α1A-Adrenergic Receptor-Directed Autoimmunity Induces Left Ventricular Damage and Diastolic Dysfunction in Rats

Background

Agonistic autoantibodies to the α₁-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain.

Methods/Principal Findings

We immunized Lewis rats with the second extracellular-loop peptides of the human α_1A-adrenergic receptor and maintained them for one year. α_1A-adrenergic antibodies (α_1A-AR-AB) were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human α_1A-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt_max demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt_min. Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang) II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats.

Conclusions/Significance

We show that α_1A-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that α_1A-AR-AB could contribute to cardiovascular endorgan damage.     

The Metabolic Syndrome and ECG Detected Left Ventricular Hypertrophy – Influences from IGF-1 and IGF-Binding Protein-1

Background and Aims

The metabolic syndrome (MetS) is associated with an increased risk for left ventricular hypertrophy (LVH) and cardiovascular mortality. The aim of this study was to investigate potential influences from insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) on the relationship between the MetS and LVH, also taking into account the role of physical activity (PA), use of oestrogen and gender.

Methods and Results

In a population-based cross-sectional study of 60-year-old men (n = 1822) and women (n = 2049) participants underwent physical examination and laboratory tests, including electrocardiography (ECG), and completed an extensive questionnaire. Women showed higher levels of IGFBP-1 than men (37.0 vs. 28.0 µg/l, p<0.001), and women with LVH had lower levels of IGFBP-1 than women without LVH (31.0 µg/l vs. 37.0 µg/l, p<0.001). Furthermore, women with low levels of IGFBP-1 had a significantly increased risk of having LVH (crude OR≈2.5). When stratifying for PA and oestrogen, respectively, a weaker association between IGFBP-1 and LVH was demonstrated in physically active men and women, compared to inactive individuals, as well as in women using oestrogen, compared to non-users.

Conclusion

In a representative sample of 60-year-old Swedish men and women, the main findings were higher levels of IGFBP-1 in women than in men; lower levels of IGFBP-1 in women with LVH, compared to women without LVH; and an increased risk of having LVH in women with low levels of IGFBP-1. The association between IGFBP-1 and LVH was diminished in physically active men and women, as well as in women using oestrogen.     

Qishenyiqi Protects Ligation-Induced Left Ventricular Remodeling by Attenuating Inflammation and Fibrosis via STAT3 and NF-κB Signaling Pathway

Aim

Qi-shen-yi-qi (QSYQ), a formula used for the routine treatment of heart failure (HF) in China, has been demonstrated to improve cardiac function through down-regulating the activation of the Renin-Angiotensin-Aldosterone System (RAAS). However, the mechanisms governing its therapeutic effects are largely unknown. The present study aims to demonstrate that QSYQ treatment can prevent left ventricular remodeling in heart failure by attenuating oxidative stress and inhabiting inflammation.

Methods

Sprague-Dawley (SD) rats were randomly divided into 6 groups: sham group, model group (LAD coronary artery ligation), QSYQ group with high dosage, middle dosage and low dosage (LAD ligation and treated with QSYQ), and captopril group (LAD ligation and treated with captopril as the positive drug). Indicators of fibrosis (Masson, MMPs, and collagens) and inflammation factors were detected 28 days after surgery.

Results

Results of hemodynamic alterations (dp/dt value) in the model group as well as other ventricular remodeling (VR) markers, such as MMP-2, MMP-9, collagen I and III elevated compared with sham group. VR was accompanied by activation of RAAS (angiotensin II and NADPHoxidase). Levels of pro-inflammatory cytokines (TNF-α, IL-6) in myocardial tissue were also up-regulated. Treatment of QSYQ improved cardiac remodeling through counter-acting the aforementioned events. The improvement of QSYQ was accompanied with a restoration of angiotensin II-NADPHoxidase-ROS-MMPs pathways. In addition, “therapeutic” QSYQ administration can reduce both TNF-α-NF-B and IL-6-STAT3 pathways, respectively, which further proves the beneficial effects of QSYQ.

Conclusions

Our study demonstrated that QSYQ protected LAD ligation-induced left VR via attenuating AngII -NADPH oxidase pathway and inhabiting inflammation. These findings provide evidence as to the cardiac protective efficacy of QSYQ to HF and explain the beneficial effects of QSYQ in the clinical application for HF.     

Ventricular pacing – Electromechanical consequences and valvular function

Although great strides have been made in the areas of ventricular pacing, it is still appreciated that dyssynchrony can be malignant, and that appropriately placed pacing leads may ameliorate mechanical dyssynchrony. However, the unknowns at present include:1. The mechanisms by which ventricular pacing itself can induce dyssynchrony;2. Whether or not various pacing locations can decrease the deleterious effects caused by ventricular pacing;3. The impact of novel methods of pacing, such as atrioventricular septal, lead-less, and far-field surface stimulation;4. The utility of ECG and echocardiography in predicting response to therapy and/or development of dyssynchrony in the setting of cardiac resynchronization therapy (CRT) lead placement;5. The impact of ventricular pacing-induced dyssynchrony on valvular function, and how lead position correlates to potential improvement.This review examines the existing literature to put these issues into context, to provide a basis for understanding how electrical, mechanical, and functional aspects of the heart can be distorted with ventricular pacing. We highlight the central role of the mitral valve and its function as it relates to pacing strategies, especially in the setting of CRT. We also provide future directions for improved pacing modalities via alternative pacing sites and speculate over mechanisms on how lead position may affect the critical function of the mitral valve and thus overall efficacy of CRT.     

Left–Right Determination: Involvement of Molecular Motor KIF3, Cilia,and Nodal Flow

Mammalian left–right determination is a good example for how multiple cell biological processes coordinate in the formation of a basic body plan. The leftward movement of fluid at the ventral node, called nodal flow, is the central process in symmetry breaking on the left–right axis. Nodal flow is autonomously generated by the rotation of posteriorly tilted cilia that are built by transport via KIF3 motor on cells of the ventral node. How nodal flow is interpreted to create left–right asymmetry has been a matter of debate. Recent evidence suggests that the leftward movement of sheathed lipidic particles, called nodal vesicular parcels (NVPs), may result in the activation of the noncanonical hedgehog signaling pathway, an asymmetric elevation in intracellular Ca²⁺ and changes in gene expression.Although the human body is apparently bilaterally symmetrical on the surface, the visceral organs are arranged asymmetrically in a stereotyped manner. The heart, spleen, and pancreas reside on the left side of the body, whereas the gall bladder and most of the liver are on the right side (Fig. 1A). Because the human body is formed from a spherically symmetrical egg (oocyte), symmetry breakdown is one of the fundamental processes of development.Open in a separate windowFigure 1.(A) Left–right asymmetric arrangements of internal organs in the human body. (Left) Normal arrangement (situs solitus). Most humans (>99%) have the heart on the left side and the liver on the right side. (Right) Mirrored arrangement (situs inversus). Half of patients with Kartagener''s syndrome have this arrangement, whereas the remaining patients are normal. Therefore, the left–right bilateral symmetry is randomly broken in this disease. (B–E) Scanning electron micrographs of wild-type (B, D) and Kif3b^−/− (C, E) mouse embryos. (B, C) Full-length images. Wild-type embryos at this stage have already turned with a right-sided tail (B), whereas Kif3b^−/− embryos remain unturned (C). In panel C, the dilated pericardial sac has been removed, and the heart loop is inverted (arrow). (D, E) Higher-magnification images and schematic representations of the heart loops showing a normal loop in the wild-type embryo (D) and an inverted loop in the mutant embryo (E). (F–I) Scanning electron micrographs of a mouse node. (F) Low-magnification view of a mouse embryo at 7.5 days postcoitum. Reichert''s membrane is removed, and the embryo is observed from the ventral side. The node is indicated by a black rectangle. The orientation is indicated in the panel as anterior (A), posterior (P), left (L), and right (R). Scale bar = 100 µm. (G) Higher-magnification view of the mouse node. The orientation is the same as in panel A. Scale bar = 20 µm. (H) Higher-magnification view of the nodal cilia (arrows) and nodal pit cells. Scale bar = 5 µm. (I) Nodal pit cells of Kif3b^−/− embryos. Nodal cilia are absent in these genetically manipulated embryos. (J) Intraflagellar transport. Protein components in the cilia and flagella are transported by KIF3A/B complexes (light and dark blue) along the doublet microtubules of the axoneme. (Panels A and J were reproduced with permission from JT Biohistory Research Hall/TokyoCinema. B–I were modified from Nonaka et al. 1998, Okada et al. 2005, and Hirokawa et al. 2006, with permission.)In many lower vertebrates and invertebrates, eggs are asymmetrical even before fertilization (as in Drosophila [Gilbert 2003]). In some organisms, such as fish and frog, the dorsoventral (DV) and anteroposterior (AP) axes are determined at fertilization by the distribution of the yolk and the entry position of the sperm (Gilbert 2003). In human, mouse, and other mammals, the embryo is initially cylindrically symmetrical when it implants itself into the wall of the uterus. The DV axis is first to be specified as the proximal–distal axis from the implantation site. Subsequently, the AP axis is arbitrarily determined in the plane perpendicular to the DV axis (Alarcon and Marikawa 2003; Beddington and Robertson 1999). In either case, L/R is thus the last axis to be determined, and needs to be consistent with the preceding DV and AP axes. Because the chirality of the body is predetermined by chiral molecules, such as amino acids and nucleic acids, the laterality or orientation of the L/R axis is established theoretically or potentially once the AP and DV axes are determined. The problem here is how this potentially established laterality is materialized through developmental events. This mechanism is still totally unknown for the invertebrates. However, recent studies of mouse embryo clarified the L/R determination mechanism in mammalian embryos (Hirokawa et al. 2006).Until recently, little was known about the mechanism for breaking L/R symmetry. The initial clue to tackling this question was a human genetic disease called Kartagener''s syndrome. Approximately half of these patients have their organs in the reversed orientation (situs inversus). Thus, the L/R determination is randomized in this syndrome. Patients with Kartagener''s syndrome also suffer from sinusitis and bronchiectasis (Kartagener 1933). A number of male patients with Kartagener''s syndrome are sterile. Affected individuals have immotile sperm and defective cilia in their airway (Afzelius 1976). Airway cilia and sperm from these patients have abnormal ultrastructures. Specifically, the axonemes, the interior supramolecular complexes that produce the movement of cilia and flagella, lack dynein arms, the molecular motors required for cilia and flagella motility (Afzelius 1976). However, the relationships between these phenotypes and the causes of situs inversus remained unknown for more than 20 years.Approximately 10 years ago, molecular biological studies identified several genes that are asymmetrically expressed in the L/R orientation before L/R asymmetric morphogenesis of the embryo. Morphological L/R asymmetry first becomes apparent with the orientation of the heart-tube loop (Fig. 1B,D) (Kaufman 1992), but initial L/R asymmetric gene expression precedes the morphological changes. In early embryos (7.5 days for mice) at the stage of somatogenesis, genes such as Lefty-2 (Ebaf), Nodal, and Pitx2 are expressed in the left lateral plate mesoderm, a structure located on the side of the embryos (Capdevila et al. 2000; Hamada 2002; Harvey 1998; Levin 2005; Yost 1999). However, the upstream phenomena that cause asymmetrical expression of these genes remain enigmatic.Many studies have suggested that the so-called node, a concave triangular region transiently formed during gastrulation at the ventral midline surface of early embryos, is important for L/R determination (Harvey 1998). When viewed from above the ventral side, the node of mouse embryos appears as a roughly triangular depression with the apex pointed toward the anterior (Fig. 1F,G), and it is 50–100 µm in width and 10–20 µm in depth. This nodal pit is covered by Reichert''s membrane, and the cavity is filled with extraembryonic fluid. The ventral embryonic surface of the nodal pit consists of an epithelial sheet of a few hundred monociliated cells (nodal pit cells).Nodal pit cells have one or sometimes two cilia that appear as rodlike protrusions approximately 5 µm in length and 0.3 µm in diameter (Fig. 1G,H). Because Kartagener''s syndrome suggests a potential link between cilia motility and L/R determination, the cilia in the node have been postulated to be motile and responsible for L/R determination.However, the ultrastructure of these nodal cilia is similar to that of immotile primary cilia. In motile cilia and flagella, nine pairs of doublet microtubules are arranged longitudinally along the axes (Fig. 2A) (Satir and Christensen 2007). Adjacent pairs of doublet microtubules are connected by dynein arms, which generate the motility of cilia and flagella. In addition, there are two microtubules in the center of cilia and flagella, referred to as the central pair, which define the direction of the beating plane. This essential central pair of microtubules is missing in primary cilia. Similar to other immotile primary cilia, the monocilia of nodal pit cells lack the central pair of microtubules and thus have a 9 + 0 microtubule arrangement. Therefore, based on their ultrastructure and initial video-microscopic observations, nodal monocilia were originally considered immotile (Bellomo et al. 1996).Open in a separate windowFigure 2.(A) Ultrastructures of normal cilia and primary cilia. (Left) Normal cilia and flagella have nine pairs of doublet microtubules (yellow) and two central microtubules (yellow). Adjacent doublet microtubules are connected with dynein motors (blue and green). The orientation of the central pair of microtubules is considered to determine the beating plane (purple). (Right) The central pair of microtubules is missing in immotile primary cilia and nodal cilia. In nodal cilia, the dynein motors remain in a chiral arrangement and produce a rotation-like movement (purple). (B–E) Rotation of nodal cilia and leftward nodal flow. The images are views from the ventral side. The orientation is indicated in the panels as anterior (A), posterior (P), left (L), and right (R). (B) Trajectory of a fluorescent bead attached to the tip of a nodal cilium (Movies 1 and 2). Three consecutive video frames with 33-ms exposures at 16-ms intervals (interlaced scan) are shown. The moving bead produces arc-shaped images (traced by green arrows). The beads rotate clockwise when viewed above the node. (C) Trajectories of the tips of nodal cilia traced from a high-speed video sequence (500 frames/s) (Movie 3). The red circles show the positions of the ends of the cilia at 10-ms time intervals, and the yellow circles show the positions of the roots of the cilia. The white ellipses show the trajectories of the tips. Scale bar = 5 µm. (D) The positions of beads that entered the node from the right edge traced for 4 seconds at 0.33-second intervals. Different symbols indicate different beads. Most beads go straight to the left edge of the node. Scale bar = 20 µm. (E) The trajectories of four beads selected to illustrate the streamline of the nodal flow. The flow is mostly laminar and straight in the middle of the node, but often makes small vortices near the left edge (arrowheads). (Panel A was reproduced with permission from JT Biohistory Research Hall/TokyoCinema. B–E were modified from Okada et al. [1999, 2005] with permission.)

Movie 1

Download video file.^{(3.2M, mov)}Leftward nodal flow. Nodal flow was visualized by adding fluorescent beads to the medium surrounding the ventral node of a mouse embryo at the early somite stage. 4× time lapse.

Movie 2

Open in a separate windowClick here to view.^{(104K, gif)}Rotatory movement of nodal cilia.

Movie 3

Download video file.^{(39M, mov)}Posteriorly-tilted rotation of nodal cilia. Nodal cilia were observed by high-speed video microscopy (500 frames/s). The focus was adjusted to approximately 3 µm above the surface of the ventral node. The images of the cilia thus blur when they are near the floor and become clear when they come up to the focal plane. Note that the particle (highlighted by a red circle) does not go down to the surface but eventually goes toward the left side of the node due to the movement of the cilia. Reproduced from Okada et al. (2005) with permission.Through studies of the flow of materials within cells, we serendipitously found that nodal cilia are actually motile and vigorously rotating. This rotation generates the leftward flow of extraembryonic fluid in the nodal pit. The directionality of this flow, termed nodal flow, determines laterality. Thus, quite unexpectedly, a physical process, fluid flow, was identified as the initial L/R symmetry-breaking event. In this review, we first summarize the discovery of nodal flow and then discuss how this leftward linear flow is generated in a fluid dynamic manner by the rotational movement of cilia. We further discuss the mechanisms by which L/R asymmetry is determined by this nodal flow.     

Left Atrial Appendage Dysfunction in a Patient with Premature Ventricular Contractions - A Risk Factor for Stroke?

A 16-year-old female with ventricular dysfunction and frequent ventricular arrhythmia presented with a cardioembolic stroke. Prior electrophysiology study and ablation was performed for ventricular tachycardia (VT). For remaining ventricular ectopy, the patient was maintained on carvedilol and mexiletine. After one year on this regimen, she presented with an acute stroke. Transesophageal echocardiography revealed no evidence of an intracardiac or ventricular thrombus but demonstrated markedly decreased left atrial appendage (LAA) flow velocity worsened during frequent premature ventricular contractions (PVC). In the absence of atrial fibrillation (AF), the LAA dysfunction was considered secondary to the frequent PVCs and was thought to be the underlying cause for the stroke. We present this case to highlight a potential under recognized association between LAA dysfunction and ventricular arrhythmia, similar to that observed with atrioventricular dyssynchronous pacing.     

Up Regulation of cystathione γ lyase and Hydrogen Sulphide in the Myocardium Inhibits the Progression of Isoproterenol–Caffeine Induced Left Ventricular Hypertrophy in Wistar Kyoto Rats

Hydrogen sulphide (H₂S) is an emerging molecule in many cardiovascular complications but its role in left ventricular hypertrophy (LVH) is unknown. The present study explored the effect of exogenous H₂S administration in the regression of LVH by modulating oxidative stress, arterial stiffness and expression of cystathione γ lyase (CSE) in the myocardium. Animals were divided into four groups: Control, LVH, Control-H₂S and LVH-H₂S. LVH was induced by administering isoprenaline (5mg/kg, every 72 hours, S/C) and caffeine in drinking water (62mg/L) for 2 weeks. Intraperitoneal NaHS, 56μM/kg/day for 5 weeks, was given as an H₂S donor. Myocardial expression of Cystathione γ lyase (CSE) mRNA was quantified using real time polymerase chain reaction (qPCR).There was a 3 fold reduction in the expression of myocardial CSE mRNA in LVH but it was up regulated by 7 and 4 fold in the Control-H₂S and LVH-H₂S myocardium, respectively. Systolic blood pressure, mean arterial pressure, pulse wave velocity were reduced (all P<0.05) in LVH-H₂S when compared to the LVH group. Heart, LV weight, myocardial thickness were reduced while LV internal diameter was increased (all P<0.05) in the LVH-H₂S when compared to the LVH group. Exogenous administration of H₂S in LVH increased superoxide dismutase, glutathione and total antioxidant capacity but significantly reduced (all P<0.05) plasma malanodialdehyde in the LVH-H₂S compared to the LVH group. The renal cortical blood perfusion increased by 40% in LVH-H₂S as compared to the LVH group. Exogenous administration of H₂S suppressed the progression of LVH which was associated with an up regulation of myocardial CSE mRNA/ H₂S and a reduction in pulse wave velocity with a blunting of systemic hemodynamic. This CSE/H₂S pathway exhibits an antihypertrophic role by antagonizing the hypertrophic actions of angiotensin II(Ang II) and noradrenaline (NA) but attenuates oxidative stress and improves pulse wave velocity which helps to suppress LVH. Exogenous administration of H₂S augmented the reduced renal cortical blood perfusion in the LVH state.     

Left–Right-Position,party affiliation and regional differences explain low COVID-19 vaccination rates in Germany

Established vaccine hesitancy measurement instruments, such as the Vaccine Hesitancy Determinants Matrix, are not sufficiently equipped to adequately and consistently measure political and ideological attitudes. Focusing on Germany, which is a particularly interesting case since it witnessed the establishment of the by far most well-organized and sustained ‘anti-Covid’ movement in Europe, this quantitative study explores the impact of political ideology and partisanship on the degree of vaccine hesitancy based on four surveys (February—October 2021) among more than 30,000 individuals. We demonstrate that party affiliation, political ideology and region of residence all impact vaccine hesitancy. In fact, they turn out to have a greater impact than two factors often analysed with respect to vaccine hesitancy: gender and educational background. Further interaction models show that the effect of political ideology on vaccine hesitancy is moderated by age, gender and region of residency. For instance, while the more rightwing a young individual is, the more hesitant they are towards SARS-CoV-2 vaccination—for older individuals, this is not the case. Our findings are relevant for future investigators measuring vaccine hesitancy and policy makers contemplating the differential impact of complex public health interventions: as the impact of political and ideological attitudes on vaccine hesitancy are not adequately captured by established vaccine hesitancy measurement instruments, we recommend its modification to include a clear and harmonised definition of the political-ideological dimension of vaccine hesitancy together with pre-validated measurement items that improve future studies. In addition, we reason that vaccine hesitancy, while being an outcome of complex socio-political factors, is in itself an indicator for societal cohesion and anomie, the degree of which is associated with trust in (health) policy makers, (public) health authorities, health service providers, etc. Therefore, we further recommend that vaccine hesitancy questions should be integrated in pertinent national surveys.     

Cardiac-Specific Inhibition of Kinase Activity in Calcium/Calmodulin-Dependent Protein Kinase Kinase-β Leads to Accelerated Left Ventricular Remodeling and Heart Failure after Transverse Aortic Constriction in Mice

Background

The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.

Methods and Results

We generated cardiac-specific kinase-dead (kd) calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) transgenic (α-MHC CaMKKβ^kd TG) mice using α-myosin heavy chain (α-MHC) promoter. Although CaMKKβ activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic binding (TAC) in α-MHC CaMKKβ^kd TG mice led to accelerated death and left ventricular (LV) dilatation and dysfunction, which was accompanied by significant clinical signs of heart failure. CaMKKβ downstream signaling molecules, including adenosine monophosphate-activated protein kinase (AMPK), were also suppressed in α-MHC CaMKKβ^kd TG mice compared with wild-type (WT) mice. The expression levels of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, which is a downstream target of both of CaMKKβ and calcium/calmodulin kinases, were also significantly reduced in α-MHC CaMKKβ^kd TG mice compared with WT mice after TAC. In accordance with these findings, mitochondrial morphogenesis was damaged and creatine phosphate/β-ATP ratios assessed by magnetic resonance spectroscopy were suppressed in α-MHC CaMKKβ^kd TG mice compared with WT mice after TAC.

Conclusions

These data indicate that CaMKKβ exerts protective effects on cardiac adaptive energy pooling against pressure-overload possibly through phosphorylation of AMPK and by upregulation of PGC-1α. Thus, CaMKKβ may be a therapeutic target for the treatment of heart failure.     

Left Ventricular Hypertrophy in Rhesus Macaques (Macaca mulatta) at the California National Primate Research Center (1992–2014)

Necropsy records and associated clinical histories from the rhesus macaque colony at the California National Primate Research Center were reviewed to identify mortality related to cardiac abnormalities involving left ventricular hypertrophy (LVH). Over a 21-y period, 162 cases (female, 90; male, 72) of idiopathic LVH were identified. Macaques presented to necropsy with prominent concentric hypertrophy of the left ventricle associated with striking reduction of the ventricular lumen. Among all LVH cases, 74 macaques (female, 39; male, 35), mostly young adults, presented for spontaneous (sudden) death; more than 50% of these 74 cases were associated with a recent history of sedation or intraspecific aggression. The risk of sudden death in the 6- to 9-y-old age group was significantly higher in male macaques. Subtle histologic cardiac lesions included karyomegaly and increased cardiac myocyte diameter. Pedigree analyses based on rhesus macaque LVH probands suggested a strong genetic predisposition for the condition. In humans, hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, associated with diverse clinical outcomes ranging from asymptomatic disease to sudden death. Although the overall risk of disease complications such as sudden death, end-stage heart failure, and stroke is low (1% to 2%) in patients with HCM, the absolute risk can vary dramatically. Prima facie comparison of HCM and LVH suggest that further study may allow the development of spontaneously occurring LVH in rhesus macaques as a useful model of HCM, to better understand the pathogenesis of this remarkably heterogeneous disease.Abbreviations: HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophyNaturally occurring hypertrophic cardiomyopathy (HCM) has been recognized in a variety of species including pigs,¹³ cats^18,32 and humans. HCM emerged as an accepted clinical entity in humans during the late 1950s, with the publication of 2 key papers.^5,46 Since then, a vast, complex, and sometimes contradictory body of research has developed around this clinically, phenotypically, and genotypically heterogeneous disease. HCM is defined as left ventricular hypertrophy without chamber dilation in the absence of either a systemic or other cardiac disease that would result in pressure overload and compensatory hypertrophy.^22,39 The primary physiologic abnormality in HCM is reduced stroke volume due to impaired diastolic filling, which is secondary to reduced chamber size and impaired relaxation of the left ventricular myocardium during diastole; this impaired relaxation is due to the reduced compliance or increased stiffness of the hypertrophied left ventricle.⁴⁹Phenotypically, hearts affected by HCM exhibit a wide variety of changes summarized as left ventricular hypertrophy, which may be symmetric or asymmetric and which results in reduced left ventricular lumen volume, reduced stroke volume, and typically increased ejection fraction. These changes can be accompanied by valvular changes, some of which can be obstructive. Small intramural coronary arteries may have thickened walls and narrowed lumens due to proliferation of smooth muscle cells and collagen.³⁰ Histologic changes in the left ventricle associated with—but not prerequisite for—HCM include myocyte hypertrophy and disarray, nuclear atypia, and expansion of the interstitial collagen compartment.^14,22In the 1980s, growing recognition that HCM was familial directed efforts toward identifying a genetic defect. Primary HCM in humans has been identified as an autosomal dominant disease with variable penetrance and a remarkable diversity in clinical presentation and disease course.^27,40 The first mutation associated with HCM was a missense mutation in the gene encoding the β-myosin heavy chain.¹¹ More than 2 decades of subsequent investigation has demonstrated the extensive heterogeneity of the HCM phenotype, with at least 11 causative genes and more than 1400 mutations identified. These genes primarily encode thick and thin myofilament proteins of the sarcomere or Z disc (sarcomere structural proteins). The majority of mutations occur in 3 genes—β-myosin heavy chain, myosin-binding protein C, and troponin T—whereas other genes, including troponin I, α-tropomyosin and α-actin, account for a smaller proportion of patients.²² Mutations in several additional sarcomere and calcium-handling genes have been proposed but with less evidence to support pathogenicity. At present, the precise mutation does not alter management. However, adverse outcomes (sudden death, stroke, progressive symptoms) are more prominent in patients with sarcomere mutations than in those without an identifiable mutation.³⁷In other animal species, naturally occurring familial HCM has been best characterized in cats. Maine coon cats¹⁸ and ragdoll cats³² develop HCM that is strongly similar to the human disease in clinical presentation and histopathology. Similar to humans, HCM in cats is inherited as an autosomal dominant trait, with the responsible gene, the cardiac myosin-binding protein C gene, recently identified.^32,33 In addition, a genetically manipulated model has been developed in rabbits,²¹ as well as a vast array of mouse models.^1,7,45The purposes of this report were: 1) to identify cases of LVH diagnosed at necropsy in the rhesus macaque colony at the California National Primate Research Center since 1992; 2) to provide a preliminary pathologic characterization of these cases; and 3) to compare and contrast rhesus LVH and human HCM to assess the extent to which LVH might be developed as a model of HCM in a species closely related to humans.     

A Common Left Occipito-Temporal Dysfunction in Developmental Dyslexia and Acquired Letter-By-Letter Reading?

Background

We used fMRI to examine functional brain abnormalities of German-speaking dyslexics who suffer from slow effortful reading but not from a reading accuracy problem. Similar to acquired cases of letter-by-letter reading, the developmental cases exhibited an abnormal strong effect of length (i.e., number of letters) on response time for words and pseudowords.

Results

Corresponding to lesions of left occipito-temporal (OT) regions in acquired cases, we found a dysfunction of this region in our developmental cases who failed to exhibit responsiveness of left OT regions to the length of words and pseudowords. This abnormality in the left OT cortex was accompanied by absent responsiveness to increased sublexical reading demands in phonological inferior frontal gyrus (IFG) regions. Interestingly, there was no abnormality in the left superior temporal cortex which—corresponding to the onological deficit explanation—is considered to be the prime locus of the reading difficulties of developmental dyslexia cases.

Conclusions

The present functional imaging results suggest that developmental dyslexia similar to acquired letter-by-letter reading is due to a primary dysfunction of left OT regions.     

Left and right in the amphibian world: which way to develop and where to turn?

The last decade has seen a dramatic increase in studies on the development, function and evolution of asymmetries in vertebrates, including amphibians. Here we discuss current knowledge of behavioral and anatomical asymmetries in amphibians. Behavioral laterality in the response of both adult and larval anurans to presumed predators and competitors is strong and may be related, respectively, to laterality in the telencephalon of adults and the Mauthner neurons of tadpoles. These behavior lateralities, however, do not seem to correlate with visceral asymmetries in the same animals. We briefly compare what is known about the evolution and development of asymmetry in the structure and function of amphibians with what is known about asymmetries in other chordate and non-chordate groups. Available data suggest that the majority of asymmetries in amphibians fall into two independent groups: (1) related to situs viscerum and (2) of a neurobehavioral nature. We find little evidence linking these two groups, which implies different developmental regulatory pathways and independent evolutionary histories for visceral and telencephalic lateralizations. Studies of animals other than standard model species are essential to test hypotheses about the evolution of laterality in amphibians and other chordates.     

Left helix of polyproline II type and genesis of β-structures in spidroins 1 and 2 and their recombinant analogs

The distribution of secondary structure elements along the polypeptide chains of spider silk proteins spidroins 1 and 2 and their recombinant analogs has been studied by statistical methods. It was found that these proteins as monomers contain only traces of β-structure, while the Ala-rich and the Gly-rich regions are predicted as α-helices and as left-handed helices of polyproline II type. Analysis of literature and our CD data shows that the major polypeptide chain conformation of spidroins 1 and 2 and their recombinant analogs in aqueous solutions is the polyproline II helix, with some α-helices and a very small share of β-structures. The transition to the state with extended conformations, which are characteristic of mature silk fibers, requires dehydration of the polypeptide backbone. Thus, the genesis of β-structure in spider web proteins is determined by the conditions of transitions between the main regular backbone conformations.