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The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies.

The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Nitrates may facilitate syncope through various pathways, but the precise mechanism of nitrate-induced syncope is still under debate. The purpose of the present study was to compare the underlying haemodynamic mechanisms in subjects without and with presyncopal symptoms during a nitroglycerin-stimulated tilt-table test. WHAT THIS STUDY ADDS • A major decrease in systemic vascular resistance was documented in subjects with presyncope during 0.25 mg nitroglycerin-stimulated tilt-table test, in the absence of changes in cardiac output. These findings indicated that even a small dose of nitroglycerin significantly decreased arterial resistance and cardiac afterload. AIMS The mechanism of nitrate-induced syncope remains controversial. We examined the haemodynamic changes in healthy volunteers during nitroglycerin-stimulated tilt-table test. METHODS Continuous radial pulse wave analysis, whole-body impedance cardiography and plethysmographic finger blood pressure were recorded in a supine position and during head-up tilt in 21 subjects with presyncopal symptoms (6 male/15 female, age 43 ± 3 years) after 0.25 mg sublingual nitroglycerin and 21 control subjects (6 male/15 female, age 43 ± 2 years). The drug was administered in the supine position and a passive head-up tilt followed 5 min later. Additionally, nitroglycerin was only administered during head-up tilt in 19 subjects and the haemodynamics were recorded. RESULTS Supine and upright haemodynamics were similar before nitroglycerin administration in the two groups. During the nitroglycerin-stimulated tilt test, aortic and radial mean blood pressure decreased significantly more in the presyncope group when compared with the controls (P= 0.0006 and P= 0.0004, respectively). The decreases in systemic vascular resistance (P= 0.0008) and heart rate (P= 0.002), and increase in aortic reflection time (P= 0.0002) were greater in the presyncope group, while the change in cardiac index was not different between the groups (P= 0.14). If nitroglycerin was administered during the upright tilt and not in supine position, the haemodynamic changes were quite corresponding. CONCLUSIONS Presyncopal symptoms during nitrate-stimulated tilt test were explained by decreased systemic vascular resistance and increased aortic reflection time, while cardiac output remained unchanged. These findings indicated reduced arterial resistance in nitroglycerin-induced presyncope.

To non-invasively measure central haemodynamics, arterial stiffness, cardiac function and vascular resistance, with the subject in the supine position and during head-up tilt, in order to examine the haemodynamic changes associated with alterations in the augmentation index, and to investigate repeatability and reproducibility of the measurement protocol.Thirty-three healthy volunteers (21-51 years) were investigated using continuous pulse wave analysis from the radial artery with a tonometric sensor, whole-body impedance cardiography and plethysmographic blood pressure (BP) recordings from the fingers. The measurements were performed with the subject supine and during passive head-up tilt, and repeated during the same session and on four separate days.During the head-up tilt, diastolic BP (5.2+/-0.6%), heart rate (27.6+/-1.9%) and vascular resistance (12.5+/-1.7%) increased (all p0.05), while systolic BP (-3.2+/-0.6%), aortic pulse pressure (-23.3+/-1.4%), augmentation index (-11.6+/-0.7%), aortic reflection time (-7.0+/-1.0%), ejection duration (-21.4+/-0.7%), stroke volume (-26.1+/-1.2%) and cardiac output (-5.0+/-1.5%) decreased (all p0.05). Augmentation index at rest correlated with aortic systolic BP (r = 0.423), aortic reflection time (r = -0.647), pulse wave velocity (r = 0.287) and age (r = 0.480). The change in augmentation index during head-up tilt correlated with the change in aortic systolic BP (r = 0.469), aortic pulse pressure (r = 0.606), ejection duration (r = 0.374) and heart rate (r = -0.445). According to Bland-Altman and repeatability index analyses, repeatability and reproducibility of the measurements were good during the same session and on separate days.Combined pulse wave analysis and impedance cardiography with the subject in the supine position and during head-up tilt is a repeatable and reproducible method for comprehensive investigation of the cardiovascular function.

Background In a cross-sectional study we examined whether the haemodynamic response to upright posture could be divided into different functional phenotypes, and whether the observed phenotypes were associated with known determinants of cardiovascular risk. Methods Volunteers (n = 470) without medication with cardiovascular effects were examined using radial pulse wave analysis, whole-body impedance cardiography, and heart rate variability analysis. Based on the passive head-up tilt induced changes in systemic vascular resistance and cardiac output, the principal determinants of blood pressure, a cluster analysis was performed. Results The haemodynamic response could be clustered into 3 categories: upright increase in vascular resistance and decrease in cardiac output were greatest in the first (+45 % and -27 %, respectively), smallest in the second (+2 % and -2 %, respectively), and intermediate (+22 % and -13 %, respectively) in the third group. These groups were named as ‘constrictor’ (n = 109), ‘sustainer’ (n = 222), and ‘intermediate’ (n = 139) phenotypes, respectively. The sustainers were characterized by male predominance, higher body mass index, blood pressure, and also by higher pulse wave velocity, an index of large arterial stiffness, than the other groups (p

The human MPV17-related mitochondrial DNA depletion syndrome is an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein MPV17. Although more than 30 MPV17 gene mutations were shown to be associated with mitochondrial DNA depletion syndrome, the function of MPV17 is still unknown. Mice deficient in Mpv17 show signs of premature aging. In the present study, we used electrophysiological measurements with recombinant MPV17 to reveal that this protein forms a non-selective channel with a pore diameter of 1.8 nm and located the channel’s selectivity filter. The channel was weakly cation-selective and showed several subconductance states. Voltage-dependent gating of the channel was regulated by redox conditions and pH and was affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17−/− mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.

Background Liquorice ingestion often elevates blood pressure, but the detailed haemodynamic alterations are unknown. We studied haemodynamic changes induced by liquorice consumption in 20 subjects versus 30 controls with average blood pressures of 120/68 and 116/64 mmHg, respectively. Methods Haemodynamic variables were measured in supine position before and after two weeks of liquorice consumption (daily glycyrrhizin dose 290–370 mg) with tonometric recording of radial blood pressure, pulse wave analysis, and whole-body impedance cardiography. Thirty age-matched healthy subjects maintaining their normal diet were studied as controls. Results Two weeks of liquorice ingestion elevated peripheral and central systolic and diastolic blood pressure (by 7/4 and 8/4 mmHg, 95% confidence intervals [CI] 2-11/1-8 and 3-13/1-8, respectively, P ClinicalTrials.gov NCT01742702

OBJECTIVE Hypertension is characterized by increased vascular resistance and arterial stiffness, but information about upright hemodynamics is scarce. We compared hemodynamics in hypertensive versus normotensive patients at rest and during passive head-up tilt. METHODS Volunteers (n = 387, 19-72 years) without antihypertensive medication were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Seated office blood pressure was 4/10 mmHg (systolic/diastolic) higher than average supine values during hemodynamic measurements. As there is no accepted cut-off for hypertension during tilt-table tests, supine level at least 135/85 mmHg defined hypertension (n = 155) versus normotension (n = 232). Age, BMI, and proportion of men were higher among hypertensives (49 vs. 42 years, 28 vs. 25, 55 vs. 38%, respectively), and analyses were adjusted for these differences. RESULTS Both at rest and during head-up tilt radial and aortic blood pressure and pulse pressure, cardiac index (CI) and work, systemic vascular resistance (SVR), and augmentation pressure were higher in hypertensive patients (P

To evaluate the hemodynamic characteristics of metabolic syndrome (MetS) in the absence and presence of hypertension.Altogether 166 subjects without previously diagnosed cardiovascular disease, diabetes, or antihypertensive medication, were allocated to four groups: control, hypertension only, MetS without hypertension, and MetS with hypertension (mean age 44-46 years). Cut-point for hypertension was blood pressure ≥140/90 mmHg. Other criteria of MetS were as defined by Alberti et al. 2009. Hemodynamic variables were measured using whole-body impedance cardiography and pulse wave analysis.Pulse wave velocity was higher in hypertensive and normotensive subjects with MetS than controls (p0.05), and in the hypertensive MetS group than subjects with hypertension only (p0.05). Aortic pulse pressure was higher in the two hypertensive groups than the two normotensive groups (p0.05). Systemic vascular resistance index was higher in the hypertensive than normotensive MetS group (p0.05), and in the group with hypertension alone than in controls (p0.05). Heart rate was higher in the hypertensive Mets group than in controls and subjects with hypertension only (p0.05). Cardiac index did not differ, while stroke index was lower in both groups with MetS than groups without MetS. Augmentation pressure was higher in the hypertensive MetS group than in controls and normotensive MetS group (p0.05).Pulse wave velocity, an acknowledged marker of arterial stiffness, was associated with MetS even in the absence of hypertension. This emphasizes the importance of the prevention and treatment of MetS.

Pulse wave analysis is widely applied to measure the haemodynamic effects of nitroglycerin and salbutamol as an endothelium-independent and endothelium-dependent vasodilator, respectively. The recordings are usually performed in supine position from 10 to 20 successive heartbeats without simultaneous measurement of vascular resistance and cardiac function. Our objective was to examine the effects of nitroglycerin and salbutamol on central haemodynamics, arterial stiffness, cardiac function, and vascular resistance in supine and upright positions.A placebo-controlled, randomized and double-blinded passive head-up tilt protocol was performed after sublingual nitroglycerin (0.25 mg) or inhaled salbutamol (400 μg) in 35 healthy volunteers. Continuous tonometric pulse wave analysis, whole-body impedance cardiography, and plethysmographic finger blood pressure recordings were applied.Nitroglycerin decreased aortic and finger blood pressure, radial DBP, vascular resistance, augmentation index and pulse wave velocity, and increased heart rate, cardiac index, stroke index and aortic reflection time (P 0.030 for all). Salbutamol moderately decreased radial and aortic blood pressure and finger DBP, augmentation index and vascular resistance, but increased heart rate and cardiac index (P 0.030 for all). Almost all of the strong haemodynamic effects of nitroglycerin were emphasized during the head-up tilt, whereas the effects of salbutamol on heart rate and cardiac index were more pronounced in the supine position.The haemodynamic changes induced by nitroglycerin and salbutamol were dependent on body position: the effects of nitroglycerin were accentuated during the head-up tilt, whereas those of salbutamol were more evident in the supine position.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Haemodynamic effects of endothelial stimuli induced by salbutamol and L-arginine in humans have been previously studied predominantly at rest in selected vascular beds. • We studied the effects of salbutamol, L-arginine and nitroglycerin on cardiac and vascular function by continuous recording of pulse wave analysis and impedance cardiography both in the supine position and during passive head-up tilt. WHAT THIS STUDY ADDS • The divergent effects of the research drugs in supine position and during head-up tilt indicate that human haemodynamics should also be studied in the upright position. • Since inhaled salbutamol induced more pronounced changes in haemodynamics, it provides a clinically more applicable tool than infused L-arginine for the assessment of endothelial function in humans. AIMS To examine the effects of salbutamol and L-arginine, two compounds acting largely on the endothelium, and the endothelium-independent agent nitroglycerin on blood pressure, arterial compliance, cardiac function and vascular resistance. METHODS Continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic blood pressure from fingers in the supine position and during head-up tilt were recorded in nine healthy subjects. Data were captured before and after L-arginine (10 mg mg−1 min−1) or saline infusion, salbutamol (400 µg) or placebo inhalation, and sublingual nitroglycerin (0.25 mg) or placebo resoriblet. RESULTS The results of all measurements were comparable before drug administration. The effects of inhaled salbutamol were apparent in the supine position: systemic vascular resistance (−9.2 ± 2.6%) and augmentation index (−4.0 ± 1.5%) decreased, and heart rate (8.6 ± 2.5%) and cardiac output (8.8 ± 3.1%) increased. L-arginine had no clear effects on supine haemodynamics, but during head-up tilt blood pressure was moderately decreased and reduction in aortic reflection time prevented, indicating improved large arterial compliance. Nitroglycerin reduced supine vascular resistance (−6.7 ± 1.8%) and augmentation index (−7.4 ± 1.6%), and increased cardiac output (+9.2 ± 2.7%). During head-up tilt, nitroglycerin increased cardiac output (+10.6 ± 5.6%) and heart rate (+40 ± 7.5%), decreased vascular resistance (−7.8 ± 5.8%) and augmentation index (−18.7 ± 3.2%), and prevented the decrease in aortic reflection time. CONCLUSIONS Inhaled salbutamol predominantly changed supine haemodynamics, whereas the moderate effects of L-arginine were observed during the head-up tilt. In contrast, small doses of nitroglycerin induced major changes in haemodynamics both supine and during the head-up tilt. Altogether, these results emphasize the importance of haemodynamic measurements in both the supine and upright positions.

Objective Ageing is associated with increased postural blood pressure changes and attenuated cardiovascular reactivity. As the background of these changes remains uncertain, we examined arterial stiffness, cardiac function and vascular resistance in healthy subjects in supine position and during orthostatic challenge. Methods Haemodynamics of 179 normotensive subjects (109 female and 70 male, 21–59 years) were examined using continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic finger blood pressures. Results Both in supine position and during head-up tilt central and peripheral blood pressure and augmentation index (amplitude of the reflected pressure wave divided by pulse pressure) increased, and time of pulse wave reflection decreased with age. Supine pulse wave velocity progressively increased with age. There were only minor differences in supine and upright systemic vascular resistance, cardiac index, stroke index, and heart rate that were not systematically related to age. In regression analysis, the explanatory factors for a more pronounced decrease in central systolic blood pressure during the head-up tilt were in the age of 50–59 years, higher baseline pulse wave velocity and central systolic BP. None of the changes in other haemodynamic variables during tilt were related to age. Conclusion As no systematic age-related differences were observed in cardiac function or vascular resistance, these results support the view that progressive reduction of large arterial compliance contributes to the exaggerated age-related decrease in central systolic blood pressure in response to head-up tilt.

There is a multitude of data showing that coronary heart disease is affected by the quality of dietary fat. The fatty acid composition of serum lipids has been shown to reflect that of the diet. It is likely that, after myocardial infarction, both the health-care professionals and the patients themselves pay more attention to dietary guidelines. In order to assess the correctness of this assumption, we compared the composition of serum fatty acids in 40 male subjects with a history of myocardial infarction (MI) with that of 40 age-matched controls, both from the FINRISK study. The percentage composition of fatty acids of total serum lipids was analysed by gas chromatography. In comparison with the control group, the MI group had higher body mass index (BMI), a higher prevalence of diabetes, higher level of serum triglycerides and a lower level of serum high-density lipoprotein (HDL) cholesterol, all indicators of the metabolic syndrome. The MI group had higher proportions of serum palmitic (16:0) and oleic acids (18:1), and a lower proportion of linoleic (18:2 n-6) acid than the control group. The metabolic syndrome is accompanied by an elevated level of serum insulin, which is known to enhance the synthesis of saturated and monounsaturated fatty acids, such as 16:0 and 18:1, and to stimulate the activity delta-6 desaturase, decreasing the concentration of linoleic acid. Our results suggest that the observed serum fatty acid composition in subjects with coronary heart disease is dependent on metabolic factors in addition to dietary fatty acid composition.

Background High resting heart rate (HR) is associated with increased cardiovascular risk in general populations, possibly due to elevated blood pressure (BP) or sympathetic over-activity. We studied the association of resting HR with cardiovascular function, and examined whether the hemodynamics remained similar during passive head-up tilt. Methods Hemodynamics were recorded using whole-body impedance cardiography and continuous radial pulse wave analysis in 522 subjects (age 20–72 years, 261 males) without medication influencing HR or BP, or diagnosed diabetes, coronary artery, renal, peripheral arterial, or cerebrovascular disease. Correlations were calculated, and results analysed according to resting HR tertiles. Results Higher resting HR was associated with elevated systolic and diastolic BP, lower stroke volume but higher cardiac output and work, and lower systemic vascular resistance, both supine and upright (p