Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.

AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis. METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.

Early increase of serum ferritin among COVID-19 patients is associated with need of invasive mechanical ventilation and with in-hospital death.

BACKGROUND: COVID-19 may trigger an acute hyperinflammatory syndrome characterised by heightened levels of acute phase reactants and is associated with adverse outcomes among hospitalised individuals. The relationship between 48-hour changes in acute phase reactants and adverse outcomes is unclear. This study evaluated the relationship between change in four acute phase reactants (interleukin-6, procalcitonin, ferritin, and C-reactive protein), and the risk for in-hospital death and invasive mechanical ventilation. METHODS: A retrospective cohort among 2,523 adult patients hospitalised with COVID-19 pneumonia was conducted. Changes in IL-6, procalcitonin, ferritin, and CRP from admission to 48 h after admission were recorded. Delta was calculated using the difference in each acute phase reactant at admission and at 48-hours. Delta in acute phase reactants and the risk for in-hospital death and invasive mechanical ventilation was assessed using logistic regression models adjusting for demographics and comorbidities. RESULTS: Patients with both admission and 48-hour measurement for interleukin-6 (IL-6) (n = 541), procalcitonin (n = 828), ferritin (n = 1022), and C-reactive protein (CRP) (n = 1919) were included. Baseline characteristics were similar across all four populations. Increases in ferritin associated with a heightened risk of in-hospital death (OR 1.00032; 95%CI 1.00007- 1.00056; p < .001) and invasive mechanical ventilation (OR 1.00035; 95%CI 1.00014- 1.00055; p = .001). Therefore, for every 100 ng/mL increase in ferritin, the odds for in-hospital death and invasive mechanical ventilation increase by 3.2% and 3.5%, respectively. CONCLUSIONS: Delta in ferritin is associated with in-hospital death and invasive mechanical ventilation. Other acute phase reactants were not associated with these outcomes among COVID-19 inpatients.

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4+ and CD8+ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.

Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis.

AIMS: This study aimed to estimate the incidence of cardiac immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). METHODS AND RESULTS: First, we performed an ICI pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than those treated with anti-CTLA-4 (69.4% vs. 20%). Then, we analysed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to 31 August 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the ClinicalTrials.gov database, finding an incidence of 3.1% for ICI monotherapies, 5.8% for dual ICI therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were reported in 2.5% of patients treated solely with chemotherapy. CONCLUSIONS: Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rates of cardiac irAEs than monotherapies or ICIs plus chemotherapy.

The Hospital Zambrano Hellion venous thromboembolism rapid response team (PREVENTION-team): Improving pulmonary embolism and deep venous thrombosis patient care / Equipo de respuesta rápida para tromboembolismo venoso del Hospital Zambrano Hellion (PREVENTION-Team): Mejorando el manejo del tromboembolismo pulmonar y trombosis venosa profunda

Abstract Background: Fast-track worldwide reperfusion programs improve outcomes in ST-elevation myocardial infarction and stroke. Similar programs called Program Evaluation and Review Technique (PERT) focus on submassive and massive pulmonary embolism (PE) excluding deep venous thrombosis (DVT). Methods: PREVENTION-team (Hospital Zambrano Hellion Venous Thromboembolism [VTE] Rapid Response). Primary objective: Fast-track stratification, diagnostics, and treatment (60-90 min) to improve proximal DVT and submassive and massive PE patients care. Secondary objectives: Increase diagnosis rate of low-risk PE and distal DVT; exploration of cause; long-term anticoagulation; identify high-risk profile for chronic complications; community-based support groups and patient education to extend the concept of the thrombosis-free hospital to thrombosis-free home. Structure and organization: The team includes cardiologists, vascular medicine, angiologist, echocardiographer, cardiovascular imaging, and interventional cardiologists. The team will be accessible 24 h a day, 7 days a week, 365 days a year, and base on previous national experience. The cardiology fellow on call will be responsible for activation and evaluation. We will design several tools to accelerate these processes. Risk stratification and therapeutic approach will be based on clinical presentation, echocardiogram, and biomarkers findings. According to PERT stratification based on resources and medical specialties, Hospital Zambrano Hellion has level 1 PERT. PREVENTION-team links physicians with different expertise, provide fast, efficient, and time-saving treatment, potentially saving lives and reducing bleeding and chronic complications in VTE patients. Finally, establishing a network in our hospital and health system to improve VTE patients care. To the best of our knowledge, this is the first rapid response team focused on VTE in Mexico.

Resumen Antecedentes: Programas de reperfusión mejoraron la evolución en infarto con elevación del ST y accidente cerebrovascular embólico. Programas similares llamados PERT para TEP masiva o submasiva excluyen TVP. Métodos: Equipo PREVENTION (Hospital Zambrano Hellion Venous Thromboembolism Rapid Response). Objetivo primario: Estratificación, diagnóstico y tratamiento acelerado (60-90 minutos) para mejorar atención del TVP proximal y TEP masiva o submasiva. Objetivos secundarios: Incrementar diagnóstico de TEP de riesgo bajo y TVP distal; explorar causa; anticoagulación a largo plazo; perfil de riesgo alto para complicaciones crónicas; grupos de soporte en la comunidad y educación para pacientes, y extender el concepto de hospital libre de trombosis a hogar libre de trombosis. Estructura y organización: Incluye cardiólogos, medicina vascular, angiólogo, ecocardiografistas, imagen cardiovascular. Basado en experiencia nacional, el equipo estará accesible 24 horas del día, siete días de la semana, 365 días del año. El residente de cardiología realizará la activación y estratificación. Diseñamos herramientas para acelerar el proceso. La estratificación de riesgo y el abordaje terapéutico se basará en presentación clínica, hallazgos ecocardiograficos y biomarcadores. El Hospital Zambrano Hellion tiene nivel PERT 1 de acuerdo a la estratificación PERT basada en recursos y especialidades. Equipo-PREVENTION en TEV vincula médicos con diferentes capacidades, ofrece rápido y eficiente tratamiento para preservar vidas y reducir complicaciones hemorrágicas y crónicas. En nuestro hospital y sistema de salud establecer una sólida red de trabajo para mejorar la atención. Hasta nuestro conocimiento, en México este podría ser el primer equipo de respuesta rápida enfocado en TEV.

Management of Myocarditis-Related Cardiomyopathy in Adults.

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

Incidence and outcomes of cancer treatment-related cardiomyopathy among referrals for advanced heart failure.

BACKGROUND: Approximately 2-3% of patients undergoing advanced heart failure therapies such as left ventricular assist devices (LVAD) and orthotropic heart transplantation (OHT) have chemotherapy-related cardiomyopathy, according to analyses of large databases such as United Network for Organ Sharing (UNOS) or Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registries. While these studies have shown similar survival outcomes post-interventions, these databases by definition exclude patients referred for advanced therapies but do not receive them, and thus there is little data on overall outcomes of such patients. Given the lack of nuance in the diagnoses in large registries and the possibility that many cancer treatment-related cardiomyopathy (CCMP) patients might be misclassified by the generic "non-ischemic" or "dilated" cardiomyopathies, we investigated the incidence and clinical outcomes of CCMP patients among advanced heart failure (HF) referrals at a single high volume institution. METHODS: All referrals from 2013 to 2016 were evaluated for type of cardiomyopathy, with careful chart review. Outcomes such as LVAD, OHT and death were compared between CCMP and other cardiomyopathies. RESULTS: Of 553 referrals for advanced HF, 19 (3.4%) were for CCMP. There was a higher percentage of patients receiving advanced therapies in the CCMP vs. non-ischemic cardiomyopathy (NICMP) and ischemic cardiomyopathy (ICMP) (42.1% vs 30.2% vs 33.6%, not significant). Of the CCMP patients, 3 had OHT directly, 2 had LVAD followed by OHT, and 3 had LVADs as bridge to candidacy or destination therapy. Fifty-eight percent of the CCMP did not receive LVAD or OHT compared to 69.8% and 66.3 of the NICMP and ICMP, respectively (p = 0.0388). Independent of type of advanced therapy, survival was significantly higher in the CCMP group compared to NICMP and ICMP (93.3% vs 84.8% vs 73.8%, respectively P = 0.0021 for 1 year, 93.3% vs 76.2% vs 58.3%, respectively, P = < 0.0001 for 3 year). CONCLUSIONS: In a single institution, CCMP accounts for more than 3% of all referrals for advanced HF therapies and almost 8% of NICMP. Contrary to concerns for previous cancer and sequelae of cancer treatment excluding patients for advanced therapies, a higher percentage of CCMP underwent advanced HF therapies and with similar outcomes. This is the first study to show that among patients referred for advanced therapies, CCMP patients do not have inferior outcomes compared to other cardiomyopathies regardless of the selected management strategy.

Silica nanoparticles induce cardiotoxicity interfering with energetic status and Ca2+ handling in adult rat cardiomyocytes.

Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+ handling, which showed impaired contractility and intracellular Ca2+ transient amplitude during ß-adrenergic stimulation in SiO2 treatment. The time to 50% Ca2+ decay increased 39%, and the Ca2+ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+ release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+ handling.

Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1α/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1α and Regulates Responsive Cardiac Angiogenesis.

The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.

Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities.

Platelets play a pivotal role in physiological hemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute ischemic events. Avocado pulp (Persea americana) is a good source of bioactive compounds, and its inclusion in the diet as a source of fatty acid has been related to reduced platelet aggregability. Nevertheless, constituents of avocado pulp with antiplatelet activity remain unknown. The present study aims to characterize the chemical nature of avocado constituents with inhibitory effects on platelet aggregation. Centrifugal partition chromatography (CPC) was used as a fractionation and purification tool, guided by an in vitro adenosine diphosphate (ADP), arachidonic acid or collagen-platelet aggregation assay. Antiplatelet activity was initially linked to seven acetogenins that were further purified, and their dose-dependent effects in the presence of various agonists were contrasted. This process led to the identification of Persenone-C (3) as the most potent antiplatelet acetogenin (IC50=3.4 mM) among the evaluated compounds. In vivo evaluations with Persenone A (4) demonstrated potential protective effects against arterial thrombosis (25 mg kg⁻¹ of body weight), as coagulation times increased (2-fold with respect to the vehicle) and thrombus formation was attenuated (71% versus vehicle). From these results, avocado may be referred to as a functional food containing acetogenin compounds that inhibit platelet aggregation with a potential preventive effect on thrombus formation, such as those that occur in ischaemic diseases.

Mechanical unloading promotes myocardial energy recovery in human heart failure.

BACKGROUND: Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. METHODS AND RESULTS: We compared metabolomic, gene transcript, and protein data from 6 paired samples of failing human left ventricular tissue obtained during left ventricular assist device insertion (heart failure samples) and at heart transplant (post-left ventricular assist device samples). Nonfailing left ventricular wall samples procured from explanted hearts of patients with right heart failure served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in heart failure tissue: 2.6-fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1A, 1.3-fold) and estrogen-related receptor α (ERRA, 1.2-fold) and γ (ERRG, 2.2-fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with left ventricular assist device improved all of these metabolic and transcriptional defects. CONCLUSIONS: These observations underscore an important pathophysiologic role for severely defective metabolism in heart failure, while the reversibility of these defects by left ventricular assist device suggests metabolic resilience of the human heart.

High proportion of patients with end-stage heart failure regardless of aetiology demonstrates anti-cardiac antibody deposition in failing myocardium: humoral activation, a potential contributor of disease progression.

AIMS: Various reports have raised the possibility of humoral immune responses as contributors for the progression of heart failure. Previous studies, however, have focused on the analysis of serum and documented circulating antibodies against a variety of cardiac proteins. However, there is little evidence on whether anti-cardiac antibodies are deposited in end-stage failing myocardium. Our objective was to determine whether or not there was evidence of deposition of anti-cardiac antibodies and/or activated complement components in end-stage failing human myocardium. METHODS AND RESULTS: Myocardial samples were obtained from 100 end-stage heart failure patients and 40 donor control biopsies. Sections were cut and stained using standard fluorescent immunohistochemistry techniques with anti-human immunoglobulin G (IgG), IgG3, and C3c. Gel electrophoresis and protein identification by mass spectrometry were used to confirm the presence of IgG and its antigen. Immunoglobulin G was localized to the sarcolemma in 71% of patients, 48% of those being positive for the subtype IgG3. The proportion of patients with ischaemic heart disease that was positive for IgG was 65% and among those with non-ischaemic aetiologies was 76%. In a subgroup analysis, the presence of IgG and its subunits were confirmed by mass spectrometry and adenosine triphosphate synthase ß subunit identified as an antigen. Complement was activated in 31% of all patients. The presence of IgG, IgG3, and C3c was directly correlated with the length of disease (r = 0.451, P = 0.006). CONCLUSION: Evidence of anti-cardiac antibodies and complement activation was found in a large number of patients with end-stage cardiomyopathy regardless of the aetiology. Adenosine triphosphate synthase appears to be a new prominent antigenic stimulus; but more interestingly, the simultaneous co-existence of activated complement components suggests that this humoral mechanism may participate in disease progression.

Use of stem cells in heart failure treatment: where we stand and where we are going.

End-stage heart failure is the final common pathway of an irreversible process associated with loss of myocardial cells. In this process, the capacity for renewal and repair of myocardial tissue is inadequate and ultimately leads to ventricular remodeling. Novel therapeutic strategies have been developed to prevent it, one being cell therapy, which has emerged as a potential approach to directly repopulate and repair the damaged heart. Here, we review the use of regenerative cell therapy for different cardiac diseases and discuss the positive effect of cell therapy mediated by paracrine factors instead of turning directly into cardiomyocytes.

Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: In an open-label blinded study, we compared intracoronary and transendocardial CD34(+) cell transplantation in patients with nonischemic dilated cardiomyopathy. METHODS AND RESULTS: Of the 40 patients with dilated cardiomyopathy, 20 were randomized to receive intracoronary injection and 20 received transendocardial CD34(+) cell delivery. In both groups, CD34(+) cells were mobilized by filgrastim, collected via apheresis, and labeled with technetium-99m radioisotope for single-photon emission computed tomographic imaging. In the intracoronary group, cells were injected intracoronarily in the artery supplying segments of greater perfusion defect on myocardial perfusion scintigraphy. In the transendocardial group, electroanatomic mapping was used to identify viable but dysfunctional myocardium, and transendocardial cell injections were performed. Nuclear single-photon emission computed tomographic imaging for quantification of myocardial retention was performed 18 hours thereafter. At baseline, groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide levels. The number of CD34(+) cells was also comparable (105 ± 31 × 10(6) in the transendocardial group versus 103 ± 27 × 10(6) in the intracoronary group, P=0.62). At 18 hours after procedure, myocardial retention was higher in the transendocardial group (19.2 ± 4.8%) than in the intracoronary group (4.4 ± 1.2%, P<0.01). At 6 months, left ventricular ejection fraction improved more in the transendocardial group (+8.1 ± 4.3%) than in the intracoronary group (+4.2 ± 2.3%, P=0.03). The same pattern was observed for the 6-minute walk test distance (+125 ± 33 m in the transendocardial group versus +86 ± 13 m in the intracoronary group, P=0.03) and N-terminal pro-brain natriuretic peptide (-628 ± 211 versus -315 ± 133 pg/mL, P=0.04). CONCLUSIONS: In patients with dilated cardiomyopathy, transendocardial CD34(+) cell transplantation is associated with higher myocardial retention rates and greater improvement in ventricular function, N-terminal pro-brain natriuretic peptide, and exercise capacity compared with intracoronary route. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up.

RATIONALE: CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance. OBJECTIVE: We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response. METHODS AND RESULTS: Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs. 18%; P=0.03), but not of sudden cardiac death (9% vs. 16%; P=0.39). CONCLUSIONS: Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.

Heart transplantation and end-stage cardiac amyloidosis: a review and approach to evaluation and management.

Cardiac amyloidosis is one of the most common of the infiltrative cardiomyopathies and is associated with a poor prognosis. The extent of cardiac involvement with amyloid deposition is an important determinant of treatment options and is the major determinant of outcome in patients with amyloidosis. Several small case series with sequential orthotopic heart transplantation and autologous stem cell transplant have demonstrated an improvement in post-transplant outcome and have revived enthusiasm about heart transplantation for patients with end-stage heart failure due to AL amyloidosis. The purpose of this review is to summarize the evaluation and management of cardiac amyloidosis and to provide our single-center experience with end-stage heart failure due to AL amyloidosis treated with heart transplantation followed by an autologous stem cell transplant.