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Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM.Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile.We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls.We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca2+-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca2+-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca2+-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here.

Cardiac imaging suffers from both respiratory and cardiac motion. One of the proposed solutions involves double gated acquisitions. Although such an approach may lead to both respiratory and cardiac motion compensation there are issues associated with (a) the combination of data from cardiac and respiratory motion bins, and (b) poor statistical quality images as a result of using only part of the acquired data. The main objective of this work was to evaluate different schemes of combining binned data in order to identify the best strategy to reconstruct motion free cardiac images from dual gated positron emission tomography (PET) acquisitions.A digital phantom study as well as seven human studies were used in this evaluation. PET data were acquired in list mode (LM). A real-time position management system and an electrocardiogram device were used to provide the respiratory and cardiac motion triggers registered within the LM file. Acquired data were subsequently binned considering four and six cardiac gates, or the diastole only in combination with eight respiratory amplitude gates. PET images were corrected for attenuation, but no randoms nor scatter corrections were included. Reconstructed images from each of the bins considered above were subsequently used in combination with an affine or an elastic registration algorithm to derive transformation parameters allowing the combination of all acquired data in a particular position in the cardiac and respiratory cycles. Images were assessed in terms of signal-to-noise ratio (SNR), contrast, image profile, coefficient-of-variation (COV), and relative difference of the recovered activity concentration.Regardless of the considered motion compensation strategy, the nonrigid motion model performed better than the affine model, leading to higher SNR and contrast combined with a lower COV. Nevertheless, when compensating for respiration only, no statistically significant differences were observed in the performance of the two motion models considered. Superior image SNR and contrast were seen using the affine respiratory motion model in combination with the diastole cardiac bin in comparison to the use of the whole cardiac cycle. In contrast, when simultaneously correcting for cardiac beating and respiration, the elastic respiratory motion model outperformed the affine model. In this context, four cardiac bins associated with eight respiratory amplitude bins seemed to be adequate.Considering the compensation of respiratory motion effects only, both affine and elastic based approaches led to an accurate resizing and positioning of the myocardium. The use of the diastolic phase combined with an affine model based respiratory motion correction may therefore be a simple approach leading to significant quality improvements in cardiac PET imaging. However, the best performance was obtained with the combined correction for both cardiac and respiratory movements considering all the dual-gated bins independently through the use of an elastic model based motion compensation.

Editorial

The mid- and long-term outcome of revascularization procedures is still uncertain in patients with chronic left ventricular systolic dysfunction due to coronary artery disease. The identification of dysfunctional myocardial segments with residual viability that can improve after revascularization is pivotal for further patient management. Hibernating myocardium (chronically dysfunctional but still viable tissue) can be identified by positron emission tomography and cardiac magnetic resonance and its presence and extent can predict functional recovery after revascularization. Before beta-blockers were introduced as routine care for heart failure, surgical revascularization appeared to improve survival in these patients. Nowadays, novel medical treatments and devices such as cardiac resynchronization therapy and implantable cardioverter-defibrillators have improved prognosis of these patients and their use is supported by a number of clinical trials. A recently concluded randomized trial, the STICH (Surgical Treatment for Ischemic Heart Failure) trial, has assessed the prognostic benefit derived from revascularization added to optimal medical therapy in patients with ischemic left ventricular dysfunction. This is an overview of the pathophysiological mechanisms as well as the main clinical studies and meta-analyses that have addressed this issue in the past four decades. Furthermore, a brief proposal for a randomized trial to assess effect on prognosis of revascularization of hibernating myocardium will be presented.

This study was designed to evaluate the efficacy and tolerability of once-daily dosing of lercanidipine (REC 15/2375) tablets and hard gelatin capsules versus placebo in the treatment of mild to moderate hypertension. A total of 156 patients were recruited for this double-blind, randomized, multicenter trial. Each patient completed a 7-day washout period and a 21-day single-blind, placebo run-in. Patients were then randomly assigned to receive lercanidipine 10-mg tablets, lercanidipine 10-mg hard gelatin capsules, or placebo for 1 week, followed by 3 weeks of treatment at the beginning of which the dose was increased to 20 mg. The split-plot analysis of variance performed on the primary end-point (diastolic blood pressure [DBP] showed a highly significant difference among groups ( P P

This phase II pilot study investigated the once-daily activity of the calcium antagonist REC 15/2375 in the treatment of mild to moderate hypertension. Forty-nine patients were recruited for this double-blind, randomized trial, in which two dosing regimens of 10 mg or 20 mg once daily were administered for two treatment periods of 10 days each. Each patient completed a 14-day washout period and 7 days of a single-blind placebo run-in. The response after 10 days was evaluated. Sixty-four percent of the patients in the 20-mg group and 67% of the patients in the 10-mg group were classified as responders, that is, their diastolic blood pressure decreased to 90 mmHg or less. The responders continued with the same once-daily dosage, and the nonresponders continued with the same dosage given twice a day. On day 20 DBP was increased above 90 mmHg again in 3 of 16 responders in the 10-mg group; none of the responders in the 20-mg group worsened. No clinically relevant increase in heart rate was seen. REC 15/2375 was well tolerated in each dosage group. Our results indicate that REC 15/2375 might be effective in a once-daily regimen in the treatment of hypertension.

Blood oxygenation level-dependent (BOLD) MRI clinical studies at 1.5 Tesla (T) have been principally limited by low signal to noise. We sought to apply this method at 3T in patients with coronary artery disease (CAD) and normal volunteers, and validated it against perfusion measurements by PET. Twenty-two patients (age 62±8 yrs, 16 men) with CAD (at least 1 stenosis > 50% on quantitative coronary angiography-QCA) and 10 normal volunteers (age 52±7 yrs, 7 men) underwent 3T BOLD MRI and PET. For BOLD MRI a mid-ventricular slice was acquired every 30sec at rest and during adenosine stress (140 μg/kg/min). A set of 6 images was acquired at rest and at peak stress. Using PET with oxygen-15 labelled water, myocardial blood flow (MBF) was measured at baseline and during adenosine hyperemia. The BOLD short-axis view was divided into 6 segments, according to the mid-ventricular segments of the 17-AHA segment model, and mean signal intensities (SI) were calculated using QMass (Medis) software. PET images were analyzed with MATLAB software (MathWorks Inc.) and registered with the BOLD short-axis image using anatomical landmarks. Taking QCA as the gold standard, cut-off values for stress MBF (< 2.57ml/min/g - AUC 0.79) and BOLD SI change (< 4.75% -AUC 0.78) were determined to define ischemic segments. Rest MBF, stress MBF, coronary flow reserve and BOLD-SI change of ischemic (n=69), remote to ischemia (n=73) and normal segments (n=60) are shown in table . BOLD MRI and PET agreed on the presence or absence of ischemia in 18 of the 22 patients (82%), and in all normals. With regards to per segment analysis: taking PET as the gold standard and by applying the cut-off values for stress MBF and BOLD SI, BOLD MRI had only moderate sensitivity (61%) but good specificity (88%) for the identification of ischemia. T2-prepared SSFP 3T BOLD imaging is feasible in the clinical setting and has good agreement with PET perfusion measurements for the detection of myocardial ischemia.

An increase in human cardiac α1-adrenoceptor (α1-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [11C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to α1-AR. However, α1-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the α1-AR density is comparable to man, and to validate a method for quantification before PET studies in man. Seven [11C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg−1 (pilot, test–retest and baseline–predose studies) or 8.22 MBq kg−1 (baseline–displacement studies), were performed in four anaesthetised pigs (39.5 ± 3.9 kg). Total myocardial volume of distribution (V T) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 μmol kg−1 of unlabeled GB67 was given 20 min before [11C]GB67 administration in the predose study and 45 min after administration of [11C]GB67 in the displacement study. In addition, [15O]CO (3,000 MBq) and [15O]H2O, with weight adjusted target dose of 10.57 MBq kg−1, were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively. [11C]GB67 V T values (in ml cm−3) were estimated to be 24.2 ± 5.5 (range, 17.3–31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within each pig, including between baseline and predose conditions. Predose and displacement studies showed that specific binding of [11C]GB67 to myocardial α1-ARs accounts for approximately 50% of V T. The present study offers a methodology for using [11C]GB67 as a radioligand to quantify human myocardial α1-ARs in clinical PET studies.

Although physical exercise is the preferred stimulus for cardiac stress testing, pharmacologic agents are useful in patients who are unable to exercise. Previous studies have demonstrated short-term repeatability of exercise and adenosine stress, but little data exist regarding dobutamine (Dob) stress or the long-term reproducibility of pharmacologic stressors in coronary artery disease (CAD) patients. PET allows accurate, noninvasive quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR). The aim of the study was to investigate the long-term reproducibility of Dob stress on MBF and CFR in CAD patients using PET.Fifteen patients with chronic stable angina and angiographically proven CAD (70% stenosis in at least 1 major coronary artery) underwent PET with (15)O-labeled water and Dob stress at baseline (time [t] = 0) and after 24 wk (t = 24). MBF at rest and MBF during Dob stress were calculated for the whole left ventricle, the region subtended by the most severe coronary artery stenosis (Isc), and remote myocardium subtended by arteries with minimal or no disease (Rem). Reproducibility was assessed using the Bland-Altman (BA) repeatability coefficient and was also expressed as a percentage of the mean value of the 2 measurements (%BA).Dob dose (30 +/- 11 vs. 031 +/- 11 microg/kg/min; P = not significant [ns]) and peak Dob rate.pressure product (20,738 +/- 3,947 vs. 20,047 +/- 3,455 mm Hg x beats/min; P = ns) were comparable at t = 0 and t = 24. There was no significant difference in resting or Dob MBF (mL/min/g) between t = 0 and t = 24 for the whole left ventricle (1.03 +/- 0.19 vs. 1.10 +/- 0.20 and 2.02 +/- 0.44 vs. 2.09 +/- 0.57; P = ns for both), Isc (1.05 +/- 0.24 vs. 1.10 +/- 0.26 and 1.79 +/- 0.53 vs. 1.84 +/- 0.62; P = ns for both), or Rem (1.03 +/- 0.23 vs. 1.10 +/- 0.26 and 2.27 +/- 0.63 vs. 2.26 +/- 0.63; P = ns for both) territories. Global (1.98 +/- 0.40 vs. 1.90 +/- 0.46; P = ns) and regional CFR (Isc: 1.65 +/- 0.40 vs. 1.67 +/- 0.47, and Rem: 2.25 +/- 0.57 vs. 2.06 +/- 0.51; P = ns) were reproducible. The BA repeatability coefficients (and %BA) for MBF in ischemic and remote territories were 0.3 (28%) and 0.26 (24%) at rest and 0.49 (27%) and 0.58 (26%) during Dob stress.In patients with clinically stable CAD, Dob induces reproducible changes in both global and regional MBF and CFR over a time interval of 24 wk. The reproducibility of MBF and CFR with Dob was comparable with the short-term repeatability reported for adenosine and physical exercise in healthy subjects.

Brief myocardial ischemia/reperfusion has complex effects on the myocardium. In the short term the myocardium may be stunned with temporarily reduced contractile function, though this may also be accompanied by the modification and de novo synthesis of proteins that protect the heart against subsequent early or delayed insults. Repeated episodes of non-lethal ischemia, which are common in the clinical setting, combine all of these phenomena and may ultimately result in chronic contractile dysfunction. Nitric oxide is intimately linked to many of these alterations in cellular function and defense. This article examines data predominantly from in vivo large animal studies that relate to these ischemia-induced changes, the evidence for the proposed mechanisms behind both myocardial stunning and preconditioning while concentrating on the role of nitric oxide in these conditions.

The effects of cell density on transformation frequencies were studied in C3H10T1/2 cells exposed to 0.5 and 7 Gy of 200 kVp X-rays. Initial cell density strongly influenced transformation frequency; this decreased by a factor of between 4 and 10 when the initial seeding density was changed from 50 to 2500 cells/10 cm diameter Petri dish. The data were fitted with two equations: (a) an allometric function represented on a log-log scale by a straight line and (b) a sigmoidal function with plateaux between 50 and 250 cells/dish and above 600. The two curves are compared and their probabilities discussed. Our data indicate that the region between 50 and 250 cells/dish would be the most suitable region for dose-effect measurements. A study of the growth curves at 0.5 and 8.5 Gy shows that cell growth rates are not influenced by initial cell density.