Atrial electrical and structural changes associated with longstanding hypertension in humans: implications for the substrate for atrial fibrillation

Atrial Remodeling in Human Hypertension Introduction: Hypertension (HT) is the most common modifiable risk factor for atrial fibrillation (AF), yet little is known of the atrial effects of chronic HT in humans. We aimed to characterize the electrophysiologic (EP) and electroanatomic (EA) remodeling of the right atrium (RA) in patients with chronically treated systemic HT and left ventricular hypertrophy (LVH) without a history of AF. Methods and Results: Twenty patients with (systolic BP 145 ± 10 mmHg) and without (BP 119 ± 11 mmHg, P < 0.01) systemic HT underwent detailed conventional EP and EA voltage and activation mapping. We measured RA refractoriness at the coronary sinus and high septum at cycle lengths (CLs) 600 and 450 ms, and RA conduction velocities, activation times, and voltages at a global and regional level at CLs 600 ms and 300 ms. HT was associated with slowing of global (73 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) and regional conduction velocity particularly in the posterior RA (70 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) at the crista terminalis (fractionation and double potentials in HT 72%± 4 vs 43%± 23 in controls, P = 0.04). Mean RA voltage was similar between the 2 groups, however HT was associated with an increase in areas of low voltage (<0.5 mV; HT 13% vs controls 9%, P = 0.04). Sustained AF was induced in 30% HT patients and no controls. Conclusion: Chronically treated systemic HT with LVH is accompanied by atrial remodeling characterized by: (i) global conduction slowing, (ii) regional conduction delay particularly at the crista terminalis, and (iii) increased AF inducibility. These changes may in part be responsible for the increased propensity to AF associated with systemic HT. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1317‐1324, December 2011)     

Failure of Bay K 8644 to induce RhoA kinase-dependent calcium sensitization in rabbit blood vessels

Background and purpose:

Checkpoint kinase 2 (CHK2) is activated by DNA damage and can contribute to p53 stabilization, modulating growth arrest and/or apoptosis. We investigated the contribution of CHK2 to oxaliplatin-mediated toxicity in a colorectal cancer model.

Experimental approach:

We evaluated the ability of CHK2 small molecule inhibitors to potentiate oxaliplatin-induced toxicity. The role of CHK2 in oxaliplatin-induced apoptosis was investigated in HCT116 cells that were wild-type (WT) or KO for CHK2. Small molecule inhibitors of CHK2 were used in combination studies with oxaliplatin in this cell model.

Key results:

In oxaliplatin-treated CHK2 KO cells, accelerated apoptosis was accompanied by attenuated p53 stabilization and p21^WAF-1 up-regulation correlating with increased Bax expression, cytochrome c release and elevated caspase activity. The higher levels of apoptosis in CHK2 KO cells were restored to control (WT) levels when CHK2 was re-introduced. This ‘uncoupling’ of p53 stabilization and Bax up-regulation in CHK2 KO cells suggested oxaliplatin-induced apoptosis was due to a p53-independent response. Combination studies revealed that CHK2 inhibitor II or debromohymenialdisine antagonized the responses to oxaliplatin. This inhibitory effect correlated with decreases in apoptosis, p53 stabilization and DNA inter-strand cross-link formation, and was dependent on the presence (but not activity) of CHK2.

Conclusions and implications:

Combinations of CHK2 inhibitors with oxaliplatin should further sensitize cells to oxaliplatin treatment. However, these inhibitors produced an antagonistic effect on the response to oxaliplatin, which was reversed on the re-introduction of CHK2. These observations may have implications for the use of oxaliplatin in colorectal cancer therapy in combination with therapies targeting CHK2.     

Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy

Previous reports have established that the telomeric copy of the survival motor neuron (SMNT) gene and the intact copy of the neuronal apoptosis inhibitory protein (NAIP) gene are preferentially deleted in patients with spinal muscular atrophy (SMA). Although deletions or mutations in the SMNT gene are most highly correlated with SMA, it is not clear to what extent NAIP or other genes influence the SMA phenotype, or whether a small fraction of SMA patients actually have functional copies of both SMNT and NAIP. To evaluate further the part of SMNT in the development of SMA, we analyzed 280 asymptomatic SMA family members for the presence or absence of SMNT exons 7 and 8. We report the following observations: (i) 4% of the sample harbored a polymorphic variant of SMNT exon 7 that looks like a homozygous deletion; (ii) approximately 1% of the parents are homozygously deleted for both exons 7 and 8; (iii) one asymptomatic parent lacking both copies of SMNT exons 7 and 8 displays a 'subclinical phenotype' characterized by mild neurogenic pathology; (iv) another asymptomatic parent lacking both SMNT exons showed no signs of motor neuron disorder by clinical and neurodiagnostic analyses. The demonstration of polymorphic variants of exon 7 that masquerade as homozygous nulls, and the identification of SMA parents who harbor two disease alleles, serve as a caution to those conducting prenatal tests with these markers.      

Treatment of classic Kaposi sarcoma with a nicotine dermal patch: a phase II clinical trial

Background  Kaposi sarcoma (KS), a malignancy of dermal endothelial cells that is caused by human herpesvirus 8 (HHV8) infection, is sensitive to perturbations of immunity. Nicotine might be effective against KS because of its immunologic and vascular effects and because smoking is associated with a low risk of KS.
Objective and study design  We conducted a masked, randomized phase 2 clinical trial of transdermal nicotine and placebo patches to assess the safety and efficacy of nicotine against classic KS (cKS).
Subjects and methods  Three cKS lesions, predominantly nodules, in each of 24 non-smoking patients were randomly assigned to 15 weeks continuous treatment with nicotine patch (escalated to 7 mg), identical masked placebo patch or no patch. Changes in lesion area and elevation from baseline through six follow-up visits, by direct measurement and by two independent readers using digital photographs of the lesions, were compared using non-parametric and regression methods. Changes in longitudinal levels of HHV8 antibodies and DNA in blood cells were similarly assessed.
Results  There were no systemic or serious adverse events, and compliance was good. One patient resumed smoking and discontinued patches, and two patients withdrew at week 12 for unrelated indications. Six (29%) of the remaining 21 suspended use of patches to relieve local skin irritation; four of these six completed the trial at reduced dose. Treatment assignment was not associated with significant or consistent changes in cKS lesion area or elevation, HHV8 viral load or antibodies.
Conclusion  Transdermal nicotine and placebo patches caused no serious toxicities but had no demonstrable effect on nodular cKS lesions or HHV8 levels.     

Lymphatic sinusoids exist in chick but not in rabbit choroid

Purpose: Although it is generally thought that lymphatics do not exist in the choroid, there is mounting evidence that lymphatic-like structures do exist in primates and fowl. Methods/Results: Our comparison of the ultrastructure of chick and rabbit outer choroid indicates that major differences exist in the non-vascular areas of the choroid: notably, the chick has large lymphatic sinusoids, whereas the rabbit only has a system of large vacuoles contained within the processes of individual fibroblasts. Conclusions: These results raise questions regarding the similarities or otherwise between species of the management of retinal metabolites, excess tissue fluid and choroidal homeostasis, especially during conditions of overload.