Balloon pulmonary angioplasty under awake veno-arterial extracorporeal membrane oxygenation in a patient with class III obesity with chronic thromboembolic pulmonary hypertension complicated with multiple serious comorbidities.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic disease that can rapidly deteriorate into circulatory collapse when complicated by comorbidities. We herein describe a case involving a 43-year-old woman with class III obesity (body mass index of 63 kg/m2) and severe CTEPH associated with total occlusion of the left main pulmonary artery who subsequently developed circulatory collapse along with multiple comorbidities, including acute kidney injury, pulmonary tuberculosis, and catastrophic antiphospholipid syndrome. The patient was successfully treated with two sessions of rescue balloon pulmonary angioplasty with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support under local anesthesia without sedation, at cannulation and during the V-A ECMO run, to avoid invasive mechanical ventilation. This case suggests the potential usefulness of rescue balloon pulmonary angioplasty under awake V-A ECMO support for rapidly deteriorating, inoperable CTEPH in a patient with class III obesity complicated with multiple comorbidities.

Balloon Pulmonary Angioplasty for Takayasu Arteritis and Peripheral Pulmonary Artery Stenosis Mimicking Chronic Thromboembolic Pulmonary Hypertension.

Balloon pulmonary angioplasty (BPA) has been reported to be effective and safe to an acceptable level in patients with distal-type, inoperable chronic thromboembolic pulmonary hypertension (CTEPH), resulting in improved long-term survival. However, evidenced treatment options and strategy including medical therapy of antithrombotic therapy, glucocorticoids, immunosuppressants, and pulmonary hypertension (PH)-specific therapies are scarce in patients with significant PH and right heart failure associated with Takayasu arteritis and peripheral pulmonary artery stenosis, both of which mimic CTEPH. Moreover, there has been still concern on safety and lack of established methodology in performing BPA for these conditions. In this report, we would like to review recent publications including several case reports and discuss the efficacy, safety, and suitable methods of BPA in this population.

Asymptomatic takotsubo syndrome occurring during Holter monitoring.

Asymptomatic takotsubo syndrome was observed during periodic Holter monitoring in a man in his 60s undergoing maintenance dialysis. No emotional or physical stress was noticed. The electrocardiographic changes at onset were determined, and repeated ST elevation and progressive formation of giant negative T waves were recorded.

Genetic correction using engineered nucleases for gene therapy applications.

Genetic mutations in humans are associated with congenital disorders and phenotypic traits. Gene therapy holds the promise to cure such genetic disorders, although it has suffered from several technical limitations for decades. Recent progress in gene editing technology using tailor-made nucleases, such as meganucleases (MNs), zinc finger nucleases (ZFNs), TAL effector nucleases (TALENs) and, more recently, CRISPR/Cas9, has significantly broadened our ability to precisely modify target sites in the human genome. In this review, we summarize recent progress in gene correction approaches of the human genome, with a particular emphasis on the clinical applications of gene therapy.

Mutational analysis of Kir6.1 in Japanese patients with coronary spastic angina.

The etiology of coronary spastic angina (CSA) remains uncertain. Mice lacking the gene encoding the inwardly rectifying K(+) channel Kir6.1 were developed as an animal model of CSA. We investigated whether mutation in the coding region of the Kir6.1 gene is detected in Japanese patients with CSA. The study population included 19 Japanese patients with CSA (10 men and 9 women with a mean age of 61+/-14 years). Mutational analysis of the coding region of Kir6.1 was performed by direct sequencing. We found no missense or nonsense mutations in these samples, but we found in one female CSA patient, a single base substitution (C to T) at nucleotide position 111 in exon 2 of the coding region, which was heterozygous and did not cause amino acid substitution (Ile37Ile, silent mutation). In the remaining 18 patients, no base substitution was detected in the coding region of the Kir6.1 gene. No mutation that alters primary structure of Kir6.1 was detected in Japanese patients with CSA. The results indicate that abnormality in the primary structure of Kir6.1 may not be involved in the genetic pathogenesis of CSA in humans.

Circulating coupling factor 6 in human hypertension: role of reactive oxygen species.

OBJECTIVE: Coupling factor 6 is an endogenous inhibitor of prostacyclin synthesis and might function as an endogenous vasoconstrictor in the fashion of a circulating hormone in rats. We investigated the role of coupling factor 6 in human hypertension. METHODS AND RESULTS: The patients with essential hypertension (EH) (n = 30) received a series of normal salt diet (12 g salt/day) for 3 days, low salt diet (2 g salt/day) for 7 days, and high salt diet (20-23 g salt/day) for 7 days. Normotensive control subjects (n = 27) received normal and low salt diets. The plasma level of coupling factor 6, measured by radioimmunoassay, during normal salt diet was higher in patients with EH than in normotensive subjects (17.6 +/- 1.7 versus 12.8 +/- 0.5 ng/ml, P < 0.01). Whereas the plasma level of coupling factor 6 was unchanged after salt restriction in normotensive subjects, it was decreased after salt restriction (from 12 g/day to 2 g/day) and was increased after salt loading (from 2 g/day to 20-23 g/day) in patients with EH. This increase in plasma level of coupling factor 6 was abolished by oral administration of ascorbic acid, but the level of blood pressure was unaffected. The percentage changes in plasma coupling factor 6 level after salt restriction and loading were positively correlated with those in mean blood pressure (r = 0.57, P < 0.01), and negatively correlated with those in plasma nitric oxide level (r = -0.51, P < 0.05). CONCLUSION: These indicate that circulating coupling factor 6 is elevated in human hypertension and modulated by salt intake presumably via reactive oxygen species.

Phospholipase C activity is enhanced in skin fibroblasts obtained from patients with essential hypertension.

OBJECTIVES: In human hypertension, the response of phospholipase C (PLC) to stimuli is enhanced in signal transduction where receptors are coupled to pertussis toxin-sensitive G protein. We investigated PLC activity and its role in human hypertension. METHODS AND RESULTS: Skin fibroblasts were cultured from 15 normotensives subjects (53 +/- 4 years, four men and 11 women) and 19 essential hypertension (EH) patients (58 +/- 2 years, nine men and 10 women). Plasma membrane PLC activity, assessed by conversion of the tritiated exogenous phosphatidylinositol-4,5-bisphosphate to inositol trisphosphate, was greater in EH patients than in normotensive subjects (1.4 +/- 0.2 versus 0.7 +/- 0.1 pmol/mg protein/min, P <0.05). There was a positive correlation between PLC activity and mean blood pressure measured at admission and 7 days after admission (r = 0.47 and 0.37 respectively, both P <0.05). The value of the Michaelis constant was lower in EH patients than in normotensive subjects (32.1 +/- 5.6 versus 58.3 +/- 10.0 micromol/l, P <0.05), despite the fact that maximal velocity of the reaction was no different. Western blot analysis against PLC beta2 and beta3, gamma, delta1, and G protein gamma2 and gamma5 revealed that most PLC and G protein isoforms detected were delta1 of PLC and gamma2 of G protein, and no difference was detected in their amount between two groups. CONCLUSIONS: We conclude that enhanced PLC delta1 activity may be involved in the pathogenesis of human hypertension.

Enhanced activities and gene expression of phosphodiesterase types 3 and 4 in pressure-induced congestive heart failure.

Phosphodiesterase (PDE) was shown to be downregulated in the failing hearts of transplant recipients, while it was upregulated in hypertrophied hearts induced by isoproterenol and calsequesterin overexpression. We examined the time course of gene expression and the activity of PDE3 and PDE4 in an animal model of salt-induced hypertension, left ventricular hypertrophy, and congestive heart failure (CHF). Dahl salt-sensitive (DS, n = 25) and salt-resistant rats (DR, n = 25) were fed with an 8% NaCl diet after the age of 6 weeks. At 11 weeks (hypertension and hypertrophy stage in DS), PDE4 activity in the heart was higher in DS than in DR. At 18 weeks (hypertension and CHF stage in DS), both PDE3 and PDE4 activity in both the heart and aorta was approximately twofold higher in DS than in DR. The ratios of PDE3 and PDE4 mRNA to GAPDH mRNA in the heart were both approximately twofold higher in DS than in DR at 11 and 18 weeks. The cardiac cyclic adenosine monophosphate content and plasma nitric oxide concentration were higher in DS than in DR at 11 weeks but both of them were lower in DS than in DR at 18 weeks of age. In this animal model, gene expressions of PDE3 and PDE4 were augmented from the hypertrophic stage. PDE3 and PDE4 activities were subsequently enhanced in the CHF stage and seemed to contribute to the development and exacerbation of CHF.

Enhanced activity of variant phospholipase C-delta1 protein (R257H) detected in patients with coronary artery spasm.

BACKGROUND: We recently demonstrated that phospholipase C (PLC)-delta1 activity in cultured skin fibroblasts obtained from patients with coronary spastic angina (CSA) is enhanced. We tested the hypothesis that structural abnormality in PLC-delta1 isoform is a cause of the enhanced activity. METHODS AND RESULTS: Sequence analysis of the cDNA coding for PLC-delta1 obtained from fibroblasts revealed that one conversion of guanine to adenine (A) was present at nucleotide position 864 in one CSA patient, resulting in the amino acid replacement of arginine 257 by histidine (R257H). The incidence of 864A/A in genomic DNA, analyzed by single-strand conformation polymorphism, was greater in patients with CSA than in male control subjects (6 of 57 patients with CSA versus 1 of 62 control subjects, P<0.05). The activity of the variant PLC-delta1 protein under free calcium concentration between 10(-8) and 10(-7) mol/L was 2-fold higher than that of the wild-type protein. Baseline intracellular calcium concentration ([Ca2+]i) in human embryonic kidney 293 cells transfected with the variant PLC-delta1 was higher than that in cells with the wild type. The peak increase in [Ca2+]i in response to acetylcholine at 10(-6) and 10(-5) mol/L was greater in the cells with the variant PLC-delta1 than in those with the wild type. CONCLUSIONS: These findings indicate that the R257H variant in the PLC-delta1 gene detected in patients with CSA is associated with enhancement of enzyme activity, and they describe a novel mechanism for the enhanced coronary vasomotility in CSA.