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In the hypertrophic heart the myostructural afterload in the form of endoepicardial networks is predominant, which enhances myocardial hypertrophy. The intrinsic antagonism is derailed. Likewise, the connective tissue scaffold, i.e. the stromatogenic afterload, is enriched in the response to the derailment of antagonism in a hypertrophic heart up to regional captivation of the heart musculature. Due to the selective susceptibility of the auxotonic, contracting oblique transmural myocardial network for low dose negative inotropic medication, this promises to attenuate progress in myocardial hypertrophy. Volume reduction surgery is most effective in reducing wall stress as long as the myocardium is not critically fettered by fibrosis. The use of external mechanical circulatory support is then effective if the heart is supported in its resting mode, which means around a middle width and at minimal amplitude of motion. The takotsubo cardiomyopathy might possibly reflect an isolated, extreme stimulation of the intrinsic antagonism as a response to hormonally induced sensitization of the myocardium to catecholamine. A particular significant conclusion with respect to the diseased heart is that clinical diagnostics need new impulses with a focus on the analysis of local motion patterns and on myocardial stiffness reflecting disease-dependent antagonistic intensity. This would become a relevant diagnostic marker if corresponding (noninvasive) measurement techniques would become available.

In the tradition of Harvey and according to Otto Frank the heart muscle structure is arranged in a strictly tangential fashion hence all contractile forces act in the direction of ventricular ejection. In contrast, morphology confirms that the heart consists of a 3-dimensional network of muscle fibers with up to two fifths of the chains of aggregated myocytes deviating from a tangential alignment at variable angles. Accordingly, the myocardial systolic forces contain, in addition to a constrictive also a (albeit smaller) radially acting component. Using needle force probes we have correspondingly measured an unloading type of force in a tangential direction and an auxotonic type in dilatative transversal direction of the ventricular walls to show that the myocardial body contracts actively in a 3-dimensional pattern. This antagonism supports the autoregulation of heart muscle function according to Frank and Starling, preserving ventricular shape, enhances late systolic fast dilation and attenuates systolic constriction of the ventricle wall. Auxotonic dilating forces are particularly sensitive to inotropic medication. Low dose beta-blocker is able to attenuate the antagonistic activity. All myocardial components act against four components of afterload, the hemodynamic, the myostructural, the stromatogenic and the hydraulic component. This complex interplay critically complicates clinical diagnostics. Clinical implications are far-reaching (see Part II, https://doi.org/10.1007/s00059-018-4735-x).

Background: Prolonged apnea by breath-hold (BH) divers leads to hypoxemia and compensatory mechanisms of the cardiovascular system (i.e. increase of total peripheral resistance, increase of systolic blood-pressure, left-ventricular enlargement) to maintain oxygen supply to oxygen sensitive organs such as the brain. All these changes may result in structural myocardial or subclinical brain alterations. Therefore, the aim of this study was to investigate mid-term effects of repetitive prolonged apnea using cardiac magnetic resonance imaging (CMR) and magnetic resonance imaging of the brain., Materials and Methods: 17 elite BH divers (15 males) were investigated at baseline, from whom 9 (7 males) were investigated again at follow-up one year later. CMR included functional imaging and tissue characterization using T1- and T2-mapping as well as late gadolinium enhancement. Results were compared intra-individually and with 50 age matched controls., Results: Mean BH time were 297 ± 52 s (entire cohort) and 315 ± 56 s (sub-cohort) at initial, and 334 ± 104 s at follow-up examination. Apnea resulted in a progressive increase of the left ventricle and impaired function, whichfully resolved after cessation of apnea. At rest, no dilation of the left ventricle was notable (LV-EDV: 106.7 ± 28.8 ml; LV-EDV/BSA: 52.2 ± 12.7 ml/m 2 ). Compared to controls, the apnea group showed significantly lower volumes (LV-EDV: 106.7 ± 28.8 ml vs. 140.9 ± 36.3 ml, p = .008; LV-EDV/BSA: 52.2 ± 12.7 ml/m 2 vs. 73.7 ± 12.8 ml/m 2 ). In contrast, LV-EF showed no significant differences between both groups (61.0 ± 7.0% vs. 60.9 ± 3.6%). T1- and T2-mapping revealed no significant differences, neither intra-individually nor in comparison with age matched controls. (T1 pre-contrast: 974.1 ± 12.9 ms vs. 969.4 ± 29.0 ms, p = .2; T1 post-contrast: 368.9 ± 38.5 ms vs. 966.7 ± 40.5 ms, p = .4; ECV: 29.2 ± 1.5% vs. 29.8 ± 1.6%, p = .3; T2. 52 ± 2 ms vs. 52 ± 3 ms; p = .4). Except for one old embolic lesion no structural changes were found in brain imaging., Conclusion: Although, prolonged apnea leads to impressive adaptions of the cardiovascular system (i.e. dilation of the left ventricle) and hypertension due to peripheral vasoconstriction no mid-term morphological changes could be observed in both, the myocardium and the brain. BH divers are suitable as a model to investigate acute physiological changes of prolonged apnea and hypoxemia, but not as a model for chronic alterations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Numerous studies report gender differences in emotional reactivity in health and disease and the perception of odors is closely linked to the limbic system. In order to investigate gender differences in the emotional perception of odors we extended the Sniffin' Stick Test with analogue rating scales for hedonic (pleasantness/unpleasantness) and intensity estimates. We matched 172 healthy subjects (86 females and 86 males) on age in order to balance the study population for three age strata (A: 19-39 years, B: 40-59, C: 60 years and above). Overall odors in our statistical analysis demonstrated significant gender differences for the absolute hedonic estimates but not for the relative hedonic and not for the intensity estimates. These findings demonstrate that women evaluate the pleasantness of perceived odors in a more extreme manner than men without significant differences in hedonic polarity (pleasantness/unpleasantness). Thus, we report a singular significant effect of gender on the dimension valence (hedonic estimation) independent from the dimension intensity. Our findings are in accordance with gender differences in facial reactivity to auditory stimuli and differences in the evaluation of emotional pictures. Investigating olfactory sensitivity females detected n-butanol and discriminated the 16 odors of the test significantly better than males. These results indicate that females possess higher olfactory sensitivity.

An earlier study in humans comparing the olfactory sensitivity of both nostrils revealed a small but significant advantage of the right nostril for detection and for olfactory quality discrimination. However lateralization was not evaluated for the perception of odor intensity and hedonic evaluation (pleasantness/unpleasantness). Thus we investigated lateralization of olfactory intensity and hedonic evaluation in right-handed healthy volunteers (n=186) from the HeDoS-F database (Hedonic Database of Smell-Franconia). For olfactory evaluation the Sniffin' Stick Test was employed with the parameters detection, discrimination, identification and extended by analogue hedonic and intensity rating scales. Over all odors subjects rated the perceived intensity significantly higher following stimulation of the right compared to the left nostril. The analysis of the single odors of the Sniffin' Stick Test consistently confirmed higher intensity ratings for the right compared to the left nostril reaching a statistically significant difference for 10 out of 16 odors. In contrast we found no significant differences between the nostrils for the hedonic estimates over all odors. Differences in odor detection, discrimination and identification did not reach a statistically significant level, but for all these parameters the scores of the right nostril were slightly higher compared to the left nostril. For odor identification, however, a statistical tendency was observed. Based on our results we concluded that olfactory intensity estimates represent the most sensitive parameter of olfactory lateralization.

Cytochrome P450 CYP2D6 represents an extensively characterized polymorphic drug-metabolizing enzyme. The CYP2D6-gene is highly polymorphic and more than 70 different alleles are known currently. The activity of the enzyme markedly varies among individuals from poor to intermediate and extensive up to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. Association studies provide growing evidence for the clinical importance of the CYP2D6 polymorphism investigating whether the CYP2D6 genotype distribution differs from that of the normal population either in patients with marked adverse effects or in nonresponders during treatment with CYP2D6 substrates. However, these scientifically important studies present less information for dose adjustments necessary to individualize pharmacotherapy in a given clinical case. With respect to psychopharmacological drug metabolism several antidepressants were characterized as being CYP2D6 substrates. Thus, this review summarizes dose recommendations of current antidepressants.

Nicotine presented to the nasal cavity at low concentrations evokes 'odorous' sensations, and at higher concentrations 'burning' and 'stinging' sensations. A study in smokers and nonsmokers provided evidence of a relationship between the experience with the pharmacological action of S-(-)-nicotine and the perceived pleasantness/unpleasantness following nasal stimulation with S-(-)-nicotine. Mecamylamine, a nicotinic acetylcholine-receptor-(nAch-R) antagonist, was able to block painful responses following chemical stimulation of the human tongue and to block responses from the rat's ethmoidal nerve. The aim of our study in humans was to investigate the effects of mecamylamine on the olfactory and the trigeminal chemoreception of nicotine enantiomers. In order to achieve this aim, we determined-before and after mecamylamine-(1) detection thresholds, trigeminal thresholds, and intensity estimates (stimulus intensity) and (2) recorded the negative mucosal potential (NMP) following nasal stimulation with nicotine in a placebo-controlled double blind study (n = 15). CO(2) was used as a trigeminal and H(2)S as an olfactory control stimulus. Mecamylamine significantly increased trigeminal thresholds of S-(-)-nicotine and reduced intensity estimates and NMPs following stimulation with nicotine enantiomers, whereas mecamylamine did not influence NMPs and trigeminal intensity estimates following stimulation with CO(2). In contrast, mecamylamine did neither influence detection thresholds nor olfactory intensity estimates following stimulation with olfactory nicotine concentrations. These results demonstrate that the trigeminal nasal chemoreception of nicotine enantiomers, in contrast to CO(2), is mediated by nAch-Receptors and give evidence that the olfactory chemoreception of nicotine is independent from peripheral nAch-Receptors.

Objective: Treatment with antidepressants is frequently associated with adverse effects or insufficient clinical response. Several antidepressants are metabolized by cytochrome P450 (CYP) 2D6. The activity of this enzyme markedly varies among individuals from poor to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. This association study investigated whether the CYP2D6 genotype distribution differs from that of the German white population either in patients with marked adverse effects or in nonresponders during treatment with antidepressants metabolized by CYP2D6., Methods: By use of a retrospective, naturalistic approach, outpatient practices and hospitals in southern Germany were asked to report on patients who either had had adverse drug effects or were nonresponsive during treatment with CYP2D6-dependent antidepressants. CYP2D6 genotyping was performed by a panel of polymerase chain reaction techniques. Poor and intermediate metabolizer alleles, as well as allelic duplications of CYP2D6, were detected., Results: Of 28 patients with adverse effects during treatment with a CYP2D6-dependent antidepressant, 8 (29%) had 2 inactive alleles and thus were poor metabolizers. This is a 4-fold increase as compared with the German population (P <.0001). Amplification of fully functional alleles (associated with ultrarapid metabolism) was found in 3 (19%) of the 16 nonresponders (approximately 5.0-fold higher in nonresponders than in the population) (P =.0012)., Conclusion: The results suggest that the CYP2D6 genotype is associated with the occurrence of adverse effects and clinical nonresponse in psychiatric patients treated with CYP2D6-dependent antidepressants.