Generation and characterization of induced pluripotent stem cells from breast cancer patients carrying ATM mutations.

We generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of breast cancer patients carrying germline ATM mutations, a gene associated with a 7% prevalence in breast cancer. These iPSC lines displayed typical morphology, expressed pluripotency markers, maintained a stable karyotype, and retained the ability to differentiate into the three germ layers. These patient-specific iPSC lines hold great potential for mechanistic investigations and the development of drug screening strategies aimed at addressing ATM-related cancer.

A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis.

OBJECTIVES: The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system. BACKGROUND: Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis. METHODS: We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed. RESULTS: At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl. CONCLUSIONS: Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

Dipeptidyl peptidase 4 inhibition increases myocardial glucose uptake in nonischemic cardiomyopathy.

BACKGROUND: Glucose and fatty acids comprise the primary substrates for myocardial energy metabolism. The normal myocardium switches toward glucose metabolism in the setting of stress; the inability to affect such a switch is a fundamental mechanism behind "diabetic" or "insulin-resistant" cardiomyopathy. The purpose of this mechanistic study was to evaluate the effects of treatment with the dipeptidyl peptidase (DPP) 4 inhibitor sitagliptin on myocardial glucose uptake in patients with nonischemic cardiomyopathy. METHODS AND RESULTS: Twelve nondiabetic subjects with nonischemic cardiomyopathy underwent metabolic testing and assessment of myocardial glucose uptake by (18)F-fluorodeoxyglucose positron-emission tomographic/computerized tomographic imaging at baseline and after 4 weeks of sitagliptin therapy. Sitagliptin therapy resulted in a significant increase in myocardial glucose uptake (19% increase; P = .04). Although most patients had at least a slight increase in glucose uptake, there was an overall bimodal response, with 6 patients ("responders") demonstrating large increases (>20%) in glucose uptake and 6 patients ("nonresponders") demonstrating <5% increases or slight decreases. Triglyceride-high-density lipoprotein ratios significantly dropped in the 6 responders compared with the 6 nonresponders (P < .02). CONCLUSIONS: Therapy with the DPP-4 inhibitor sitagliptin results in increased myocardial glucose uptake in nondiabetic patients with nonischemic cardiomyopathy.

Chemotherapy-associated cardiotoxicity: how often does it really occur and how can it be prevented?

Cardiotoxicity remains the limiting factor for many forms of cancer therapy and is the focus of growing research and clinical emphasis. This article outlines the current clinical evidence for left ventricular dysfunction and heart failure for the two most important classes of cardiotoxic chemotherapeutic agents, examines the potential pitfalls that have led to underestimated rates of left ventricular dysfunction from these agents, and reviews strategies for screening for and providing prophylaxis against chemotherapy-associated left ventricular dysfunction.

Measurement precision in the optimization of cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether atrioventricular (AV) and interventricular (VV) pacing interval optimization confers further clinical improvement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals; however, the precision of their estimates and the ramifications of an imprecise estimate have not been characterized previously. METHODS AND RESULTS: An objective methodology for quantifying the precision of estimated optimum AV/VV intervals was developed, allowing physiologic effects to be distinguished from measurement variability. Optimization using multiple conventional techniques was conducted in individual sessions with 20 patients. Measures of stroke volume and dyssynchrony were obtained using impedance cardiography and echocardiographic methods, specifically, aortic velocity-time integral, mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yielded statistically insignificant data in the majority of patients (62%-82%). In contrast, impedance cardiography yielded statistically significant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual cases demonstrated that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worse cardiac function than default values. CONCLUSIONS: Consideration of statistical significance is critical for validating clinical optimization data in individual patients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge of its precision can result in worse cardiac function than default settings and a misinterpretation of observed changes over time. In this study, only impedance cardiography yielded statistically significant AV and VV interval optimization data in the majority of patients.

Dyssynchrony Assessment with Tissue Doppler Imaging and Regional Volumetric Analysis by 3D Echocardiography Do Not Predict Long-Term Response to Cardiac Resynchronization Therapy.

Background. Currently there are no reliable predictors of response to cardiac resynchronization therapy (CRT) before implantation. We compared pre-CRT left ventricular (LV) dyssynchrony by tissue Doppler imaging (TDI) and regional volumetric analysis by 3-dimensional transthoracic echocardiography (3DTTE) in predicting response to CRT. Methods. Thirty-eight patients (79% nonischemic cardiomyopathy) with symptomatic heart failure who underwent CRT were enrolled. Clinical and echocardiographic responses were defined as improvement in one NYHA class and reduction in LV end-systolic volume by ≥15% respectively. Functional status was assessed by Minnesota Living with Heart Failure questionnaire and 6-minute walk distance. Results. In 33 patients, after CRT for 7.86 ± 2.27 months, there were 24 (73%) clinical and 19 (58%) echocardiographic responders. Functional parameters, LV dimensions, volumes and synchrony by TDI and 3DTTE improved significantly in responders. There was no difference in the number of responders and nonresponders when cut-off values for dyssynchrony by different measurements validated in other trials were applied. Area under receiver-operating-characteristic curve ranged from 0.4 to 0.6. Conclusion. CRT improves clinical and echocardiographic parameters in patients with systolic heart failure. The dyssynchrony measurements by TDI and 3DTTE are not comparable and are unable to predict response to CRT.

Worsening of left ventricular end-systolic volume and mitral regurgitation without increase in left ventricular dyssynchrony on acute interruption of cardiac resynchronization therapy.

BACKGROUND: Responders to cardiac resynchronization therapy (CRT) have greater left ventricular (LV) dyssynchrony than nonresponders prior to CRT. AIM: We conducted this study to see whether the long term responders have more worsening of LV dyssynchrony and LV function on acute interruption of CRT. MATERIALS AND METHODS: We identified 22 responders and 13 nonresponders who received CRT as per standard criteria for 23.73 +/- 7.9 months (median 24.5 months). We assessed the acute change in LV function, mitral regurgitation (MR) and compared LV dyssynchrony in CRT on and off modes. RESULTS: On turning off CRT, there was no significant worsening of LV dyssynchrony in both responders and nonresponders. The dyssynchrony measurements by SPWMD, TDI and 3D echocardiography did not correlate significantly. LVESV increased (p = 0.02) and MR (p = 0.01) worsened in CRT-off mode in responders only without significant change in LVEF or LV dimensions. DISCUSSION AND CONCLUSION: In long-term responders to CRT, there is alteration in the function of remodeled LV with acute interruption of CRT, without significant worsening of LV dyssynchrony. The role of different echocardiographic parameters in the assessment of LV dyssynchrony remains controversial. Even after long-term CRT reversely remodels the LV, the therapy needs to be continued uninterrupted for sustained benefits.

Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options.

Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.

Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Our purpose was to evaluate the impact of nesiritide on renal function in patients with acute decompensated heart failure and baseline renal dysfunction. BACKGROUND: Although nesiritide is approved for the treatment of acute decompensated heart failure, retrospective analyses have raised concerns that it may cause worsened renal function. To date, no randomized clinical trials have prospectively evaluated this issue. METHODS: Consecutive patients with acute decompensated heart failure and baseline renal dysfunction were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive nesiritide (0.01 microg/kg/min with or without a 2-microg/kg bolus) or placebo (5% dextrose in water) for 48 h in addition to their usual care. Predefined primary end points of the trial were a rise in serum creatinine by > or =20% and change in serum creatinine. RESULTS: Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs. 75.5 years, respectively), blood pressure (123/64 vs. 125/64 mm Hg) and serum creatinine (1.82 vs. 1.86 mg/dl). There were no significant differences in the incidence of a 20% creatinine rise (23% vs. 25%) or in the change in serum creatinine (-0.05 vs. +0.05 mg/dl). There were no significant differences in the secondary end points of change in weight (-2.19 vs. -1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%). CONCLUSIONS: In this randomized, double-blind, placebo-controlled clinical trial, nesiritide had no impact on renal function in patients with acute decompensated heart failure. (BNP-CARDS trial; http://www.clinicaltrials.gov/ct/show/NCT00186329?order=1; NCT00186329).

Beta-blocker dosing in community-based treatment of heart failure.

BACKGROUND: Community patients with heart failure (HF) are older, less often treated by HF specialists, and have more comorbidity than those in randomized clinical trials. These differences might affect beta-blocker prescribing in HF. METHODS: To explore patterns of beta-blocker prescribing for HF in the community and their association with outcomes, we determined carvedilol doses at end titration in 4113 patients from a community-based beta-blocker HF registry according to physician and patient characteristics, HF severity, and rates of hospitalization and death. RESULTS: Female sex, age > or = 65 years, and left ventricular ejection fraction > or = 35% were associated with lower beta-blocker doses. Average daily dose of beta-blocker was lower with worse baseline New York Heart Association class. More patients of cardiologists achieved carvedilol doses > or = 25 mg twice daily, whereas in those of noncardiologists lower doses were more common. Relative risk of HF hospitalizations or all-cause death was significantly lower with higher doses of beta-blocker. CONCLUSIONS: Beta-blocker dosing in community HF appears lower than in randomized clinical trials, especially when prescribed by noncardiologists. At all doses, patients taking the beta-blocker carvedilol have a lower incidence of death and HF hospitalization than those discontinuing it, regardless of physician type in the community setting.

Comparison of outcomes and usefulness of carvedilol across a spectrum of left ventricular ejection fractions in patients with heart failure in clinical practice.

Heart failure (HF) in the community differs meaningfully from that in clinical trials, particularly the higher prevalence of patients with preserved left ventricular (LV) ejection fraction (EF) typically excluded from clinical trials, thus limiting knowledge of their responsiveness to beta-blocker therapy. From a community-based registry of 4,280 patients with HF starting treatment with the beta blocker carvedilol, we compared characteristics, carvedilol titration, and outcomes of patients according to LVEF >40% or <40% (as in clinical trials) and across the spectrum of LVEF <21%, 21% to 30%, 31% to 40%, and >40%. Patients with preserved EF (LVEF >40%) were older and more often women and hypertensive. Lower LVEF was associated with worse functional class and more HF hospitalizations in the previous year. Carvedilol dose decreased with increasing LVEF. Hospitalization rates for HF related inversely to LVEF before starting carvedilol therapy and decreased from the previous year in all LVEF groups during follow-up. Although 1-year mortality rate decreased from 8% with LVEF < or =20% to 6% with LVEF >40%, adjusted hazard ratios were not significantly different across LVEF groups. Thus, characteristics of community patients with HF vary across the spectrum of LVEF. Patients with HF and preserved EF treated with carvedilol in the community improve symptomatically and experience fewer HF hospitalizations after initiating carvedilol. In conclusion, without a control group, the effect of carvedilol on outcomes is not conclusive and trials of carvedilol in patients with HF and preserved EF should be undertaken.

Tolerability, safety, and efficacy of beta-blockade in black patients with heart failure in the community setting: insights from a large prospective beta-blocker registry.

Heart failure (HF) clinical trials suggest different responses of blacks and whites to beta-blockers. Differences between clinical trial and community settings may also have an impact. The Carvedilol Heart Failure Registry (COHERE) observed experience with carvedilol in 4280 patients with HF in a community setting. This analysis compares characteristics, outcomes, and carvedilol dosing of blacks and whites in COHERE. Compared with whites (n=3433), blacks (n=523) had more severe HF symptoms despite similar systolic function. At similar carvedilol maintenance doses, symptoms improved in 33% of blacks vs 28% of whites, while worsening in 10% and 11%, respectively (both nonsignificant), and HF hospitalization rates were reduced comparably in both groups (-58% vs -56%, respectively; both P<.001). Incidence and hazard ratios of death were similar in blacks and whites (6.9% vs 7.5%, hazard ratio 1.2 vs 1.0, P=.276). Thus carvedilol was similarly effective in blacks and whites with HF in the community setting, consistent with carvedilol clinical trials.

Heart failure in community practice: relationship to age and sex in a beta-blocker registry.

Women and the elderly are underrepresented in clinical trials of heart failure (HF). The authors analyzed, by sex and age groups, a registry of 4280 community patients initiating carvedilol for HF. Women (n=1485) were older than men (n=2793) and had worse functional class with higher left ventricular ejection fraction and blood pressure. Women also had more HF hospitalizations, less use of angiotensin-converting enzyme inhibitors, and lower doses of carvedilol. Nevertheless, during 1-year follow-up, both groups experienced greater than 40% reductions in HF hospitalizations (P<.001), with mortality of 7.3% in women vs 9.1% in men (P=.085). With increasing age, left ventricular ejection fraction, blood pressure, and functional class increased, whereas angiotensin-converting enzyme inhibitor use and carvedilol doses decreased. HF hospitalizations fell at least 40% in all age groups after starting carvedilol (P<.001). Characteristics of women and the elderly with HF in the community suggest increased risk, but both populations respond well after initiating carvedilol.

Emerging therapies for the management of decompensated heart failure: from bench to bedside.

While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.

Predictors of clinical outcomes in patients given carvedilol for heart failure.

Risk factors for outcomes in heart failure (HF) were derived from populations in clinical trials, at hospital discharge, or in localized geographic or socioeconomic strata before the widespread use of beta blockers. This study observed 4,280 patients in a community-based HF registry for 1 year after completing carvedilol titration. Independent risk factors for death, hospitalization for HF, or hospitalization for cardiovascular reasons other than HF were first identified by age-, gender-, and race-adjusted analyses, then by multivariate analysis adjusted simultaneously for all factors. Over this period, 7% of patients died, 11% were hospitalized for HF, 12% were hospitalized for other cardiovascular reasons, and 27% had > or =1 of these events. The most significant outcome predictors were New York Heart Association class III or IV, history of hospitalization for HF or other cardiovascular reasons, and angina pectoris, all associated with increased odds of having an adverse outcome (all p < or =0.001). The left ventricular ejection fraction was not a significant outcome predictor by multivariate analysis. The odds ratio for an adverse outcome was significantly reduced for patients with hypertensive or idiopathic causes of HF and for those whose physicians had graduated from medical school > or =24 years earlier compared with <14 years earlier (all p <0.005). In conclusion, easily obtained historical information predicts clinical outcomes in patients with HF in the year after initiating carvedilol. In this unselected community population, these historical factors were better predictors of risk than the left ventricular ejection fraction.

The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis.

BACKGROUND: Although beta-blocker therapy has been shown to improve survival in patients with chronic heart failure, this class of drugs tends to be underutilized in diabetic patients due to concerns about adverse metabolic effects, especially on glycemic control. No randomized clinical trial has specifically evaluated the effect of beta-blocker therapy on mortality in diabetic patients with heart failure. Previous meta-analyses combining results of heart failure trials with pharmacologically diverse beta-blockers suggest that the survival benefit in diabetic patients may be diminished compared to benefits in non-diabetic patients. However, some trial results indicate that carvedilol, which blocks beta1-, beta2-, and alpha1-receptors and is a potent antioxidant, may produce at least comparable effects in both patient groups. OBJECTIVES: To evaluate the effect of carvedilol in patients with heart failure and diabetes, specifically to determine if the survival benefit of carvedilol demonstrated in heart failure trials was as great in the subgroups of patients with diabetes. METHODS: A meta-analysis was performed that included 5757 patients with heart failure, 25% of whom had diabetes, from seven large placebo-controlled randomized trials with carvedilol. All large (> 100 patients) placebo-controlled, randomized trials with carvedilol in heart failure were included. The endpoint of all-cause mortality was examined in the overall population, patients without diabetes, and patients with diabetes. The number of patients needed to treat (NNT) for 1 year to prevent one death associated with carvedilol use in diabetic versus non-diabetic patients was also calculated. The log-rank test and the Cox proportional hazards regression were used to compare the event time distributions of carvedilol versus placebo with respect to the outcome of mortality. RESULTS: Similar survival benefits were seen with carvedilol use in diabetic and non-diabetic patients (relative risk reductions of 28% [95% confidence interval (CI) 3-46%; p = 0.03] and 37% [95% CI 22-48%; p < 0.001], respectively). There were no significant differences between the relative mortality risk reductions or the NNT with carvedilol use in diabetic versus non-diabetic patients. The NNT for 1 year to prevent one death was 23 for all patients, as well as for non-diabetic patients, and 25 for the diabetic group. CONCLUSIONS: This meta-analysis provides evidence that the same survival benefit may occur with carvedilol in heart failure patients with and without diabetes. The low NNT in the severe heart failure trial, COPERNICUS, and the diabetic subgroup in this meta-analysis suggests that severe heart failure patients and heart failure patients with diabetes may particularly derive benefit from therapy with carvedilol.