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•Dietary cyanide poisoning and protein malnutrition are major risk factors of konzo.•Thiocyanate may underestimate the level of cyanide poisoning in konzo patients.•Konzo etiopathogenesis probably results from an interplay of multiple factors.•Geo-environmental and psycho-emotional factors are plausible determinants of konzo.•New insights on the etiology of konzo are raised, but more are still needed.

Traditionally the heart is considered a terminally differentiated organ. However, at the beginning of this century increased mitotic activity was reported in ischemic and idiopathic dilated cardiomyopathy hearts, compared to healthy controls, underscoring the potential of regeneration after injury. Due to the presence of adult stem cells in bone marrow and their purported ability to differentiate into other cell lineages, this cell population was soon estimated to be the most suited candidate for cardiac regeneration. Clinical trials with autologous bone marrow-derived mononuclear cells, using either an intracoronary or direct intramyocardial injection approach consistently showed only minor improvement in global left ventricular ejection fraction. This was explained by their limited cardiomyogenic differentiation potential. To obtain more convincing improvement in cardiac function, based on true myocardial regeneration, the focus of research has shifted towards resident cardiac progenitor cells. Several isolation procedures have been described: the c-kit surface marker was the first to be used, however experimental research has clearly shown that c-kit+ cells only marginally contribute to regeneration post myocardial infarction. Sphere formation was used to isolate the so-called cardiosphere derived cells (CDC), and also in this cell population cardiomyogenic differentiation is a rare event. Recently a new type of stem cells derived from atrial tissue (cardiac atrial stem cells – CASCs) was identified, based on the presence of the enzyme aldehyde dehydrogenase (ALDH). Those cells significantly improve both regional and global LV ejection fraction, based on substantial engraftment and consistent differentiation into mature cardiomyocytes (98%).

L-type calcium channel (LTCC) and NaCa2exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics.

Introduction:Although doxorubicin (DOX) is an efficient anthracycline agent used to treat cancer, it induces cardiotoxicity and mortality in cancer survivors. Cardioprotection is inadequate. The vitamin B6-derivative pyridoxamine (PM) has shown to be cardioprotective in diverse cardiac diseases. Whether PM offers cardioprotection after DOX treatment is unknown. We hypothesized that PM limits cardiac impairment after DOX treatment by reducing cardiac fibrosis and inflammation.Methods:Female Sprague Dawley rats were weekly treated with 2 mg/kg DOX or saline IV for 8 weeks. At DOX treatment onset, 2 extra groups received PM (1 g/L) via the drinking water. Echocardiographic (4D) and hemodynamic parameters were assessed at week 8, together with plasma BNP. PCR analysis was performed on left ventricular tissue to evaluate fibrosis and inflammation. Data were compared using 1-way ANOVA, Kruskal-Wallis test or 2-way ANOVA with post-hoc tests as appropriate.Results:As shown in Table 1, cardiac impairment by DOX was prevented by PM. In addition, DOX significantly increased the expression of fibrosis markers, such as TGFβ (0.29 ± 0.02 vs. 0.69 ± 0.09 a.u., p<0.0001), LOX (0.055 ± 0.002 vs. 0.590 ± 0.174 a.u., p<0.01), collagen type 1 (0.21 ± 0.02 vs. 0.62 ± 0.11 a.u., p<0.001) and interstitial collagen (4.6 ± 0.3 vs. 7.7 ± 0.6%, p<0.001). DOX also increased the inflammation marker IL-6 (0.13 ± 0.03 vs. 0.73 ± 0.13 a.u., p<0.01). PM treatment significantly lowered all these parameters (p<0001, p<0.001, p<0.01, p<0.01 and p<0.01 respectively).Conclusions:In conclusion, our data show that DOX causes dilated cardiomyopathy with reduced ejection fraction, accompanied by cardiac fibrosis and myocarditis. As PM limits this adverse phenotype, it could be a novel cardioprotective strategy for DOX-treated cancer patients.

Smads are intracellular signaling proteins that transduce signals elicited by members of the transforming growth factor (TGF)-β superfamily. Smad5 and Smad1 are highly homologous, and they mediate primarily bone morphogenetic protein (Bmp) signals. We used the Cre-loxPsystem and Sm22-Creand Tie-1-Cremice to study the function of Smad5 in the developing blood vessel wall. Analysis of embryos demonstrated that deletion of Smad5in endothelial or smooth muscle cells resulted in a normal organization of embryonic and extra-embryonic vasculature. Angiogenic assays performed in adult mice revealed that mutant mice display a comparable angiogenic and vascular remodeling response to control mice. In Sm22-Cre;Smad5fl/−mice, Smad5is also deleted in cardiomyocytes. Echocardiographic analysis on those 9-month-old female mice demonstrated larger left ventricle internal diameters and decreased fractional shortening compared with control littermates without signs of cardiac hypertrophy. The decreased cardiac contractility was associated with a decreased performance in a treadmill experiment. In isolated cardiomyocytes, fractional shortening was significantly reduced compared with control cells. These data demonstrate that restricted deletion of Smad5in the blood vessel wall results in viable mice. However, loss of Smad5 in cardiomyocytes leads to a mild heart defect.

KB130015 [KB; 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran] is a novel amiodarone derivative designed to retain the antiarrhythmic effects without the side effects. Unlike amiodarone, KB slows Na(+) current inactivation and could, via an increase in [Na(+)](i), potentially lead to Ca(2+) overload. Therefore, we studied the effects of KB on Na(+) and Ca(2+) handling in single pig ventricular myocytes using the whole-cell ruptured patch-clamp technique and K(5)fluo-3 as [Ca(2+)](i) indicator. KB at 10 muM did not prolong action potential duration but slightly increased the early plateau; spontaneous afterdepolarizations were not observed. The amplitude of the [Ca(2+)](i) transient was larger (434.9 +/- 37.2 versus 326.8 +/- 39.8 nM at baseline, n = 13, P < 0.05), and the time to peak [Ca(2+)](i) was prolonged. During voltage-clamp pulses, [Ca(2+)](i) transient peak was also larger (578.1 +/- 98.9 versus 346.4 +/- 52.6 nM at baseline, P < 0.05). Although L-type Ca(2+) current was reduced (by 21.9% at +10 mV, n = 9, P < 0.05), sarcoplasmic reticulum Ca(2+) content was significantly enhanced with KB. Forward Na(+)/Ca(2+) exchange was significantly decreased after KB application, but reverse mode of the Na(+)/Ca(2+) exchanger was significantly larger, suggesting an increase in [Na(+)](i) with KB. This was confirmed by a 2-fold increase of the [Na(+)]-dependent current generated by the Na/K-ATPase (from 0.17 +/- 0.02 to 0.38 +/- 0.06 pA/pF, P < 0.05). In conclusion, as predicted from the slowing of I(Na) inactivation, KB130015 leads to an increase in [Na(+)](i) and consequently in cellular Ca(2+) load. This effect is partially offset by a decrease in I(CaL) resulting in a mild inotropic effect without the signs of Ca(2+) overload and related arrhythmias usually associated with Na(+) channel openers.

The effect of ruthenium red on calcium and sodium currents was studied in guinea‐pig isolated ventricular heart cells with the whole cell patch‐clamp technique.Ruthenium red very efficiently blocked the L‐type calcium current in a dose‐dependent manner. A significant block was observed for concentrations as low as 0.3 μM. Analysis of the dose‐response curve with the logistic equation indicated an EC50of 0.8 μM, a maximum inhibition of 85% reached at 5 μM, and a coefficient of 2.37.There was no shift in the voltage‐dependence of the Ca current activation, nor in that of its steady‐state inactivation determined with a 1 s prepulse. However, removal of Ca current inactivation at positive voltage was considerably reduced in the presence of concentrations of ruthenium red above 1 μM. A slowing of the time‐course of inactivation of the Ca current was also observed.At 10 μM, a concentration generally used to block the sarcoplasmic Ca release channels or the mitochondrial Ca uptake, ruthenium red blocked 26.7±4.3% (n=8) of the sodium current, and slowed its inactivation time‐course. No effect was observed on the voltage‐dependence of the current activation or inactivation. The peak sodium current was also decreased at a 10 times lower concentration by 7.6±2.7% (n=3).Thus, at concentrations used to assess intracellular Ca movements, ruthenium red induced in heart cells a significant block of both Ca and Na channels.

Cardiovascular diseases and exercise intolerance elevate mortality in type 1 diabetes mellitus (T1DM). Left ventricular systolic and diastolic function are already affected in T1DM adolescents displaying poor glycaemic control (A1c>7.5%) and exercise intolerance. We investigated to what extent left ventricular function is affected by disease severity/duration and whether this is related to exercise capacity.

Introduction:Myocardial infarction (MI) is the leading cause of heart failure (HF) worldwide. Current therapies are unable to replace lost cardiac tissue after MI and fail to prevent progression towards HF. Our research group identified a new cardiac stem cell type, the cardiac atrial appendage stem cells (CASCs), with superior cardiomyogenic differentiation potential. Whether CASCs transplantation can prevent loss of cardiac function and adverse cellular remodeling following MI, remains unknown.Methods:Permanent LAD ligation was performed in female Sprague Dawley rats. MI animals were randomly assigned to either CASCs injection (2.5x106? 1x106cells) in the MI border zone (MI+CASCs, n=12) or no injection (MI, n=12) at surgery. SHAM-operated animals served as control (n=10). Four weeks post-surgery, global cardiac function was assessed by conventional echocardiography and hemodynamic measurements. LV single cardiomyocytes were enzymatically isolated from the border zone. Contractile properties of single cardiomyocytes were assessed by unloaded cell shortening at 4Hz. Interstitial collagen deposition was evaluated from cryosections.Results:CASCs transplantation improved LV ejection fraction (86%?3 MI+CASCs vs 58%?5 MI) and reduced the increased end-systolic volume seen in MI (26?l?7 MI+CASCs vs 101?l?20 MI). Anterior wall thickness was normalized in the MI+CASCs group (1.47?0.06 cm vs 1.06?0.08 cm in MI group). Mean LV systolic pressure significantly decreased (32mmHg?2 MI+CASCs vs 45mmHg?2 MI) and dP/dtmaxsignificantly increased after CASCs transplantation (9001 mmHg/s?704 vs 6224 mmHg/s?234 in MI). There was no difference in dP/dtmin. Unloaded cell shortening of single cardiomyocytes from the transplanted group (7.1%?0.5) was improved compared to MI cardiomyocytes (5.4%?0.3). Finally, global cardiac fibrosis tended to be smaller in the MI+CASCs group.Conclusions:CASCs transplantation improves global cardiac function in vivoand prevents adverse cardiomyocyte remodeling after MI. Altogether, this study suggests that CASCs therapy is a promising cellular tool to restore cardiac function after ischemic injury.