Cardiovascular magnetic resonance-derived left ventricular mechanics-strain, cardiac power and end-systolic elastance under various inotropic states in swine.

BACKGROUND: Cardiovascular magnetic resonance (CMR) strain imaging is an established technique to quantify myocardial deformation. However, to what extent left ventricular (LV) systolic strain, and therefore LV mechanics, reflects classical hemodynamic parameters under various inotropic states is still not completely clear. Therefore, the aim of this study was to investigate the correlation of LV global strain parameters measured via CMR feature tracking (CMR-FT, based on conventional cine balanced steady state free precession (bSSFP) images) with hemodynamic parameters such as cardiac index (CI), cardiac power output (CPO) and end-systolic elastance (Ees) under various inotropic states. METHODS: Ten anaesthetized, healthy Landrace swine were acutely instrumented closed-chest and transported to the CMR facility for measurements. After baseline measurements, two steps were performed: (1) dobutamine-stress (Dobutamine) and (2) verapamil-induced cardiovascular depression (Verapamil). During each protocol, CMR images were acquired in the short axisand apical 2Ch, 3Ch and 4Ch views. MEDIS software was utilized to analyze global longitudinal (GLS), global circumferential (GCS), and global radial strain (GRS). RESULTS: Dobutamine significantly increased heart rate, CI, CPO and Ees, while Verapamil decreased them. Absolute values of GLS, GCS and GRS accordingly increased during Dobutamine infusion, while GLS and GCS decreased during Verapamil. Linear regression analysis showed a moderate correlation between GLS, GCS and LV hemodynamic parameters, while GRS correlated poorly. Indexing global strain parameters for indirect measures of afterload, such as mean aortic pressure or wall stress, significantly improved these correlations, with GLS indexed for wall stress reflecting LV contractility as the clinically widespread LV ejection fraction. CONCLUSION: GLS and GCS correlate accordingly with LV hemodynamics under various inotropic states in swine. Indexing strain parameters for indirect measures of afterload substantially improves this correlation, with GLS being as good as LV ejection fraction in reflecting LV contractility. CMR-FT-strain imaging may be a quick and promising tool to characterize LV hemodynamics in patients with varying degrees of LV dysfunction.

[Refeeding syndrome during alcohol detoxification]. / Refeedingsyndroom bij alcoholdetoxificatie.

Refeeding syndrome (RS) can occur when malnourished patients are reintroduced to carbohydrates. The symptoms are caused by a combination of electrolyte shifts and fluid retention. Symptoms are wide-ranging; some patients may suffer from harmless muscle cramps, others from more severe neurological and cardiological symptoms that can even lead to death. Although alcohol dependence is a risk factor for the development of RS, little attention is being given to this problem in addiction treatment. In this article we report a case of RS that occurred during alcohol detoxification. We also present the results of a pilot study on the incidence of RS during the alcohol detoxification of 12 patients.

Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction?

Heart failure with preserved ejection fraction, i.e. HFpEF, is highly prevalent in ageing populations, accounting for more than 50 % of all cases of heart failure in Western societies, and is closely associated with comorbidities such as obesity, diabetes and arterial hypertension. However, all large multicentre trials of potential HFpEF treatments conducted to date have failed to produce positive outcomes. These disappointing results suggest that a 'one size fits all' strategy may be ill-suited to HFpEF and support the use of tailored, personalised therapeutic approaches with specific treatments designed for specific comorbidity-related HFpEF phenotypes. The accumulation of a multitude of cardiovascular comorbidities over time leads to increased systemic inflammation, oxidative stress and coronary microvascular endothelial inflammation, eventually resulting in degradation of cyclic guanosine monophosphate (cGMP) via multiple pathways, thereby reducing protein kinase G (PKG) activity. The importance of cGMP-PKG pathway modulation is supported by growing evidence that suggests that this pathway may be a promising therapeutic target, evidence that is mainly based on its role in the phosphorylation of the giant cytoskeletal protein titin. This review will focus on the preclinical and early clinical evidence in the field of cGMP-enhancing therapies and PKG activation.

Pulmonary 4D-flow MRI imaging in landrace pigs under rest and stress.

4D-flow MRI is a promising technique for assessing vessel hemodynamics. However, its utilization is currently limited by the lack of reference values, particularly for pulmonary vessels. In this work, we have analysed flow and velocity in the pulmonary trunk (PT), left and right pulmonary arteries (LPA and RPA, respectively) in Landrace pigs at both rest and stress through the software MEVISFlow. Nine healthy Landrace pigs were acutely instrumented closed-chest and transported to the CMR facility for evaluation. After rest measurements, dobutamine was administered to achieve a 25% increase in heart rate compared to rest. 4D-flow MRI images have been analysed through MEVISFlow by two independent observers. Inter- and intra-observer reproducibility was quantified using intraclass correlation coefficient. A significant difference between rest and stress regarding flow and velocity in all the pulmonary vessels was observed. Mean flow increased 55% in PT, 75% in LPA and 40% in RPA. Mean peak velocity increased 55% in PT, 75% in LPA and 66% in RPA. A good-to-excellent reproducibility was observed in rest and stress for flow measurements in all three arteries. An excellent reproducibility for velocity was found in PT at rest and stress, a good one for LPA and RPA at rest, while poor reproducibility was found at stress. The current study showed that pulmonary flow and velocity assessed through 4D-flow MRI follow the physiological alterations during cardiac cycle and after stress induced by dobutamine. A clinical translation to assess pulmonary diseases with 4D-flow MRI under stress conditions needs investigation.

PexLoc-Parallel excitation using local encoding magnetic fields with nonlinear and nonbijective spatial profiles.

With the recent proposal of using magnetic fields that are nonlinear by design for spatial encoding, new flexibility has been introduced to MR imaging. The new degrees of freedom in shaping the spatially encoding magnetic fields (SEMs) can be used to locally adapt the imaging resolution to features of the imaged object, e.g., anatomical structures, to reduce peripheral nerve stimulation during in vivo experiments or to increase the gradient switching speed by reducing the inductance of the coils producing the SEMs and thus accelerate the imaging process. In this work, the potential of nonlinear and nonbijective SEMs for spatial encoding during transmission in multidimensional spatially selective excitation is explored. Methods for multidimensional spatially selective excitation radiofrequency pulse design based on nonlinear encoding fields are introduced, and it is shown how encoding ambiguities can be resolved using parallel transmission. In simulations and phantom experiments, the feasibility of selective excitation using nonlinear, nonbijective SEMs is demonstrated, and it is shown that the spatial resolution with which the target distribution of the transverse magnetization can be realized varies locally. Thus, the resolution of the target pattern can be increased in some regions compared with conventional linear encoding. Furthermore, experimental proof of principle of accelerated two-dimensional spatially selective excitation using nonlinear SEMs is provided in this study.

Vesicular transfer of membrane components to bovine epididymal spermatozoa.

Epididymosomes (apocrine secreted epididymal vesicles) are assumed to play a crucial role in sperm maturation. Our aim has been to analyze the fusogenic properties of bovine epididymosomes and their involvement in the transfer of membrane components (lipids, proteins, plasma membrane Ca(2+)-ATPase 4 [PMCA4]) into bovine sperm. The fusogenic properties of epididymosomes with spermatozoa were investigated in vitro by using octadecyl rhodamine-B (R18)-labeled epididymosomes. Spermatozoa isolated from the epididymal caput showed a higher fusion rate than those taken from the cauda. The fusion rate was dependent on pH and time. Furthermore, the lipid and protein content in spermatozoa changed during epididymal transit and after in vitro fusion with epididymosomes. Following the in vitro fusion of caput spermatozoa with epididymosomes, the cholesterol/total phospholipid ratio of the sperm plasma membrane decreased. The effect was comparable with the cholesterol/total phospholipid ratio of native cauda spermatozoa. Co-incubation experiments of spermatozoa with biotinylated epididymosomes additionally revealed that proteins were transferred from epididymosomes to sperm. To examine the potential transfer of epididymis-derived PMCA4 to spermatozoa, immunofluorescence analysis and Ca(2+)-ATPase activity assays were performed. In caput spermatozoa, the PMCA4 fluorescence signal was slightly raised and Ca(2+)-ATPase activity increased after in vitro fusion. Thus, our experiments indicate significant changes in the lipid and protein composition of epididymal sperm following interaction with epididymosomes. Moreover, our results substantiate the presumption that PMCA4 is transferred to spermatozoa via epididymosomes.

Time to reimbursement of novel anticancer drugs in Europe: a case study of seven European countries.

BACKGROUND: Time to reimbursement (TTR) of new anticancer medicines differs between countries and contributes to unequal access. We aimed to investigate TTR of new anticancer medicines and explore factors influencing the reimbursement process in seven high-income European countries. MATERIALS AND METHODS: We carried out a retrospective case study of anticancer medicines with European Union Market Access (EU-MA) and a positive Committee for Medicinal Products for Human Use opinion from 2016 until 2021 with subsequent national reimbursement approval (NRA). The National Health Technology Assessment (HTA) and reimbursement websites of Germany, France, UK, the Netherlands, Belgium, Norway and Switzerland were used to identify TTR, defined as time from EU-MA to NRA. Additionally, we investigated medication-, country-, indication- and pharma-related factors potentially influencing TTR. RESULTS: Thirty-five medicines were identified for which TTR ranged from -81 days to 2320 days (median 407 days). At data cut-off, 16 (46%) were reimbursed in all seven countries. Overall, the shortest TTR was in Germany (median 3 days, all medicines reimbursed <5 days). The time limit for reimbursement of 180 days stated by the Council of European Communities after the EU-MA (EU Transparency Directive) was met for 100% of included medicines in Germany, 51% in France, 29% in the UK and the Netherlands, 14% in Switzerland, 6% in Norway and 3% in Belgium. The TTR was significantly different between countries (P < 0.001). In multivariate analysis, factors associated with shorter TTR were higher gross domestic product (GDP), absence of a pre-assessment procedure and submission by a big pharmaceutical company. CONCLUSIONS: TTR of anticancer medicines varies significantly between seven high-income European countries and leads to inequality in access. Among explored medication-, country-, indication- and pharma-related factors we found that a high GDP, the absence of a pre-assessment procedure and submission by big pharmaceutical companies were associated with shorter TTR.

Effect of a prediction tool and communication skills training on communication of treatment outcomes: a multicenter stepped wedge clinical trial (the SOURCE trial).

Background: For cancer patients to effectively engage in decision making, they require comprehensive and understandable information regarding treatment options and their associated outcomes. We developed an online prediction tool and supporting communication skills training to assist healthcare providers (HCPs) in this complex task. This study aims to assess the impact of this combined intervention (prediction tool and training) on the communication practices of HCPs when discussing treatment options. Methods: We conducted a multicenter intervention trial using a pragmatic stepped wedge design (NCT04232735). Standardized Patient Assessments (simulated consultations) using cases of esophageal and gastric cancer patients, were performed before and after the combined intervention (March 2020 to July 2022). Audio recordings were analyzed using an observational coding scale, rating all utterances of treatment outcome information on the primary outcome-precision of provided outcome information-and on secondary outcomes-such as: personalization, tailoring and use of visualizations. Pre vs. post measurements were compared in order to assess the effect of the intervention. Findings: 31 HCPs of 11 different centers in the Netherlands participated. The tool and training significantly affected the precision of the overall communicated treatment outcome information (p = 0.001, median difference 6.93, IQR (-0.32 to 12.44)). In the curative setting, survival information was significantly more precise after the intervention (p = 0.029). In the palliative setting, information about side effects was more precise (p < 0.001). Interpretation: A prediction tool and communication skills training for HCPs improves the precision of treatment information on outcomes in simulated consultations. The next step is to examine the effect of such interventions on communication in clinical practice and on patient-reported outcomes. Funding: Financial support for this study was provided entirely by a grant from the Dutch Cancer Society (UVA 2014-7000).

Painful lower limb nodules as first symptom of resectable pancreatic acinar cell cancer: a case report.

BACKGROUND: Pancreatic panniculitis is characterized by subcutaneous fat necrosis and is a rare presentation of an underlying pancreatic disease, appearing in approximately 2-3% of all patients with a pancreatic disease. The nodules usually involve the lower extremities. Pancreatic panniculitis is commonly associated with acute or chronic pancreatitis, and occasionally with pancreatic cancer, especially acinar cell carcinoma. CASE PRESENTATION: A 77-year-old Caucasian woman with no significant medical history was referred to our center with multiple painful, itchy, and warm red/blue cutaneous nodules on the left lower leg. These skin lesions were consistent with the clinical diagnosis of panniculitis. The skin biopsy obtained showed a predominantly lobular panniculitis with fat necrosis of which the aspect was highly suspicious for pancreatic panniculitis. Further analysis revealed high lipase serum of > 3000 U/L (normal range < 60 U/L), and on computed tomography scan a mass located between the stomach and the left pancreas was seen. Endoscopic ultrasonography-guided fine-needle biopsy confirmed the diagnosis of acinar cell carcinoma. After discussing the patient in the pancreatobiliary multidisciplinary team meeting, laparoscopic distal pancreatectomy including splenectomy and en bloc wedge resection of the stomach due to tumor in-growth was performed. The cutaneous nodules on both legs disappeared 1-2 days after surgery. No long-term complications were reported during follow-up. One year after surgery, the patient presented with similar symptoms as preoperatively. Computed tomography scan showed local recurrence and distal metastases, which were subsequently confirmed by biopsy. She started with palliative folinic acid-fluorouracil-irinotecan-oxaliplatin chemotherapy but stopped after two cycles because of disease progression. The patient died 2 months later, 13 months after surgical resection. CONCLUSION: This case illustrates the importance of clinically recognizing cutaneous nodules and pathological recognizing the specific microscopic changes as sign of a (malignant) pancreatic disease.

Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under "pathological" conditions ex vivo.

Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic "pathological" wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams' E medium or in unsupplemented medium under "pathological" conditions (i.e. hypoxia [5% O2], oxidative damage [10 mM H2O2], absence of insulin, excess glucose). Under these "pathological" conditions, dermal-epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (p < 0.001), associated with reduced keratinocyte proliferation (p < 0.001), cytokeratin 6 expression (p < 0.001) and increased apoptosis (p < 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under "pathological" wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (p < 0.001) and promoted both epidermal keratinocyte proliferation (p < 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under "pathological" conditions (p < 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters.

Arrangement of PMCA4 in bovine sperm membrane fractions.

The plasma membrane Ca(2+) -ATPase (PMCA) is the main restorer of Ca(2+) balance in sperm. Particularly, PMCA isoform 4 has an essential function in sperm fertility by its participation in gaining sperm hypermotility. PMCA activity is influenced by its lipid environment. Sperm membranes exhibit lipid raft microdomains or detergent-resistant membrane domains, enriched in sphingolipids and cholesterol, forming functional specialized areas. Lipid and protein composition of lipid rafts alters during the capacitation process, which is characterized by a cholesterol efflux. In this study, the localization of PMCA4 in lipid membrane fractions of the sperm plasma membrane was investigated. We identified PMCA4 in both the detergent-resistant membrane (DRM) and in the detergent-soluble (DS) fraction of caput and cauda sperm, respectively. Capacitation did not influence PMCA4 localization. In immunocytochemical studies PMCA4 was co-localized with the lipid raft/DRM marker caveolin in the mid piece of caput and cauda sperm. Functional studies with seminal vesicle major protein PDC-109 showed that the Ca(2+) -ATPase activity in DS fractions of cauda sperm and capacitated cauda sperm was stronger enhanced than in the DRMs. In both fractions the effect was statistically significant. In contrast, in lipid overlay experiments PDC-109 interacted stronger with the lipids extracted from DRMs than with lipids extracted from DS. Our results indicate a possible functional compartmentalization of PMCA in bull sperm membranes and point to a presumptive, yet unknown interaction partner of Ca(2+) -ATPase and PDC-109, mediating the PDC-109 action from DRMs to the DS fraction of sperm plasma membrane.

Estimation of total collagen volume: a T1 mapping versus histological comparison study in healthy Landrace pigs.

Right ventricular biopsy represents the gold standard for the assessment of myocardial fibrosis and collagen content. This invasive technique, however, is accompanied by perioperative complications and poor reproducibility. Extracellular volume (ECV) measured through cardiovascular magnetic resonance (CMR) has emerged as a valid surrogate method to assess fibrosis non-invasively. Nonetheless, ECV provides an overestimation of collagen concentration since it also considers interstitial space. Our study aims to investigate the feasibility of estimating total collagen volume (TCV) through CMR by comparing it with the TCV measured at histology. Seven healthy Landrace pigs were acutely instrumented closed-chest and transported to the MRI facility for measurements. For each protocol, CMR imaging at 3T was acquired. MEDIS software was used to analyze T1 mapping and ECV for both the left ventricular myocardium (LVmyo) and left ventricular septum (LVseptum). ECV was then used to estimate TCVCMR at LVmyo and LVseptum following previously published formulas. Tissues were prepared following an established protocol and stained with picrosirius red to analyze the TCVhisto in LVmyo and LVseptum. TCV measured at LVmyo and LVseptum with both histology (8 ± 5 ml and 7 ± 3 ml, respectively) and T1-Mapping (9 ± 5 ml and 8 ± 6 ml, respectively) did not show any regional differences. TCVhisto and TCVCMR showed a good level of data agreement by Bland-Altman analysis. Estimation of TCV through CMR may be a promising way to non-invasively assess myocardial collagen content and may be useful to track disease progression or treatment response.

Cardiovascular magnetic resonance feature tracking in pigs: a reproducibility and sample size calculation study.

Cardiovascular magnetic resonance feature tracking (CMR-FT) is a novel technique for non-invasive assessment of myocardial motion and deformation. Although CMR-FT is standardized in humans, literature on comparative analysis from animal models is scarce. In this study, we measured the reproducibility of global strain under various inotropic states and the sample size needed to test its relative changes in pigs. Ten anesthetized healthy Landrace pigs were investigated. After baseline (BL), two further steps were performed: (I) dobutamine-induced hyper-contractility (Dob) and (II) verapamil-induced hypocontractility (Ver). Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS) were assessed. This study shows a good to excellent inter- and intra-observer reproducibility of CMR-FT in pigs under various inotropic states. The highest inter-observer reproducibility was observed for GLS at both BL (ICC 0.88) and Ver (ICC 0.79). According to the sample size calculation for GLS, a small number of animals could be used for future trials.

Lower cutaneous microvascular reactivity in adult cancer patients receiving chemotherapy.

Cancer patients with a history of anticancer chemotherapy are at an increased cardiovascular disease risk compared with cancer-free populations. Therefore, we tested the hypothesis that cancer patients receiving adjuvant chemotherapy would have a lower cutaneous microvascular reactivity and lower endothelium-dependent flow-mediated dilation (FMD) of the brachial artery compared with matched cancer-free control subjects. To test this hypothesis, we performed a case control study with seven cancer patients receiving adjuvant chemotherapy and seven matched healthy reference control subjects. Red blood cell flux was measured as an index of cutaneous blood flow via laser Doppler flowmetry. Acetylcholine (ACh)-mediated vasodilation was determined by iontophoresis. Data were expressed as percent increase in cutaneous vascular conductance. Endothelium-dependent FMD of the brachial artery via ultrasonography was determined as an index of macrovessel endothelial function. Cutaneous microvascular reactivity was attenuated in cancer patients compared with control subjects [cancer: 959.9 ± 187.3%, control: 1,556.8 ± 222.2%; P = 0.03, effect size (ES) = 1.1]. Additionally, cancer patients demonstrated a significantly lower area under the curve response to ACh iontophoresis compared with healthy control subjects. Brachial artery FMD was also significantly lower in cancer patients compared with control subjects (cancer: 2.2 ± 0.6%, control: 6.6 ± 1.4%; P = 0.006, ES = 1.6), which was significantly associated with measurements of microvascular reactivity. These findings suggest that decreases in vascular reactivity can occur during cancer chemotherapy, which may have implications for the long-term risk of cardiovascular disease morbidity and mortality. NEW & NOTEWORTHY Cancer survivors treated with chemotherapy experience an increased risk of cardiovascular events, linked to both cardiac and vascular toxicity. The major finding of this study is that microvascular reactivity and macrovascular endothelium-dependent flow-mediated dilation are lower in cancer patients currently receiving adjuvant chemotherapy compared with healthy counterparts.

Unique cardioprotective action of the new calcium antagonist mibefradil.

BACKGROUND: Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations. METHODS AND RESULTS: The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3+/-10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1. 9+/-3.9% (P<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1+/-4.2%, P<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9+/-5.4%, P=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8+/-3.0%, P<0.05 versus placebo), but verapamil did not (11.6+/-8.3%, P=NS versus placebo). With glibenclamide infusion, mibefradil no longer reduced IS (13.1+/-4.3% versus 17.8+/-5.6% with glibenclamide alone, P=NS). CONCLUSIONS: The IS-limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on favorable hemodynamics but was abolished by glibenclamide, suggesting a direct cardioprotective action of mibefradil.

ACS, myocardial bridging, Tako-tsubo syndrome and mitral regurgitation.

Isolated systolic compression of the mid portion of the left anterior descending artery (LAD) by a bridge of overlying cardiac muscle is an infrequent but well-recognised angiographic anomaly that is often considered harmless. The long-term prognosis appears to be excellent, but occasional reports of patients with angina pectoris, myocardial infarction and sudden death indicate that this is not always true. The prevalence of the anomaly in the normal population is unknown, but the incidence is low and ischaemic events are rare. Tako-tsubo-like left ventricular dysfunction syndrome (TTS) is characterised by ischaemia, anterior ST-segment elevation, no significant coronary artery disease and reversible ampulla-like left ventricular ballooning in postmenopausal females after emotional or physical stress. Dynamic left ventricular outflow tract (LVOT) obstruction is a rare but potentially fatal complication of acute anterior wall infarction. We present a patient with an acute coronary syndrome (ACS) with ST-segment elevation in the anterior leads, transient TTS and transient LVOT obstruction with systolic anterior motion (SAM) of the mitral valve and severe mitral regurgitation. This is the first report of myocardial bridging associated with TTS, and the first report of TTS associated with dynamic LVOT obstruction with SAM and mitral regurgitation.

Mild hypothermia induces incomplete left ventricular relaxation despite spontaneous bradycardia in pigs.

AIM: Mild hypothermia (MH) decreases left ventricular (LV) end-diastolic capacitance. We sought to clarify whether this results from incomplete relaxation. METHODS: Ten anaesthetized pigs were cooled from normothermia (NT, 38 °C) to MH (33 °C). LV end-diastolic pressure (LVPed), volume (LVVed) and pressure-volume relationships (EDPVRs) were determined during stepwise right atrial pacing. LV capacitance (i.e. LVVed at LVPed of 10 mmHg, LV VPed10) was derived from the EDPVR. Pacing-induced changes of diastolic indices (LVPed, LVVed and LV VPed10) were analysed as a function of (i) heart rate and (ii) the ratio between diastolic time interval (t-dia) and LV isovolumic relaxation constant τ, which was calculated using a logistic fit (τL ) and monoexponential fit with zero asymptote (τZ ) and nonzero asymptote (τNZ ). RESULTS: Mild hypothermia decreased heart rate (85 ± 4 to 68 ± 3 bpm), increased τL (22 ± 1 to 57 ± 4 ms), τZ (26 ± 2 to 56 ± 5 ms) and τNZ (41 ± 1 to 96 ± 5 ms), decreased t-dia/τ ratios, and shifted the EDPVR leftwards compared to NT (all P < 0.05). During NT, pacing at ≥140 bpm shifted the EDPVR progressively leftwards. During MH, relationships between diastolic indices and heart rate were shifted towards lower heart rates compared to NT. However, relationships between diastolic indices and t-dia/τ during NT and MH were superimposable. CONCLUSION: We conclude that the loss of LV end-diastolic capacitance during MH can be explained at least in part by slowed LV relaxation. MH thereby is an example of incomplete LV relaxation at a spontaneous low heart rate. Caution may be advised, when heart rate is increased in patients treated with MH.

Enhanced reduction of myocardial infarct size by combined ACE inhibition and AT(1)-receptor antagonism.

The effects of the angiotensin-converting-enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT(1)A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. Both ACEI and AT(1)A reduce myocardial IS by a bradykinin-mediated process. It is unclear, however, whether the combination of ACEI and AT(1)A produces a more pronounced IS reduction than each of these drugs alone. Forty-six enflurane-anaesthetized pigs underwent 90 min low-flow ischaemia and 120 min reperfusion. Systemic haemodynamics (micromanometer), subendocardial blood flow (ENDO, microspheres) and IS (TTC-staining) were determined. The decreases in left ventricular peak pressure by ACEI (by 9+/-2 (s.e. mean) mmHg), AT(1)A (by 11+/-2 mmHg) or their combination (by 18+/-3 mmHg, P<0.05 vs ACEI and AT(1)A, respectively) were readjusted by aortic constriction prior to ischaemia. With placebo (n=10), IS averaged 20.0+/-3.3% of the area at risk. IS was reduced to 9.8+/-2.6% with ramiprilat (n=10) and 10.6+/-3.1% with candesartan (n=10). Combined ramiprilat and candesartan (n=10) reduced IS to 6.7+/-2.1%. Blockade of the bradykinin-B(2)-receptor with icatibant prior to ACEI and AT(1)A completely abolished the reduction of IS (n=6, 22.8+/-6.1%). The relationship between IS and ischaemic ENDO with placebo was shifted downwards by each ACEI and AT(1)A and further shifted downwards with their combination (P<0.05 vs all groups); icatibant again abolished such downward shift. The combination of ACEI and AT(1)A enhances the reduction of IS following ischaemia/reperfusion compared to a monotherapy by either drug alone; this effect is mediated by bradykinin.

Accurate T2 NMR images.

We present a method for producing accurate calculated T2 nuclear magnetic resonance (NMR) images. A modified Carr-Purcell-Meiboom-Gill pulse sequence is used to obtain a series of images with progressive T2 dependence. This image series is then analyzed pixel by pixel to generate a T2 and initial signal strength image. Tests performed using four samples of known T2 indicate accuracies of better than 9%.