Cardiac rotation and relaxation in patients with aortic valve stenosis.

BACKGROUND: Diastolic dysfunction with delayed relaxation and abnormal passive elastic properties has been described in patients with severe pressure overload hypertrophy. The purpose of this study was to evaluate the time course of rotational motion of the left ventricle in patients with aortic valve stenosis using myocardial tagging. METHODS: Myocardial tagging is a non-invasive method based on magnetic resonance which makes it possible to label ('tag') specific myocardial regions. From the motion of the tag's cardiac rotation, radial displacement and translational motion can be determined. In 12 controls and 13 patients with severe aortic valve stenosis systolic and diastolic wall motion was assessed in an apical and basal short axis plane. RESULTS: The normal left ventricle performs a systolic wringing motion around the ventricular long axis with clockwise rotation at the base (-4.4+/-1.6 degrees) and counter-clockwise rotation at the apex (+6.8+/-2.5 degrees) when viewed from the apex. During early diastole an untwisting motion can be observed which precedes diastolic filling. In patients with aortic valve stenosis systolic rotation is reduced at the base (-2.4+/-2.0 degrees; P<0.01) but increased at the apex (+12.0+/-6.0 degrees; P<0.05). Diastolic untwisting is delayed and prolonged with a decrease in normalized rotation velocity (-6.9+/-1.1 s(-1)) when compared to controls (-10.7+/-2.2 s(-1); P<0.001). Maximal systolic torsion is 8.0+/-2.1 degrees in controls and 14.1+/-6.4 degrees (P<0.01) in patients with aortic valve stenosis. CONCLUSIONS: Left ventricular pressure overload hypertrophy is associated with a reduction in basal and an increase in apical rotation resulting in increased torsion of the ventricle. Diastolic untwisting is delayed and prolonged. This may explain the occurrence of diastolic dysfunction in patients with severe pressure overload hypertrophy.

A new self-expanding aortic stent valve with annular fixation: in vitro haemodynamic assessment.

OBJECTIVE: Balloon-expandable stent valves require flow reduction during implantation (rapid pacing). The present study was designed to compare a self-expanding stent valve with annular fixation versus a balloon-expandable stent valve. METHODS: Implantation of a new self-expanding stent valve with annular fixation (Symetis, Lausanne, Switzerland) was assessed versus balloon-expandable stent valve, in a modified Dynatek Dalta pulse duplicator (sealed port access to the ventricle for transapical route simulation), interfaced with a computer for digital readout, carrying a 25 mm porcine aortic valve. The cardiovascular simulator was programmed to mimic an elderly woman with aortic stenosis: 120/85 mmHg aortic pressure, 60 strokes/min (66.5 ml), 35% systole (2.8 l/min). RESULTS: A total of 450 cardiac cycles was analysed. Stepwise expansion of the self-expanding stent valve with annular fixation (balloon-expandable stent valve) resulted in systolic ventricular increase from 120 to 121 mmHg (126 to 830+/-76 mmHg)*, and left ventricular outflow obstruction with mean transvalvular gradient of 11+/-1.5 mmHg (366+/-202 mmHg)*, systolic aortic pressure dropped distal to the valve from 121 to 64.5+/-2 mmHg (123 to 55+/-30 mmHg) N.S., and output collapsed to 1.9+/-0.06 l/min (0.71+/-0.37 l/min* (before complete obstruction)). No valve migration occurred in either group. (*=p<0.05). CONCLUSIONS: Implantation of this new self-expanding stent valve with annular fixation has little impact on haemodynamics and has the potential for working heart implantation in vivo. Flow reduction (rapid pacing) is not necessary.

Cardiac raptor deletion impairs adaptive hypertrophy, alters metabolic gene expression and causes heart failure in mice

Background: Mammalian target of rapamycin (mTOR), a central regulator of cell growth, is found in two structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC)1 and mTORC2. The specific roles of each of these branches of mTOR signaling have not been dissected in the adult heart. In the present study, we aimed to bring new insights into the function of cardiac mTORC1-mediated signaling in physiological as well as pathological situations.Methods: We generated mice homozygous for loxP-flanked raptor and positive for the tamoxifen-inducible Cre recombinase (MerCreMer) under control of the α- myosin heavy chain promoter. The raptor gene encodes an essential component of mTORC1. Gene ablation was induced at the age of 10-12 weeks, and two weeks later the raptor cardiac-knockout (raptor-cKO) mice started voluntary cagewheel exercise or were subjected to transverse aortic constriction (TAC) to induce pressure overload.Results: In sedentary raptor-cKO mice, ejection fractions gradually decreased, resulting in significantly reduced values at 38 days (P < 0.001). Raptor-cKO mice started to die during the fifth week after the last tamoxifen injection. At that time, the mortality rate was 36% in sedentary (n = 11) and 64% in exercising (n = 14) mice. TAC-induced pressure overload resulted in severe cardiac dysfunction already at earlier timepoints. Thus, at 7-9 days after surgery, ejection fraction and fractional shortening values were 22.3% vs 43.5% and 10.2% vs 21.5% in raptor-cKO vs wild-type mice, respectively. This was accompanied by significant reductions of ventricular wall and septal thickness as well as an increase in left ventricular internal diameter. Moreover, ventricular weight to tibial length ratios were increased in wild-type, but not in the raptor-cKO TAC mice. Together, this shows that raptor-cKO mice rapidly developed dilated cardiomyopathy without going through a phase of adaptive hypertrophy. Expression of ANP and β-MHC was induced in all raptor-cKO mice irrespective of the cardiac load conditions. Consistent with reduced mTORC1 activity, phosphorylation of ribosomal S6 kinase and 4E-BP1 was blunted, indicating reduced protein synthesis. Moreover, expression of multiple genes involved in the regulation of energy metabolism was altered, and followed by a shift from fatty acid to glucose oxidation.Conclusion: Our study suggests that mTORC1 coordinates protein and energy metabolic pathways in the heart. Moreover, we demonstrate that raptor is essential for the cardiac adaptation to increased workload and importantly, also for normal physiological cardiac function.

Pronostic à long terme des patients ayant bénéficié d'une thrombolyse au stade aigu de l'infarctus du myocarde [Long-term prognosis for patients undergoing thrombolysis during the acute phase of myocardial infarction]

OBJECTIVE: The objective of this study was to analyse the long-term mortality and morbidity of a group of patients undergoing thrombolysis during the acute phase of myocardial infarction and to determine the factors influencing the prognosis. One hundred and seventy five patients (149 mean and 26 women, mean age: 54 years) were included in a randomized study, comparing the efficacy of 2 thrombolytic substances administered during the acute phase of myocardial infarction. A standard questionnaire was sent to the various attending physicians to follow-up of these 175 patients. RESULTS: The hospital mortality was 5% (9 patients) and 14 patients (9%) died after a mean follow-up of 4.3 +/- 2.1 years. The 5-year actuarial survival was 81%. Fourteen patients (8%) were lost to follow-up and 49 patients (32%) underwent surgical or percutaneous revascularization during follow-up. Revascularized patients had a significantly better survival than non-revascularized patients. The mean left ventricular ejection fraction of patients who died was lower (48% versus 71%) than that of survivors. Patients with an ejection fraction < 40% also had a significantly lower survival (p = 0.01). Patency of the vessel after thrombolysis was associated with a slightly better survival; this difference was not significant. The ejection fraction at 6 month was also significantly higher (60 +/- 10% versus 49 +/- 11%) for patients with a patent artery. Three risk factors for death or reinfarction were identified: age > 65 years at the time of infarction, disease in more than one coronary vessel and absence of angina pectoris before infarction. The probability of a coronary accident varied from 2 to 88% according to the number of risk factors present. At the time of follow-up, 60% of patients presented hypercholesterolaemia versus only 7% before infarction 73% of patients received anticoagulant or antiaggregant treatment and 81% of patients were asymptomatic. CONCLUSION: The mortality and the acute and long-term morbidity of myocardial infarction remain high, as only 34% of our patients did not develop any events during follow-up, despite serious medical management and follow-up. The ejection fraction has an important prognostic value. Patient management should take the abovementioned risk factors into account.

Rivascolarizzazione miocardica con arteria radiale: tecniche chirurgiche a confronto e risultati a breve termine [Myocardial revascularization and radial artery: different surgical strategies and short-term results]

BACKGROUND: The radial artery is routinely used as a graft for surgical arterial myocardial revascularization. The proximal radial artery anastomosis site remains unknown. In this study, we analyzed the short-term results and the operative risk determinants after having used four different common techniques for radial artery implantation. METHODS: From January 2000 to December 2004, 571 patients underwent coronary artery bypass grafting with radial arteries. Data were analyzed for the entire population and for subgroups following the proximal radial artery anastomosis site: 140 T-graft with the mammary artery (group A), 316 free-grafts with the proximal anastomosis to the ascending aorta (group B), 55 mammary arteries in situ elongated with the radial artery (group C) and 60 radial arteries elongated with a piece of mammary artery and anastomosed to the ascending aorta (group D). RESULTS: The mean age was 53.8 +/- 7.7 years; 55.5% of patients had a previous myocardial infarction and 73% presented with a satisfactory left ventricular function. A complete arterial myocardial revascularization was achieved in 532 cases (93.2%) and 90.2% of the procedures were performed under cardiopulmonary bypass and cardioplegic arrest. The operative mortality rate was 0.9%, a postoperative myocardial infarction was diagnosed in 19 patients (3.3%), an intra-aortic balloon pump was used in 10 patients (1.7%) and a mechanical circulatory device was implanted in 2 patients. The radial artery harvesting site remained always free from complications. The proximal radial artery anastomosis site was not a determinant of early hospital mortality. Group C showed a higher risk of postoperative myocardial infarction (p = 0.09), together with female gender (p = 0.003), hypertension (p = 0.059) and a longer cardiopulmonary bypass time. CONCLUSIONS: The radial artery and the mammary artery can guarantee multiple arterial revascularization also for patients with contraindications to double mammary artery use. The four most common techniques for proximal radial artery anastomosis are not related to a higher operative risk and they can be used alternatively to reach the best surgical results

Variabilité des concentrations plasmatiques de l'angiotensinogène et risque d'hypertension artérielle chez le rat transgénique [Variability of plasma angiotensinogen levels and risk of hypertension in a transgenic rat model].

AIM: Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors. METHODS: Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n=3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction). RESULTS: At baseline, transgenic rats had +18mmHg higher bood pressure and -8% lower body weight compared to non-transgenic rats (P<0.05) without significant changes for the vehicle groups throughout the study (P>0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P<0.05) in transgenic and +25%, +5.3% and +6.7% (P>0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P>0.05). CONCLUSION: Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.

Impact of the Advisa MRI pacing system on the diagnostic quality of cardiac MR images and contraction patterns of cardiac muscle during scans: Advisa MRI randomized clinical multicenter study results.

BACKGROUND: The Advisa MRI system is designed to safely undergo magnetic resonance imaging (MRI). Its influence on image quality is not well known. OBJECTIVE: To evaluate cardiac magnetic resonance (CMR) image quality and to characterize myocardial contraction patterns by using the Advisa MRI system. METHODS: In this international trial with 35 participating centers, an Advisa MRI system was implanted in 263 patients. Of those, 177 were randomized to the MRI group and 150 underwent MRI scans at the 9-12-week visit. Left ventricular (LV) and right ventricular (RV) cine long-axis steady-state free precession MR images were graded for quality. Signal loss along the implantable pulse generator and leads was measured. The tagging CMR data quality was assessed as the percentage of trackable tagging points on complementary spatial modulation of magnetization acquisitions (n=16) and segmental circumferential fiber shortening was quantified. RESULTS: Of all cine long-axis steady-state free precession acquisitions, 95% of LV and 98% of RV acquisitions were of diagnostic quality, with 84% and 93%, respectively, being of good or excellent quality. Tagging points were trackable from systole into early diastole (360-648 ms after the R-wave) in all segments. During RV pacing, tagging demonstrated a dyssynchronous contraction pattern, which was not observed in nonpaced (n = 4) and right atrial-paced (n = 8) patients. CONCLUSIONS: In the Advisa MRI study, high-quality CMR images for the assessment of cardiac anatomy and function were obtained in most patients with an implantable pacing system. In addition, this study demonstrated the feasibility of acquiring tagging data to study the LV function during pacing.

Cardiac hypertrophy, low blood pressure, and low aldosterone levels in mice devoid of the three circadian PAR bZip transcription factors DBP, HLF, and TEF.

The cardiovascular system is under the control of the circadian clock, and disturbed circadian rhythms can induce cardiovascular pathologies. This cyclic regulation is probably brought about by the circadian expression of genes encoding enzymes and regulators involved in cardiovascular functions. We have previously shown that the rhythmic transcription of output genes is, in part, regulated by the clock-controlled PAR bZip transcription factors DBP (albumin D-element Binding Protein), HLF (Hepatic Leukemia Factor), and TEF (Thyrotroph Embryonic Factor). The simultaneous deletion of all three PAR bZip transcription factors leads to increased morbidity and shortened life span. Here, we demonstrate that Dbp/Tef/Hlf triple knockout mice develop cardiac hypertrophy and left ventricular dysfunction associated with a low blood pressure. These dysfunctions are exacerbated by an abnormal response to this low blood pressure characterized by low aldosterone levels. The phenotype of PAR bZip knockout mice highlights the importance of circadian regulators in the modulation of cardiovascular functions.

Hypoxia: unique myocardial morphology?

OBJECTIVE: The objective of this study was to investigate the effects of chronic and intermittent hypoxia on myocardial morphology. METHODS: Rats randomly divided into 3 groups (n = 14 per group) were exposed to room air (Fio(2) = 0.21), chronic hypoxia (Fio(2) = 0.10), and intermittent hypoxia (chronic hypoxia with 1 hour per day of room air) for 2 weeks. Weight, blood gas analysis, hematocrit, hemoglobin, red cells, and right and left ventricular pressures were measured. Hearts excised for morphologic examination were randomly divided into 2 groups (9 per group for gross morphologic measurements and 5 per group for histologic and morphometric analysis). The weight ratio of right to left ventricles plus interventricular septum, myocyte diameter, cross-sectional area, and free wall thickness in right and left ventricles were measured. RESULTS: Despite the same polycythemia, the right ventricle pressure (P <.05) and ratio of right to left ventricle pressures (P <.02) were higher after chronic hypoxia than intermittent hypoxia. The ratio of heart weight to total body weight and the ratio of right to left ventricles plus interventricular septum was higher (P <.01) in chronic and intermittent hypoxia than in normoxia. Myocyte diameter was not different between the right and left ventricles in normoxia, whereas right ventricle myocytes were larger than left ventricle myocytes in chronic hypoxia (P <.05) and intermittent hypoxia (P <.0005). There was marked dilatation of right ventricle size (P <.001) and marked reduction of left ventricle (P <.001) size in chronic and intermittent hypoxia compared with normoxia. The total ventricular area (right ventricle plus left ventricle area) remained the same in all groups. The wall thickness ratio in chronic hypoxia and intermittent hypoxia was increased (P <.001) compared with normoxia in the right ventricle but not in the left ventricle. CONCLUSIONS: Intermittent reoxygenation episodes do not induce a lesser ventricular hypertrophic response than observed with chronic hypoxia. The functional myocardial preconditioning consequence of intermittent reoxygenation is not supported by structural differences evident with the available techniques.

Transcatheter coil embolization of multiple bilateral congenital coronary artery fistulae.

Coronary artery fistulae represent the most frequent congenital anomalies of the coronary arteries, but remain a relatively uncommon clinical problem. Moreover, multiple fistulae originating from both the left and the right coronary arteries and draining into the left ventricular chamber are a rare condition. Due to the low prevalence of these anomalies, the appropriate management of patients with symptomatic coronary artery fistulae is controversial. Transcatheter closure approaches have emerged as a less invasive strategy and are nowadays considered a valuable alternative to surgical correction with similar effectiveness, morbidity and mortality. The percutaneous management, however, is mainly limited by the individual anatomic features of the fistula and an appropriate patient's selection is considered as a key determining factor to achieve complete occlusion. Thus, success rates of transcatheter closure techniques reported in the literature are extremely variable and highly dependent upon the nature of the follow up, which, at present, is not standardized. The optimal management of symptomatic patients with multiple coronary artery fistulae still remains a challenging problem and has been traditionally considered as an indication for cardiac surgery. We report here the case of a patient with double bilateral congenital coronary artery fistulae arising from both the left and right coronary arteries and draining individually into the left ventricular chamber. This patient underwent successful transcatheter anterograde closure of both fistulae using a microcoil embolization technique.

EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy.

The M-band is the prominent cytoskeletal structure that cross-links the myosin and titin filaments in the middle of the sarcomere. To investigate M-band alterations in heart disease, we analyzed the expression of its main components, proteins of the myomesin family, in mouse and human cardiomyopathy. Cardiac function was assessed by echocardiography and compared to the expression pattern of myomesins evaluated with RT-PCR, Western blot, and immunofluorescent analysis. Disease progression in transgenic mouse models for dilated cardiomyopathy (DCM) was accompanied by specific M-band alterations. The dominant splice isoform in the embryonic heart, EH-myomesin, was strongly up-regulated in the failing heart and correlated with a decrease in cardiac function (R = -0.86). In addition, we have analyzed the expressions of myomesins in human myocardial biopsies (N = 40) obtained from DCM patients, DCM patients supported by a left ventricular assist device (LVAD), hypertrophic cardiomyopathy (HCM) patients and controls. Quantitative RT-PCR revealed that the EH-myomesin isoform was up-regulated 41-fold (P < 0.001) in the DCM patients compared to control patients. In DCM hearts supported by a LVAD and HCM hearts, the EH-myomesin expression was comparable to controls. Immunofluorescent analyses indicate that EH-myomesin was enhanced in a cell-specific manner, leading to a higher heterogeneity of the myocytes' cytoskeleton through the myocardial wall. We suggest that the up-regulation of EH-myomesin denotes an adaptive remodeling of the sarcomere cytoskeleton in the dilated heart and might serve as a marker for DCM in mouse and human myocardium.

Telmisartan: a different angiotensin II receptor blocker protecting a different population?

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET()) showed that the angiotensin II receptor blocker (ARB) telmisartan was as protective as the reference-standard ramipril in a broad cross-section of patients at increased cardiovascular risk, but was better tolerated. Telmisartan has a unique profile among ARBs, with a high affinity for the angiotensin II type 1 receptor, a long duration of receptor binding, a high lipophilicity and a long plasma half life. This leads to sustained and powerful blood pressure lowering when compared with the first marketed ARBs, such as losartan and valsartan. Some pharmacological properties of telmisartan clearly distinguish it from other members of the ARB class and may contribute to the clinical effects seen with telmisartan. A class effect for ARBs cannot be assumed. To date, telmisartan is the only ARB that has been shown to reduce cardiovascular risk in at-risk cardiovascular patients.

Connexin 43 expression in human hypertrophied heart due to pressure and volume overload.

Left ventricular hypertrophy (LVH) is due to pressure overload or mechanical stretch and is thought to be associated with remodeling of gap-junctions. We investigated whether the expression of connexin 43 (Cx43) is altered in humans in response to different degrees of LVH. The expression of Cx43 was analyzed by quantitative polymerase chain reaction, Western blot analysis and immunohistochemistry on left ventricular biopsies from patients undergoing aortic or mitral valve replacement. Three groups were analyzed: patients with aortic stenosis with severe LVH (n=9) versus only mild LVH (n=7), and patients with LVH caused by mitral regurgitation (n=5). Cx43 mRNA expression and protein expression were similar in the three groups studied. Furthermore, immunohistochemistry revealed no change in Cx43 distribution. We can conclude that when compared with mild LVH or with LVH due to volume overload, severe LVH due to chronic pressure overload is not accompanied by detectable changes of Cx43 expression or spatial distribution.

Troubleshooting in extracorporeal life support.

Since the first clinical use of extracorporeal circulation in the last century [1] by John Gibbon and the first successful mechanical support of the left ventricular function by Forest Dodrill [2], the progress of techniques and technologies has helped to develop minimised systems for extracorporeal circulatory and respiratory support. However, the fact is that, despite the advanced technologies used for extracorporeal support, successful application in order to be benefit a critically ill population requires highly trained and skilled teams. Application of these highly sophisticated techniques in life-saving situations inside and/or outside the operating room is a procedure with certain pitfalls and dangers. The aim of this review is to provide a short overview of the technical aspects of extracorporeal circulation, with a look at the recent literature and clinical experiences focusing on technical as well surgical considerations regarding the urgent and/or emergent usage of a central as well as peripheral extracorporeal system.

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.