This study aimed to determine aortic disease severity in patients with Loeys-Dietz syndrome (LDS).
Thirty-three patients with LDS diagnosed and followed up at our unit were included. After reviewing ...all family trees, 25 deceased family members with clear clinical suspicion of having had LDS were also included. Clinical presentation, aortic dilation rate by echocardiography and age at aortic surgery, dissection or death were determined.
Median aortic diameter at diagnosis was 36 mm, 43% of the patients aged >40 years had a z-score <2. Median aortic root dilation rate was 0.67 mm/year (maximum 2.0 mm/year) over a median follow-up of 2 years (IQR 1.0-4.0). In the global cohort, 31/58 patients reached a clinical endpoint; 19% death, median age: 52 years; 14% dissection, median age: 36 years; 21% aortic surgery, median age: 53 years. As expected, probands had a higher z-score (2.9 vs 1.5, p=0.019) and more often required aortic surgery (33.4% vs 18.2%, p=0.035) compared with family members. TGFBR2 carriers had a higher z-score compared with TGFBR1 carriers (3.2 vs 1.5, p=0.034) and younger age at aortic surgery (HR 4.9, 95% CI 1.5 to 123, p=0.026). Craniofacial severity index was inversely correlated with age at first event (r=-0.765, p=0.045).
Although paediatric patients were not properly represented in our cohort, our patients with LDS presented a significant heterogeneity in the severity of aortic disease with large intrafamilial and interfamilial variability, aortic root aneurysm were less frequent and aortic complications less premature than previously depicted. Furthermore, aortic dilation rate was similar to that reported in Marfan syndrome and aortic root diameters appear to be larger in TGFBR2 carriers.
The effect of
mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results.
This study aims to determine the impact ...of the
mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality).
MFS patients with a pathogenic
mutation followed at two specialised units were included.
mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients.
Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-
mutation and 177 (61%) with a DN-
. At baseline, patients with HI-
had a larger aortic root diameter than patients with DN-
(HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-
(HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-
tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-
(HR: 3.3, 95% CI 1.0 to 11.4, p=0.060).
Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.
Acute myocardial infarction (AMI) and the heart failure (HF) that often complicates this condition, are among the leading causes of death and disability worldwide. To reduce myocardial infarct (MI) ...size and prevent heart failure, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). In this regard, targeting cardiac innervation may provide a novel therapeutic strategy for cardioprotection. A number of cardiac neural pathways mediate the beneficial effects of cardioprotective strategies such as ischaemic preconditioning and remote ischaemic conditioning, and nerve stimulation may therefore provide a novel therapeutic strategy for cardioprotection. In this article, we provide an overview of cardiac innervation and its impact on acute myocardial IRI, the role of extrinsic and intrinsic cardiac neural pathways in cardioprotection, and highlight peripheral and central nerve stimulation as a cardioprotective strategy with therapeutic potential for reducing MI size and preventing HF following AMI. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
To assess the usefulness of hand-held cardiac ultrasound (HCU) performed by family doctors (FDs) in primary care, with web-based remote expert support interpretation, in a cohort of patient with ...symptoms or physical examination signs suggestive of cardiovascular disease.
This prospective observational study included 1312 consecutive patients, in three remote primary care areas, with symptoms or physical examination signs suggestive of cardiovascular disease. In 859 patients (group A), FDs had indicated conventional echocardiography (CE), and in 453 (Group B) the study was performed to complement the physical examination. HCU was carried out by 14 FDs after a short training period. The scans and preliminary FD reports were uploaded on a web-based program for remote expert support interpretation in <24 h.
Experts considered HCU to be inconclusive in 116 (8.8%) patients. FD and expert agreement on diagnosis was moderate (K=0.40-0.70) except in mitral stenosis (K=0.29) and in left atrial dilation (K=0.38). Diagnostic agreement between expert interpretation and CE was good (K=0.66-0.85) except in mitral stenosis (K=0.43). After remote expert interpretation, conventional echocardiograms were finally requested by FDs in only 276 (32.1%) patients, and discharges increased by 10.2%. Furthermore, significant heart diseases were diagnosed in 32 (7%) patients of group B.
HCU performed at the point of care by FDs with remote expert support interpretation using a web-based system is feasible, rapid and useful for detecting significant echocardiographic abnormalities and reducing the number of unnecessary echocardiographic studies.
Therapeutic fibrinolysis is ineffective in 40 % of ST-segment elevation acute myocardial infarction (STEMI) patients, but understanding of the mechanisms is incomplete. It was our aim to compare the ...composition of coronary thrombus in lysis-resistant STEMI patients with that of lysis-sensitive patients. Intracoronary thrombi (n=64) were obtained by aspiration in consecutive STEMI patients. Of them, 20 had received fibrinolysis and underwent rescue percutaneous coronary intervention (r-PCI, lysis-resistant patients) and 44 underwent primary PCI (p-PCI). Lysis-sensitivity was determined in vitro by clot permeability measurements and turbidimetric lysis in plasma of 44 patients undergoing p-PCI and 20 healthy donors. Clot-lysis sensitivity was defined as a clot-lysis time not greater than 1 SD over the mean of healthy donors. Coronary thrombus composition in 20 lysis-resistant and in 20 lysis-sensitive patients was analysed by immunofluorescence with confocal microscopy. Plasma biomarkers (P-selectin, VWF, PAI-1, t-PA, D-dimer, TF pathway markers, plasmin and CD34+) were measured simultaneously on peripheral blood. Lysis-resistant clots had higher levels of fibrin (p=0.02), P-selectin (p=0.03) and VWF (p=0.01) than lysis-sensitive clots. Among thrombi obtained ≤ 6 hours after onset of symptoms, those from lysis-resistant patients showed a higher content in fibrin than those from p-PCI patients (p=0.01). Plasma PAI-1 (p=0.02) and D-dimer levels were significantly higher (p=0.003) in lysis-resistant patients, whereas plasmin levels were lower (p=0.03). Multivariate analysis showed the content of fibrin and VWF within thrombus as predictors of thrombolysis resistance. In conclusion, coronary thrombi in STEMI patients resistant to fibrinolysis are characterised by higher fibrin, P-selectin and VWF content than lysis-sensitive thrombi.
Background
Echocardiography‐ and cardiovascular magnetic resonance (CMR)‐based studies have revealed a wide range of phenotypic manifestations in hypertrophic cardiomyopathy (HCM) apart from ...hypertrophy. This study sought to comprehensively describe a number of structural abnormalities in HCM beyond hypertrophy, by multimodality imaging.
Methods
A total of 100 HCM patients were prospectively enrolled, undergoing standard and contrast echocardiography, and CMR. Morphological characteristics involving mitral valve leaflets (MVL), subvalvular apparatus, and left ventricular cavity and wall were investigated. Seventy healthy volunteers served as control population.
Results
As assessed by echo, MVLs were longer in HCM patients than in controls (anterior method 1: 2422,28 vs 1918,20 mm, P < 0.01; anterior method 2: 2724, 29 vs 2119, 23 mm, P < 0.01; posterior: 1512,19 vs 1413,15 mm, P < 0.01). Abnormal chordal attachment to anterior MVL, anterior papillary muscle displacement, and accessory apical‐basal muscle bundle were present in 42 (42%), 61 (61%), and 35 (35%) patients, respectively (P values vs controls <0.01); direct papillary muscle insertion into MVL and hypertrabeculation were found in two and five patients, respectively. Contrast echocardiography (n = 94) detected myocardial crypts in 15 patients (16%). Overall, 83% of HCM subjects had at least one of these phenotypic manifestations. Echocardiography and CMR agreement for MVL length was poor, while for structural characteristics was moderate to substantial (Cohen's Kappa: 0.53‐1.00). Except for posterior MVL length and hypertrabeculation, the phenotypic characteristics studied had acceptable reproducibility by echocardiography and CMR.
Conclusions
Structural abnormalities in HCM beyond hypertrophy are significantly common. Multimodality imaging approach to these HCM facets by echocardiography and CMR is feasible and desirable.
The aim of this study was to assess whether the clinical characteristics, management, and outcomes of infective endocarditis differ in women and men through a prospective observational cohort study ...at a single tertiary care teaching hospital. From January 2000 to December 2008, 271 new cases of infective endocarditis were diagnosed (183 in men, 88 in women) according to modified Duke criteria, and patients were followed for 1 year. Women were older than men (mean age 63 ± 16 vs 58 ± 18 years, p = 0.006); more women were taking immunosuppressants (14% vs 3%, p = 0.006) and had mitral valve involvement (52% vs 36%, p = 0.02). However, more men had human immunodeficiency virus infection than women. There were no gender differences in Charlson index, regurgitation severity, culprit pathogens, or major complications. When surgery was indicated, women were less likely to undergo the procedure (26% vs 47%, relative risk RR 0.4, 95% confidence interval CI 0.2 to 0.7), p = 0.001). Mortality tended to be higher in women in the hospital (32% vs 23%, RR 1.58, 95% CI 1 to 2.5, p = 0.05) and at 1 year (38% vs 26%, RR 1.7, 95% CI 1.0 to 2.9, p = 0.04). Surgical treatment was a protective factor against death in the hospital (RR 0.18, 95% CI 0.04 to 0.77, p = 0.02) and at 1 year (RR 0.12, 95% CI 0.03 to 0.48, p = 0.03) after adjustment for age, gender, Charlson index, infection by Staphylococcus aureus , severity at presentation, heart failure, acute renal failure, stroke, and the ejection fraction. In conclusion, women with infective endocarditis were slightly older than men but showed similar co-morbidities. Women underwent surgery less frequently and consequently had worse prognosis than men.
Background
The cGMP/protein kinase G (PKG) pathway is involved in the cardioprotective effects of postconditioning (PoCo). Although PKG signaling in PoCo has been proposed to depend on the activation ...of the phosphatidylinositol 3‐kinase (PI3K)/Akt cascade, recent data bring into question a causal role of reperfusion injury signaling kinase (RISK) in PoCo protection. We hypothesized that PoCo increases PKG activity by reducing oxidative stress–induced endothelial nitric oxide synthase (NOS) uncoupling at the onset of reperfusion.
Methods and Results
Isolated rat hearts were submitted to 40 minutes of ischemia and reperfusion with and without a PoCo protocol. PoCo reduced infarct size by 48% and cGMP depletion. Blockade of cGMP synthesis (1H‐1,2,4oxadiazolo4,3‐aquinoxalin‐1‐one) and inhibition of PKG (KT5823) or NOS (l‐NAME) abolished protection, but inhibition of PI3K/Akt cascade (LY294002) did not (n=5 to 7 per group). Phosphorylation of the RISK pathway was higher in PoCo hearts. However, this difference is due to increased cell death in control hearts because in hearts reperfused with the contractile inhibitor blebbistatin, a drug effective in preventing cell death at the onset of reperfusion, RISK phosphorylation increased during reperfusion without differences between control and PoCo groups. In these hearts, PoCo reduced the production of superoxide (O2−) and protein nitrotyrosylation and increased nitrate/nitrite levels in parallel with a significant decrease in the oxidation of tetrahydrobiopterin (BH4) and in the monomeric form of endothelial NOS.
Conclusions
These results demonstrate that PoCo activates the cGMP/PKG pathway via a mechanism independent of the PI3K/Akt cascade and dependent on the reduction of O2− production at the onset of reperfusion, resulting in attenuated oxidation of BH4 and reduced NOS uncoupling.
Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that ...underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.
The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we ...aimed at finding the link between ENDOG activity and cardiomyocyte growth. Endog deficiency induced reactive oxygen species (ROS) accumulation and abnormal growth in neonatal rodent cardiomyocytes, altering the AKT-GSK3β and Class-II histone deacethylases (HDAC) signal transduction pathways. These effects were blocked by ROS scavengers. Lack of ENDOG reduced mitochondrial DNA (mtDNA) replication independently of ROS accumulation. Because mtDNA encodes several subunits of the mitochondrial electron transport chain, whose activity is an important source of cellular ROS, we investigated whether Endog deficiency compromised the expression and activity of the respiratory chain complexes but found no changes in these parameters nor in ATP content. MtDNA also codes for humanin, a micropeptide with possible metabolic functions. Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes. These results support the involvement of redox signaling in the control of cardiomyocyte growth by ENDOG and suggest a pathway relating mtDNA content to the regulation of cell growth probably involving humanin, which prevents reactive oxygen radicals accumulation and hypertrophy induced by Endog deficiency.
•Endog deficiency induces cardiomyocyte hypertrophy and superoxide accumulation.•Hypertrophy induced by Endog deficiency requires ROS accumulation.•ENDOG is involved in mtDNA replication independently of ROS accumulation.•Electron Transport Chain activity is not affected by Endog deficiency.•Humanin restricts ROS accumulation and blocks cardiomyocyte growth.
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