Charles F Mctiernan

University of Pittsburgh | Pitt · Division of Cardiology

BACKGROUND Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel in...

Background: The pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic card...

General control of amino acid synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodyn...

B-cell lymphoma 2-associated athanogene-3 (Bag3) is expressed in all animal species, with Bag3 levels being most prominent in the heart, the skeletal muscle, the central nervous system, and in many cancers. Preclinical studies of Bag3 biology have focused on animals that have developed compromised cardiac function; however, the present studies were...

General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodyn...

Intravenous administration of a high affinity carbon monoxide (CO)-binding molecule, recombinant neuroglobin, can improve survival in CO poisoning mouse models. The current study aims to understand how biochemical variables of the scavenger determine the CO removal from the RBCs by evaluating three readily available hemoproteins, 2,3-diphosphoglyce...

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regula...

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed f...

Introduction: Exercise induced pulmonary hypertension (EIPH) portends worse prognosis compared to isolated resting PH. Exercise increases mitochondrial reactive oxygen species (mROS) production in peripheral blood mononuclear cells of patients with heart failure. Metabolic syndrome related mROS contribute to EIPH by decreasing the expression of the...

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, if BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for ca...

Background: Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM). Methods and results: 98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2...

Background: Many patients with heart failure with preserved ejection fraction (HFpEF) have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with HFpEF portend a poor prognosis; this phenotype is referred to as combined pre-and post-capillary PH (CpcPH). Therapeutic...

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status i...

Background - Ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD) show a circadian pattern of occurrence in heart failure patients. In the rodent ventricle, a significant portion of genes, including some ion channels, shows a circadian pattern of expression. However genes that define electrophysiologic properties in failing human heart...

Background Many Heart Failure with preserved Ejection Fraction (HFpEF) patients have metabolic syndrome and develop Exercise Induced Pulmonary Hypertension (EIPH). The pathogenesis of EIPH in HFpEF remains unclear as there is no rodent model. As the SGLT2 inhibitor Empagliflozin improves clinical outcome in patients with type 2 diabetes and cardiov...

Utilizing publicly available ribonucleic acid sequencing data, we identified SCUBE1 as a BMPR2-related gene differentially expressed between induced pluripotent stem cell-endothelial cells derived from pulmonary arterial hypertension (PAH) patients carrying pathogenic BMPR2 mutations and control patients without mutations. Endothelial SCUBE1 expres...

MicroRNAs (miRs) are dysregulated in pathological left ventricular hypertrophy. AntimiR inhibition of miR-23a suppressed hypertension-induced cardiac hypertrophy in preclinical models, but clinical translation is limited by a lack of cardiac-targeted delivery systems. Ultrasound-targeted microbubble cavitation (UTMC) utilizes microbubbles as nuclei...

The etiology of peripartum cardiomyopathy remains unknown. One hypothesis is that an increase in the 16-kDa form of prolactin is pathogenic and suggests that breastfeeding may worsen peripartum cardiomyopathy by increasing prolactin, while bromocriptine, which blocks prolactin release, may be therapeutic. An autoimmune etiology has also been propos...

Background: Carbon monoxide (CO) is the most common human poisoning. There is no antidote. One-third of hospitalized patients will have cardiac dysfunction and increased mortality. Little is known about the nature of cardiovascular dysfunction during acute CO poisoning. CO toxicity results from: (1) global hypoxia and decreased oxygen delivery thro...

Objective To examine the association between maternal obesity on left ventricular (LV) size and recovery in women with peripartum cardiomyopathy (PPCM). Study Design This was a prospective analysis of 100 women enrolled within 13 weeks of PPCM diagnosis and followed for a year in the Investigation of Pregnancy Associated Cardiomyopathy study. Adipo...

Importance The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated with functional genetic variants. Objective We hypothesized that Bcl2-associated anthanogene 3 (B...

Objective: Evaluate the hypothesis that the distribution of circulating immune cell subsets, or their activation state, is significantly different between PPCM and healthy postpartum (HP) women. Background: Peripartum cardiomyopathy (PPCM) is a major cause of maternal morbidity and mortality and an immune-mediated etiology has been hypothesized....

Dr. McTiernan has reported that he has no relationships relevant to the contents of this paper to disclose.

RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not...

Characterization of luciferase transgenic mice. (XLSX)

Ultrasound and Microbubble Delivery of siRNA to the Heart. (XLSX)

Microbubble Cavitation in Mouse Heart. (XLSX)

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers where it acts to promote tumor progression. A STAT3-specific transcription factor decoy has been developed to suppress STAT3 downstream signaling, but a delivery strategy is needed to improve clinical translation. Ultrasound-targeted microbubble d...

Abstract BACKGROUND: Left ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever-larger numbers of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for m...

Rationale: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy. Objective: To evaluate the efficacy of the antifibrot...

Microbubble contrast agents can specifically deliver nucleic acids to target tissues when exposed to ultrasound treatment parameters that mediate microbubble destruction. In this study, we evaluated whether microbubbles and ultrasound targeted microbubble destruction (UTMD) could be used to enhance delivery of EGFR-directed small inhibitory RNA (si...

Tumor necrosis factor α (TNFα) may contribute to the pathologic process of congestive heart failure (CHF). TNFα signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region. The 58...

The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and nor...

There is a scarcity of cardiac tissue available for research. (1) To investigate the feasibility of obtaining myocardial tissue from extracted pacemaker and defibrillator leads for gene expression analysis and (2) to examine the nitric oxide 1 adaptor protein (NOS1AP) RNA expression as a function of patient genotype. Seventeen patients (age = 56 ±...

This study was conducted to test the hypothesis that cardiac micro-ribonucleic acid (miR) profiling in severe heart failure patients at the time of ventricular assist device (VAD) placement would differentiate those who remained VAD-dependent from those with subsequent left ventricular (LV) recovery. The relationship of myocardial miR expression to...

When microbubble contrast agents are loaded with genes and systemically injected, ultrasound-targeted microbubble destruction (UTMD) facilitates focused delivery of genes to target tissues. A mouse model of squamous cell carcinoma was used to test the hypothesis that UTMD would specifically transduce tumor tissue and slow tumor growth when treated...

Caveolins are scaffolding proteins that are integral components of caveolae, flask-shaped invaginations in the membranes of all mammalian cells. Caveolin-1 and -2 are expressed ubiquitously, whereas caveolin-3 is found only in muscle. The role of caveolin-3 in heart muscle disease is controversial. The present study was undertaken to assess the eff...

This editorial refers to ‘Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation’ by M. Konishi et al. , pp. 309–319, this issue. Doxorubicin, an anthracycline drug widely used for the treatment of various solid-organ tumours and haematological malignancies, has significant cardiac toxi...

Adenoviral-mediated (AdV-T2) overexpression of TIMP-2 would blunt ventricular remodeling and improve survival in a murine model of chronic ischemic injury. Male mice (n = 124) aged 10-14 weeks underwent either (1) left coronary artery ligation to induce myocardial infarction (MI group, n = 36), (2) myocardial injection of 6 × 10¹⁰ viral particles o...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Ultrasound contrast agents are gas-filled microbubbles (MB) that can be induced to vibrate or cavitate in an ultrasound field. When the MB are loaded with genes and systemically injected, ultrasound-targeted MB destruction (UTMD) has been shown to facilitate...

the obesity-related adipokine, leptin, has multiple actions on peripheral organs, including the mitigation of adverse cardiovascular outcomes after myocardial infarction (MI). Although we recently demonstrated that leptin, its receptor, and downstream signalling are up-regulated in the heart after MI, the significance of intact cardiomyoctye leptin...

Increased circulating leptin is present in human heart failure, and leptin deficiency is linked to worse outcomes in chronic ischemic injury. In the present observational study, we tested the hypothesis that cardiac leptin production and signaling are increased in the failing human heart, and that mechanical unloading with a ventricular assist devi...

T-wave alternans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNF-alpha model of CHF and can be f...

Arrhythmias and sudden cardiac death have a circadian pattern of occurrence in humans. We hypothesized that a circadian pattern of arrhythmias is also present in transgenic mice with cardiac-specific overexpression of tumor necrosis factor alpha, which develop a dilated cardiomyopathy, arrhythmias and heart failure. To test this hypothesis, telemet...

Extracellular superoxide dismutase (EC-SOD) is an antioxidant that protects the heart from ischemia and the lung from inflammation and fibrosis. The role of cardiac EC-SOD under normal conditions and injury remains unclear. Cardiac toxicity, a common side effect of doxorubicin, involves oxidative stress. We hypothesize that EC-SOD is critical for n...

We have previously shown that activation of leptin signalling in the heart reduces cardiac morbidity and mortality after myocardial infarction (MI). In the present study, we tested the hypothesis that leptin signalling limits cardiac apoptosis after MI through activation of signal transducer and activator of transcription (STAT)-3 responsive anti-a...

We sought to promote myocardial repair using urinary bladder matrix incorporated with a fusion protein that combined hepatocyte growth factor and fibronectin collagen-binding domain in a porcine model. Collagen-binding domain acted as an intermediary to promote hepatocyte growth factor binding and enhance hepatocyte growth factor stability within u...

Left ventricular assist device (LVAD) support may facilitate myocardial recovery. We evaluated the impact of LVAD support on Fas expression in a cohort with end-stage heart failure. Myocardial gene expression was assessed pre- and post-LVAD by RNase protection assay and compared to control donor hearts. The expression of Fas is markedly elevated at...

Leptin is elevated under conditions of both obesity and heart failure (HF), and activation of leptin receptor (ObR) signalling is known to increase in vivo cardiac contractility and to have anti-hypertrophic effects on the left ventricle (LV). However, it is unknown whether ObR signalling is altered in cardiomyocytes after myocardial infarction (MI...

Caveolae are 50- to 100-nm invaginations of the plasma membrane. Caveolins are the structural protein components of caveolar membranes. The caveolin gene family is composed of three members: caveolin-1, caveolin-2, and caveolin-3. Caveolin-1 and caveolin-2 are coexpressed in many cell types, including adipocytes, endothelial cells, epithelial cells...

Sequestration of tumor necrosis factor-alpha (TNFalpha) by TNF-receptor immunoglobulin G (IgG)-Fc fusion proteins can limit heart failure progression in rodent models. In this study we directly injected an adeno-associated viruses (AAV)-2 construct encoding a human TNF receptor II IgG-Fc fusion protein (AAV-TNFRII-Fc) into healthy baboon hearts and...

Introduction In acute cardiomyopathy (ACM), lower myocardial Fas expression is predictive of greater LV recovery during follow up. Whether circulating Fas reflects myocardial activity and predicts recovery is unknown. We examined the predictive value of serum Fas, and its correlation with myocardial expression in subjects in the multicenter IMAC 1...

Introduction : Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality. PPCM is associated with acute myocardial dysfunction with a high rate of spontaneous recovery. For subjects with chronic non-ischemic cardiomyopathy, beta blockade (BB) increases left ventricular ejection fraction (LVEF), reverses remodeling a...

Introduction: The failing heart displays contractile dysfunction, increased workload and energy demands, and a switch in substrate utilization for ATP production from free fatty acid to glucose oxidation. ATP production is regulated by AMP Kinase (AMPK). In skeletal muscle, the cytokines leptin (OB) and adiponectin (AD) stimulate AMPK activity and...

It has been recently shown that recombinant adeno-associated virus serotype 8 (rAAV8) is a robust alternative serotype vector that overcomes many of the limitations of rAAV2 and transduces various tissues efficiently and globally through systemic vector administration. AAV9 is a serotype newly isolated from human tissues, but our knowledge of the b...

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration...

Heart failure (HF) and dilation are associated with increased activity of matrix metalloproteinases (MMPs) which are involved in the turnover of a broad spectrum of extracellular matrix (ECM) proteins. MMP activity is regulated not only by gene expression and processing of proenzyme, but also by the four Tissue Inhibitors of Matrix Metalloproteinas...

Altered expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) accompanies the development of heart failure (HF). However, changes in MMP and TIMP protein levels or activity during the progression from compensated to decompensated failure remains incompletely examined. Transgenic mice (Tg) with cardiac-specific overe...

When selectively overexpressed in mouse heart, TNF-alpha effects the development of a cardiomyopathy that closely mimics that seen in human failing hearts. It has been suggested that two intracellular signaling pathways, the Akt protein kinase and the NF-kappaB transcription factor, mediated TNF-alpha signaling. The present experiments assessed the...