volumes and function were measured using MR at 3T during rest and leg exercise. High energy phosphate metabolism was measured as the ratio of phosphocreatine to ATP (PCr/ATP) by 31 Phosphorus magnetic resonance spectroscopy (MRS) at 3T. Quality of life scores were calculated using the Minnesota Heart Failure Questionnaire and 6 minute walk tests were used to determine exercise capacity. All assessments were repeated after the 8 week training period. Results At baseline assessment, the average left ventricular ejection fraction (LVEF) was 38 ± 3%, which did not increase with leg exercise. After the 8 weeks of home exercise there was a 6% improvement in resting LVEF to 44 ± 3% (Figure, p <0.01) and an 8% reduction in end systolic volumes (p <0.05). Exercise training led to a further 8% improvement in cardiac LVEF (p < 0.05) during leg exericse in the MR scanner. There was a moderate negative correlation between subjects baseline exercise per week and change in LVEF during the trial (Figure 1, r = -0.62, p <0.05). Patients also had an 8% improvement in 6 minute walk test and a 27% improvement in Minnesota heart failure questionnaire scores after the exercise training (both p <0.01). Patient with DCM had impaired resting PCr/ATP, with no change after exercise training.

Stroke in patients with heart failure and reduced left ventricular ejection fraction.

Cardiac failure is associated with both stroke of presumed cardioembolic origin and a high mortality rate. Warfarin is used frequently in patients with reduced cardiac left ventricular ejection fraction (EF), although no randomized trials have confirmed that anticoagulation benefits these patients. A literature review was performed pertaining to the frequency of stroke and mortality, and the effect of antithrombotic agents on stroke and mortality rates, in patients with cardiac failure or reduced cardiac EF. We also reviewed the main features of two new proposed studies (Warfarin and Antiplatelet Therapy in Chronic Heart Failure [WATCH] and Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF]) comparing warfarin and antiplatelet agents in patients with low EF. The risk of stroke increases with decreasing EF and the risk of mortality increases with the clinical severity of cardiac failure (New York Heart Association class). Data from heart failure treatment studies suggest that warfarin may reduce stroke and mortality in patients with reduced EF, but definitive answers are lacking. The stroke rate alone is too low to be used as a primary endpoint, but an endpoint combining stroke and death (as WARCEF and WATCH propose) should allow an assessment of the effect of antithrombotics in cardiac failure. Amalgamating the data on stroke from these two trials should yield enough statistical power to compare the effects of warfarin and aspirin on stroke as an independent secondary endpoint. Whether warfarin is superior to aspirin in reducing stroke and mortality in patients with low ejection fraction is an important clinical issue that warrants prospective evaluation.

Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer

To prospectively evaluate the long term cardiac effects of high-dose epirubicin and cyclophosphamide given to women with early stage, poor prognosis breast cancer. Women with stage 2 breast cancer and 10+ nodes or 4+ nodes and estrogen receptor negative tumor, or stage 3 breast cancer received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 gm/m2 with peripheral blood progenitor cell and filgrastim support. Treatment was given every 28 days (n = 79) or 21 days (n = 20). Fifty patients received radiotherapy to the chest wall or breast, 25 of to the left side. Patients were assessed clinically regularly during chemotherapy and at least three times yearly after completion of treatment. Cardiac left ventricular ejection fraction (LVEF) was assessed by radionuclide scan before therapy, after each cycle of chemotherapy, three months and six months after completion of chemotherapy, and yearly thereafter until relapse. Ninety-nine women were treated, and 92 completed all three cycles of chemotherapy. The median age was 43 years (range 24 to 60 years). All patients were included in this analysis. The median relapse-free survival was 39 months (11 to 68 months). There was a significant fall in LVEF during chemotherapy. In general, there was no further deterioration in cardiac function from the third month after cessation of treatment, however there was substantial variation between individuals. 35 patients had at least one LVEF measure less than normal (< 50%), but the LVEF returned to normal in 20 of these with further follow-up. Cardiac dysfunction was not increased in women who received radiotherapy and was not different between cohorts given chemotherapy every three or every four weeks. One patient died of acute myocardial necrosis following the third cycle of chemotherapy. Two patients developed clinical evidence of cardiac failure, and another had radiological signs but was asymptomatic. One woman died of progressive cardiac failure, one recovered clinically but also developed recurrent breast cancer, while the third recovered after commencement of medical therapy. During follow-up after high-dose epirubicin and cyclophosphamide as delivered in this study, the LVEF fell to below normal in approximately one third of patients. However, in over half of these patients the LVEF subsequently recovered to the normal range, and the incidence of clinically evident chronic cardiac failure was low. Further follow-up is required to assess the long-term safety. A randomized comparison with standard-dose anthracycline-based chemotherapy is needed to determine whether this regimen is associated with an increased risk of clinical cardiac toxicity.