Biopsy-confirmed endothelial cell activation in patients with coronary microvascular dysfunction.

BACKGROUND: Patients with angina yet having unobstructed coronaries are found in ∼50% of cases undergoing invasive angiography. Coronary spasm and microvascular dysfunction can be responsible for the clinical presentation in ∼60% of cases. However, little is known about structural changes in the myocardium. The aim of this study was to describe findings in endomyocardial biopsies of symptomatic patients with unobstructed coronaries. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 1416 consecutive patients who underwent endomyocardial biopsy sampling and coronary angiography between 2002 and 2016 for various clinical indications. Of them, 309 patients had also undergone intracoronary acetylcholine testing (ACH-test). To be eligible for the study, patients had to have normal left ventricular ejection fraction, unobstructed coronaries and absence of viral genomes in the myocardium. RESULTS: Among the final cohort of 33 (70% female, mean age 53) patients, the ACH-test revealed coronary microvascular spasm in 11 (33.3%) patients. Twelve (36.4%) patients had epicardial spasm and 10 (30.3%) had an uneventful ACH-test. Immunohistology revealed activated macrophages in 10 (30%) cases and activated endothelial cells as well as perivascular or interstitial fibrosis in 17 (52%). Myocardial hypertrophy was seen in nine (27%) patients, and smooth muscle cell proliferation was present in 11 (33%) cases. Compared with the rest of the cohort, patients with microvascular spasm significantly more often had activated endothelial cells (P=0.003). CONCLUSION: This study gives unique insights into structural myocardial alterations in patients with angina, unobstructed coronaries and abnormal coronary vasomotion, suggesting that a combination of both structural and functional alterations is frequent.

Integrated functional visualization of eukaryotic genomes.

BACKGROUND: Increasing amounts of data from large scale whole genome analysis efforts demands convenient tools for manipulation, visualization and investigation. Whole genome plots offer an intuitive window to the analysis. We describe two applications that enable users to easily plot and explore whole genome data from their own or other researchers' experiments. RESULTS: STRIPE and GFFtool (General Feature Format Tool) are softwares designed to support integration, visualization and exploration of whole genome data from eukaryotic genomes. STRIPE, in addition to providing a highly customizable and interactive data plot, provides access to numerous well-selected databases with updated information on all genes of a genome. GFFtool provides a user-friendly solution to integrating experimental data with the genomic information available in public databases. They also obviate the need for users to maintain large annotation resources, as they link to well-known resources using standard gene and protein identifiers. CONCLUSION: The programs provide the user with broad genomic overviews of data distribution, fast access to data of interest, and the ability to navigate speedily from one resource to another, and gain a better understanding of result of whole genome analysis experiments.

Influence of waveform and current direction on short-interval intracortical facilitation: a paired-pulse TMS study.

BACKGROUND: Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF). OBJECTIVE/HYPOTHESIS: We examined whether SICF depends on waveform and current direction of the TMS pulses. METHODS: In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior-anterior (PA) or anterior-posterior (AP) current direction (AP-AP or PA-PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA-AP and AP-PA). RESULTS: Monophasic AP-AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA-PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA-AP current orientation compared with AP-PA. CONCLUSION: SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF.

Effects of lamotrigine on human motor cortex plasticity.

OBJECTIVE: Besides its use in epilepsy, lamotrigine (LTG) is also effective as mood stabilizer. The pathophysiology of mood disorders may incorporate a dysfunction of neuronal plasticity and animal experiments suggest that mood stabilizers influence induction of long-term potentiation (LTP) and -depression (LTD), two major forms of synaptic plasticity. However, the exact modes of action of LTG and its impact on neuronal plasticity in humans remain unclear. METHODS: Here, we tested the effects of a single oral dose of LTG (300 mg) on motor cortical plasticity induced by paired associative stimulation (PAS(25)), a protocol that typically induces LTP-like plasticity, in 26 young healthy adults in a placebo-controlled, randomized, double-blind crossover design. We stratified analysis of the LTG effects according to the individual PAS(25) response in the placebo session (14 LTP-responders vs. 12 LTD-responders). Plasticity was indexed by motor evoked potential (MEP) amplitudes recorded before and for 60 min after PAS(25). RESULTS: LTG resulted in a significant reduction of the LTP-like MEP increase in the LTP-responders and a reduction of the LTD-like MEP decrease in the LTD-responders, with the majority of LTD-responders even showing an MEP increase. CONCLUSIONS: In summary, LTG differentially modulated cortical plasticity induced by non-invasive brain stimulation in human subjects depending on their individual intrinsic propensity for expressing LTP-like or LTD-like plasticity. SIGNIFICANCE: Findings contribute to our understanding of the anticonvulsant and antidepressant clinical effects of LTG, which have been suggested to occur, at least in part, through downregulation of LTP (epilepsy) and LTD (depressive disorders).