Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.

Background-The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain. Methods and Results-Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by Ϸ60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1␣), which then inhibited expression of oxygen-sensitive, voltage-gated K ϩ channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H 2 O 2 ) or blocking HIF-1␣ activation (dominant-negative HIF-1␣) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3␣ (an HIF-1␣ repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1␣ activation; and reduced expression/activity of HIF-3␣, cytochrome c oxidase, and superoxide dismutase-2. Conclusions-FHRs

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published R ESUM ELe programme de lignes directrices de la Soci et e canadienne de cardiologie (SCC) en matière de fibrillation auriculaire (FA) a et e elabor e pour aider les cliniciens à prendre en charge ces patients complexes, ainsi que pour orienter les d ecideurs politiques et les systèmes de soins de sant e sur des questions connexes. La dernière edition

Abstract-The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K ϩ channels, including Kv1.5. The Kv downregulation-induced increase in [K ϩ ] i , tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H 2 O 2 , which regulate vascular tone by activating K ϩ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, PϽ0.002), PA medial thickness (28% decrease, PϽ0.0001), and right ventricular hypertrophy (34% decrease, PϽ0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H 2 O 2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondriadependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH. Key Words: apoptosis Ⅲ proliferation Ⅲ smooth muscle Ⅲ vascular remodeling P ulmonary arterial hypertension (PAH) is defined by an elevated pulmonary vascular resistance (PVR), which leads to right heart failure and premature death. The cause remains unknown and available treatments are limited, expensive, and often associated with significant side effects. 1,2 The pulmonary arteries (PAs) are affected by varying degrees of vasoconstriction and vascular remodeling, including cellular proliferation in both the intima and media and distal PA muscularization. 1,2 Vascular medial remodeling results from an imbalance between smooth muscle cell (SMC) proliferation and apoptosis, favoring proliferation. Gene microarray studies show that lungs from patients with PAH have a decrease in the proapoptotic/antiapoptotic gene expression ratio. 3 Furthermore, several loss-of-function germline or acquired mutations have been described in receptors of the transforming growth factor-␤) superfamily, such as bone morphogenetic protein receptor-2 (BM...

Pulmonary arterial hypertension (PAH) is characterized by genetic and acquired abnormalities that suppress apoptosis and enhance cell proliferation in the vascular wall, including downregulation of the bone morphogenetic protein axis and voltage-gated K + (Kv) channels. Survivin is an "inhibitor of apoptosis" protein, previously thought to be expressed primarily in cancer cells. We found that survivin was expressed in the pulmonary arteries (PAs) of 6 patients with PAH and rats with monocrotaline-induced PAH, but not in the PAs of 3 patients and rats without PAH. Gene therapy with inhalation of an adenovirus carrying a phosphorylationdeficient survivin mutant with dominant-negative properties reversed established monocrotaline-induced PAH and prolonged survival by 25%. The survivin mutant lowered pulmonary vascular resistance, RV hypertrophy, and PA medial hypertrophy. Both in vitro and in vivo, inhibition of survivin induced PA smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of WT survivin, both in vivo and in vitro. Inhibition of the inappropriate expression of survivin that accompanies human and experimental PAH is a novel therapeutic strategy that acts by inducing vascular mitochondria-dependent apoptosis. IntroductionPulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature, defined by an elevated pulmonary vascular resistance (PVR), which eventually leads to right heart failure and premature death. The cause remains unknown, and available treatments are limited, expensive, and often associated with significant side effects (1). In PAH, the pulmonary arteries (PAs) manifest pathological proliferative vascular remodeling that includes cellular proliferation in both the intima and the media and muscularization of the normally thin-walled distal PAs (1). Endothelial dysfunction results in an increase in the ratio of endothelial-derived vasoconstrictors to vasodilators. This imbalance has been the basis of therapies over the past several years; for example, exogenous delivery of vasodilating prostaglandins or blockade of the endothelin axis. However, less that 10% of the patients respond to selective pulmonary vasodilators. While vasoconstriction contributes, especially early in PAH, the obstructive vascular remodeling is the major cause of the elevated PVR and ultimately the right heart failure, which in turn accounts for the 50% 5-year mortality in this disease (1). There is now a shift in the interest of the scientific community, focusing on therapies aiming to reverse the proliferative remodeling in PAH (2).

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Background-Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K ϩ channels (Kv) in pulmonary artery (PA) smooth muscle cells (SMCs) and a shift in cellular redox balance toward a reduced state. We hypothesized that dichloroacetate (DCA), a metabolic modulator that can shift redox balance toward an oxidized state and increase Kv current in myocardial cells, would reverse CH-PHT. Methods and Results-We studied 4 groups of rats: normoxic, normoxicϩDCA (DCA 70 mg · kg Ϫ1 · d Ϫ1 PO), chronically hypoxic (CH), and CHϩDCA. CH and CHϩDCA rats were kept in a hypoxic chamber (10% FiO 2 ) for 2 to 3 weeks. DCA was given either at day 1 to prevent or at day 10 to reverse CH-PHT. We used micromanometer-tipped catheters and measured hemodynamics in closed-chest rats on days 14 to 18. CHϩDCA rats had significantly reduced pulmonary vascular resistance, right ventricular hypertrophy, and PA remodeling compared with the CH rats. CH inhibited I K , eliminated the acute hypoxia-sensitive I K , and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 mol/L) increased I K in CH-PASMCs. In a mammalian expression system, DCA activated Kv2.1 by a tyrosine kinase-dependent mechanism. When given long-term, DCA partially restored I K and Kv2.1 expression in PASMCs without altering right ventricular pyruvate dehydrogenase activity, suggesting that the beneficial effects of DCA occur by nonmetabolic mechanisms. Conclusions-DCA both prevents and reverses CH-PHT by a mechanism involving restoration of expression and function of Kv channels. DCA has previously been used in humans and may potentially be a therapeutic agent for pulmonary hypertension. (Circulation. 2002;105:244-250.)