The clinical impact of late gadolinium enhancement in Takotsubo cardiomyopathy: serial analysis of cardiovascular magnetic resonance images.

BACKGROUND: Our study aimed to investigate both the clinical implications of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) and the relation of LGE to clinical findings in patients with Takotsubo cardiomyopathy (TTC). METHODS: We evaluated 20 consecutive patients (2 men, 18 women; median age, 77 years; interquartile range [IQR] 67-82 years) who were admitted to our hospital with the diagnosis of TTC. CMR was performed within 1 week after admission, and follow-up studies were conducted 1.5 and 6 months later. RESULTS: In 8 patients, CMR imaging during the sub-acute phase revealed LGE in the area matched with wall motion impairment. Cardiogenic shock was more frequently observed in patients with LGE than in those without LGE (38% vs 0%, p = 0.049). The patients with LGE needed a longer duration for ECG normalization and recovery of wall motion than did those without LGE (median 205 days, IQR [152-363] vs 68 days, [43-145], p = 0.005; 15 days, [10-185] vs 7 days, [4-13], p = 0.030, respectively). In 5 of these 8 patients, LGE disappeared within 45-180 days (170, IQR [56-180]) of onset. The patients with LGE remaining in the chronic phase had higher peak creatine kinase levels than did those without LGE (median 307 IU/L, IQR [264-460] vs 202 IU/L, [120-218], p = 0.017). CONCLUSION: LGE by CMR in the sub-acute phase may be associated with the severity and prolonged recovery to normal of clinical findings in TTC.

Efficacy of biolimus A9-eluting stent for treatment of right coronary ostial lesion with intravascular ultrasound guidance: a multi-center registry.

The aim of this study was to assess the efficacy of a biolimus A9-eluting stent in patients with a right coronary artery (RCA) ostial lesion. Ostial lesions of the RCA have been a limitation of percutaneous coronary intervention even in the drug-eluting stent (DES) era. However, clinical outcomes after the deployment of a second generation DES to an RCA ostial lesion with intravascular ultrasound (IVUS) guidance have not been fully elucidated. From September 2011 to March 2013, 74 patients were enrolled in 17 centers from Japan. RCA ostial lesion was defined as de novo significant stenotic lesion located within 15 mm from ostium. IVUS was used for all cases to confirm the location of ostium and evaluate stent coverage of ostium. Patients with hemodialysis were excluded. The primary endpoint is a major adverse cardiac event (MACE) at 1 year. Forty two percent of patients had multi-vessel disease. Angiographically severe calcification was observed in 26% of the lesions. The mean stent diameter was 3.3 ± 0.3 mm (3.5 mm, 72%, 3.0 mm, 25%, and 2.75 and 2.5 mm, 3%), stent length was 17.5 ± 5.8 mm, and dilatation pressure of stenting was 15.6 ± 4.1 atm. RCA ostium was covered by stent in all lesions in IVUS findings. Post dilatation was performed for 64% of lesions (balloon size 3.7 ± 0.6 mm). MACE rate at 1 year was 5.4% (target lesion revascularization 5.4%, myocardial infarction 1.2%, and no cardiac death). The biolimus A9-eluting stent for RCA ostial lesions with IVUS guidance showed favorable results at 1-year follow-up.

Protein kinase A catalytic subunit alters cardiac mitochondrial redox state and membrane potential via the formation of reactive oxygen species.

BACKGROUND: The identification of protein kinase A (PKA) anchoring proteins on mitochondria implies a direct effect of PKA on mitochondrial function. However, little is known about the relationship between PKA and mitochondrial metabolism. METHODS AND RESULTS: The effects of PKA on the mitochondrial redox state (flavin adenine dinucleotide (FAD)), mitochondrial membrane potential (DeltaPsi(m)) and reactive oxygen species (ROS) production were investigated in saponin-permeabilized rat cardiomyocytes. The PKA catalytic subunit (PKAcat; 50 unit/ml) increased FAD intensities by 56.6+/-7.9% (p<0.01), 2'7'-dichlorofluorescin diacetate (DCF) intensities by 10.5+/-3.3 fold (p<0.01) and depolarized DeltaPsi(m) to 48.1+/-9.5% of the control (p<0.01). Trolox (a ROS scavenger; 100 micromol/L) inhibited PKAcat-induced DeltaPsi(m), FAD and DCF alteration. PKAcat-induced DeltaPsi(m) depolarization was inhibited by an inhibitor of the inner membrane anion channel (IMAC), 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS: 1 micromol/L) but not by an inhibitor of mitochondrial permeability transition pore (mPTP), cyclosporine A (100 nmol/L). CONCLUSIONS: PKAcat alters FAD and DeltaPsi(m) via mitochodrial ROS generation, and PKAcat-induced DeltaPsi(m) depolarization was not caused by mPTP but rather by DIDS-sensitive mechanisms, which could be caused by opening of the IMAC. The effects of PKA on mitochondrial function could be related to myocardial function under the condition of extensive beta-adrenergic stimulation.

Non-genomic effects of aldosterone on intracellular ion regulation and cell volume in rat ventricular myocytes.

Aldosterone has non-genomic effects that express within minutes and modulate intracellular ion milieu and cellular function. However, it is still undefined whether aldosterone actually alters intracellular ion concentrations or cellular contractility. To clarify the non-genomic effects of aldosterone, we measured [Na+]i, Ca2+ transient (CaT), and cell volume in dye-loaded rat ventricular myocytes, and we also evaluated myocardial contractility. We found the following: (i) aldosterone increased [Na+]i at the concentrations of 100 nmol/L to 10 micromol/L; (ii) aldosterone (up to 10 micromol/L) did not alter CaT and cell shortening in isolated myocytes, developed tension in papillary muscles, or left ventricular developed pressure in Langendorff-perfused hearts; (iii) aldosterone (100 nmol/L) increased the cell volume from 47.5 +/- 3.6 pL to 49.8 +/- 3.7 pL (n=8, p<0.05); (iv) both the increases in [Na+]i and cell volume were blocked by a Na+-K+-2Cl- co-transporter (NKCCl) inhibitor, bumetanide, or by a Na+/H+ exchange (NHE) inhibitor, 5-(N-ethyl-N-isopropyl) amiloride; and (v) spironolactone by itself increased in [Na+]i and cell volume. In conclusion, aldosterone rapidly increased [Na+]i and cell volume via NKCC1 and NHE, whereas there were no changes in CaT or myocardial contractility. Hence the non-genomic effects of aldosterone may be related to cell swelling rather than the increase in contractility.

Mitochondrial membrane potential modulates regulation of mitochondrial Ca2+ in rat ventricular myocytes.

Although recent studies focused on the contribution of mitochondrial Ca2+ to the mechanisms of ischemia-reperfusion injury, the regulation of mitochondrial Ca2+ under pathophysiological conditions remains largely unclear. By using saponin-permeabilized rat myocytes, we measured mitochondrial membrane potential (DeltaPsi(m)) and mitochondrial Ca2+ concentration ([Ca2+](m)) at the physiological range of cytosolic Ca2+ concentration ([Ca2+](c); 300 nM) and investigated the regulation of [Ca2+](m) during both normal and dissipated DeltaPsi(m). When DeltaPsi(m) was partially depolarized by carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP, 0.01-0.1 microM), there were dose-dependent decreases in [Ca2+](m). When complete DeltaPsi(m) dissipation was achieved by FCCP (0.3-1 microM), [Ca2+](m) remained at one-half of the control level despite no Ca2+ influx via the Ca2+ uniporter. The DeltaPsi(m) dissipation by FCCP accelerated calcein leakage from mitochondria in a cyclosporin A (CsA)-sensitive manner, which indicates that DeltaPsi(m) dissipation opened the mitochondrial permeability transition pore (mPTP). After FCCP addition, inhibition of the mPTP by CsA caused further [Ca2+](m) reduction; however, inhibition of mitochondrial Na+/Ca2+ exchange (mitoNCX) by a Na+-free solution abolished this [Ca2+](m) reduction. Cytosolic Na(+) concentrations that yielded one-half maximal activity levels for mitoNCX were 3.6 mM at normal DeltaPsi(m) and 7.6 mM at DeltaPsi(m) dissipation. We conclude that 1) the mitochondrial Ca2+ uniporter accumulates Ca2+ in a manner that is dependent on DeltaPsi(m) at the physiological range of [Ca2+](c); 2) DeltaPsi(m) dissipation opens the mPTP and results in Ca2+ influx to mitochondria; and 3) although mitoNCX activity is impaired, mitoNCX extrudes Ca2+ from the matrix even after DeltaPsi(m) dissipation.