Search

Aims Ca2+-induced Ca2+ release (CICR) is critical for contraction in cardiomyocytes. The transverse (t)-tubule system guarantees the proximity of the triggers for Ca2+ release [L-type Ca2+ channel, dihydropyridine receptors (DHPRs)] and the sarcoplasmic reticulum Ca2+ release channels [ryanodine receptors (RyRs)]. Transverse tubule disruption occurs early in heart failure (HF). Clinical studies of left ventricular assist devices in HF indicate that mechanical unloading induces reverse remodelling. We hypothesize that unloading of failing hearts normalizes t-tubule structure and improves CICR. Methods and results Heart failure was induced in Lewis rats by left coronary artery ligation for 12 weeks; sham-operated animals were used as controls. Failing hearts were mechanically unloaded for 4 weeks by heterotopic abdominal heart transplantation (HF-UN). HF reduced the t-tubule density measured by di-8-ANEPPS staining in isolated left ventricular myocytes, and this was reversed by unloading. The deterioration in the regularity of the t-tubule system in HF was also reversed in HF-UN. Scanning ion conductance microscopy showed the reappearance of normal surface striations in HF-UN. Electron microscopy revealed recovery of normal t-tubule microarchitecture in HF-UN. L-type Ca2+ current density, measured using whole-cell patch clamping, was reduced in HF but unaffected by unloading. The variance of the time-to-peak of the Ca2+ transient, an index of CICR dyssynchrony, was increased in HF and normalized by unloading. The increased Ca2+ spark frequency observed in HF was reduced in HF-UN. These results could be explained by the recoupling of orphaned RyRs in HF, as indicated by immunofluorescence. Conclusions Our data show that mechanical unloading of the failing heart reverses the pathological remodelling of the t-tubule system and improves CICR.

Transrectal ultrasonography (US)-guided biopsy is the standard approach for histopathologic diagnosis of prostate cancer. However, this technique has multiple limitations owing to the operator's inability in most cases to directly visualize and target prostate lesions. Magnetic resonance (MR) imaging of the prostate overcomes many of these limitations by directly depicting areas of abnormality and allowing targeted biopsies. Accuracy in the detection of prostate cancer is improved by the combined use of standard T2-weighted MR imaging and advanced MR imaging techniques such as diffusion-weighted imaging, dynamic contrast-enhanced imaging, and MR spectroscopy. Suspicious-appearing regions of the prostate seen on MR images can be targeted at real-time transrectal US-guided biopsy to improve the diagnostic yield. MR imaging also can be performed for real-time guidance of transrectal prostate biopsy. Studies among patients who underwent at least one transrectal US-guided biopsy with a negative result before undergoing an MR imaging-guided biopsy showed improved detection rates with MR imaging-guided biopsy in comparison with the detection rates achieved with a repeat transrectal US-guided biopsy; however, MR imaging-guided biopsy is a more time-consuming procedure. A technique known as fused MR imaging- and transrectal US-guided biopsy, which relies on the coregistration of previously acquired MR images with real-time transrectal US images acquired during the procedure, shows promise but is limited by deformation of the prostate; this limitation is the subject of ongoing investigation. Another technique that is currently under investigation, MR imaging-guided prostate biopsy with robotic assistance, may one day help improve the accuracy of biopsy needle placement.

Cardiac transverse (t)-tubules are altered during disease and may be regulated by stretch-sensitive molecules. The relationship between variations in the degree and duration of load and t-tubule structure remains unknown, as well as its implications for local Ca(2+)-induced Ca(2+) release (CICR). Rat hearts were studied after 4 or 8 weeks of moderate mechanical unloading [using heterotopic abdominal heart-lung transplantation (HAHLT)] and 6 or 10 weeks of pressure overloading using thoracic aortic constriction. CICR, cell and t-tubule structure were assessed using confocal-microscopy, patch-clamping and scanning ion conductance microscopy. Moderate unloading was compared with severe unloading [using heart-only transplantation (HAHT)]. Mechanical unloading reduced cardiomyocyte volume in a time-dependent manner. Ca(2+) release synchronicity was reduced at 8 weeks moderate unloading only. Ca(2+) sparks increased in frequency and duration at 8 weeks of moderate unloading, which also induced t-tubule disorganization. Overloading increased cardiomyocyte volume and disrupted t-tubule morphology at 10 weeks but not 6 weeks. Moderate mechanical unloading for 4 weeks had milder effects compared with severe mechanical unloading (37% reduction in cell volume at 4 weeks compared to 56% reduction after severe mechanical unloading) and did not cause depression and delay of the Ca(2+) transient, increased Ca(2+) spark frequency or impaired t-tubule and cell surface structure. These data suggest that variations in chronic mechanical load influence local CICR and t-tubule structure in a time- and degree-dependent manner, and that physiological states of increased and reduced cell size, without pathological changes are possible.

After the recent celebrations of the 50th anniversary of the modern description of hypertrophic cardiomyopathy (HCM) by Teare and Lord Brock, the time is ripe to reflect on what remains to be discovered.1–3 With the full realization that a massive amount of information relating to the disease has already been uncovered, and paying tribute to all those involved in this process, it is essential to concentrate on the gaps in our knowledge that require concerted efforts to advance the field, particularly in relation to patient management, which continues to be perceived as less than optimal.3 We believe that this is largely due to the partial disconnect between basic research, and an incomplete understanding of the fundamental mechanisms molding a continuously, often insidiously changing phenotype. A thorough comprehension of these processes requires a translational approach based on long-term clinical observation of large HCM cohorts, coupled with basic scientific research, and represents an essential step toward the development of innovative therapies which need to be both disease- and patient-specific.2,3 Traditionally, the focus of HCM literature has been polarized on 2 aspects of indisputable clinical relevance: the pathogenesis, clinical consequences, and management of dynamic left ventricular (LV) outflow obstruction,1 and the issue of arrhythmic risk stratification and prevention of sudden cardiac death (SCD).4,5 By comparison, limited attention has been devoted to the life-long process of LV remodeling and progressive dysfunction that occur in a substantial proportion of HCM patients and culminates in the rare but dramatic clinical evolution termed as end-stage or burned-out phase.6–9 Consequently, the stages that precede this severe condition are still relatively unknown, representing an important target for research.3 Indeed, because of the slowly evolving nature of HCM, timely identification of patients at risk …

Objectives Millions of people in the developing world may suffer from pulmonary hypertension (PHTN) because of preexisting infectious conditions. Schistosomiasis can cause pulmonary lesions that eventually lead to PHTN. The aim of this study was to assess the prevalence of PHTN together with assessment of right ventricular (RV) function in asymptomatic rural residents previously infected with schistosomiasis. Methods Three hundred and seventy asymptomatic people from an endemic area in the Nile Delta were screened for antibodies against schistosomiasis. All were scheduled for transthoracic echocardiographic study to assess pulmonary artery systolic (PASP) and diastolic (PADP) pressures as well as RV function. PASP >40 mmHg was considered elevated. Results Seropositive (SP) and seronegative (SN) groups had comparable age and body mass index. PASP >40 mmHg was met in 18 subjects (Range 42–72 mmHg) (8.6%) of SP group and in no subject in SN group (P = 0.000). Compared with SN group, the SP group had higher mean values of PASP (30 ± 10 vs. 24 ± 7 mmHg, P 40 mmHg a ete consideree comme elevee. Resultats: Les groupes seropositifs (SP) et seronegatifs (SN) avaient un âge et un indice de masse corporelle comparables. PAPS > 40 mmHg (intervalle de 42 a 72 mmHg) a ete rencontree chez 18 (8,6%) sujets du groupe SP et chez aucun sujet du groupe SN (p = 0,000). Compare au groupe SN, le groupe SP avait des valeurs moyennes plus elevees de la PAPS (30 ± 10 vs 24 ± 7 mmHg, p 40 mmHg. Resultados: Los grupos seropositivos (SP) y seronegativos (SN) tenian una edad e indice de masa corporal comparables. 18 sujetos (8.6%) del grupo SP y ningun sujeto del grupo SN (p = 0.000) tenian una PSAP >40 mmHg (rango 42-72 mmHg). Comparados con el grupo SN, el grupo SP tenia valores medios mas altos de PSAP (30 ± 10 vs. 24 ± 7 mmHg, p

Exercise-derived variables have been used in the assessment of functional capacity and prognosis in patients with chronic heart failure. The aim of this study was to assess the relationship between cardiac pumping capability represented by peak cardiac power output and peak oxygen consumption, anaerobic threshold, ventilatory efficiency slope, and peak circulatory power in patients undergoing the 'Harefield Protocol'.Haemodynamic and gas exchange measurements were undertaken during a graded treadmill exercise test. They were performed on 54 patients-18 implanted with left ventricular assist devices (LVADs), 16 explanted (recovered), and 20 moderate-to-severe heart failure patients. Peak oxygen consumption was only highly correlated with peak cardiac power output in explanted LVAD (r = 0.85, P0.01), but not in implanted LVAD and heart failure patients (r = 0.55 and 0.53, P0.05). The anaerobic threshold was only modestly correlated with peak cardiac power output in heart failure and explanted (r = 0.46 and 0.54, P0.05) and weakly in implanted LVAD patients (r = 0.37, P0.05). Peak cardiac power output was well correlated with peak circulatory power in LVAD explanted and implanted (r = 0.82, P0.01; r = 0.63, P0.01) but not in heart failure patients (r = 0.31, P0.05). Ventilatory efficiency slope was only moderately correlated with peak cardiac power output in LVAD-explanted patients (r = -0.52, P0.05).Exercise-derived prognostic indicators demonstrate limited capacity in reflecting cardiac pumping capability in patients treated with LVADs and should therefore be used with caution in interpretation of cardiac organ function.

The transverse tubules (t-tubules) are invaginations of the cell membrane rich in several ion channels and other proteins devoted to the critical task of excitation–contraction coupling in cardiac muscle cells (cardiomyocytes). They are thought to promote the synchronous activation of the whole depth of the cell despite the fact that the signal to contract is relayed across the external membrane. However, recent work has shown that t-tubule structure and function are complex and tightly regulated in healthy cardiomyocytes. In this review, we outline the rapidly accumulating knowledge of its novel roles and discuss the emerging evidence of t-tubule dysfunction in cardiac disease, especially heart failure. Controversy surrounds the t-tubules' regulatory elements, and we draw attention to work that is defining these elements from the genetic and the physiological levels. More generally, this field illustrates the challenges in the dissection of the complex relationship between cellular structure and function.

Aortic valve interstitial cells are responsible for maintaining the valve in response to their local mechanical environment. However, the complex organization of the extracellular matrix means cell strains cannot be directly derived from gross strains, and knowledge of tissue structure–function correlations is fundamental towards understanding mechanotransduction. This study investigates strain transfer through the valve, hypothesizing that organization of the valve matrix leads to non-homogenous local strains. Radial and circumferential samples were cut from aortic valve leaflets and subjected to quasi-static mechanical characterization. Further samples were imaged using confocal microscopy, to determine local strains in the matrix. Mechanical data demonstrated that the valve was significantly stronger and stiffer when loaded circumferentially, comparable with previous studies. Micromechanical studies demonstrated that strain transfer through the matrix is anisotropic and indirect, with local strains consistently smaller than applied strains in both orientations. Under radial loading, strains were transferred linearly to cells. However, under circumferential loading, strains were only one-third of applied values, with a less direct relationship between applied and local strains. This may result from matrix reorganization, and be important for preventing cellular damage during normal valve function. These findings should be taken into account when investigating interstitial cell behaviours, such as cell metabolism and mechanotransduction.

Global health continues to face increasing challenges owing to a variety of reasons that include the almost constant changes in disease appearance and evolution. Most, but not all, of these changes affect low-income countries and are influenced by climate change. Tracking the recent and anticipated changes in the demographics and global distribution of these changes is essential for evolving effective new methods for dealing with the problems. The recent recognition by the United Nations of the importance of non-communicable diseases is a major positive step. For the sake of this paper, the following diseases were chosen: dengue and malaria, to highlight the role of climate change on vector-borne diseases. Drug-resistant tuberculosis illustrates the role of globalization and reduced resources on disease evolution. The continuing rise in cardiovascular mortality and morbidity, particularly in resource-poor countries is largely attributed to lack of preventive and therapeutic measures against such conditions as hypertension, diabetes, atherosclerosis and congenital heart disease as well as neglected diseases, of which Chagas and rheumatic heart disease will be discussed further.

Background Left ventricular assist devices (LVAD)-induced unloading appear to cause reverse cardiac remodeling. However, its effect on arrhythmogenicity is a controversial issue, and prospective data are lacking. We sought to investigate the impact of LVAD-induced unloading on the electrical properties of the failing heart. Methods We prospectively studied the effects of LVAD therapy on QRS, QT, and QTc durations and ventricular arrhythmias from electrocardiograms and 24-hour ambulatory electrocardiograms recorded before and during 6 months of mechanical support in 12 LVAD patients and 7 other patients with advanced nonischemic cardiomyopathy untreated with LVAD. Results After 1 week of LVAD support, QTc duration had decreased from 479 ± 79 ms to 411 ± 57 ms ( p = 0.037), and QRS duration from 150 ± 46 ms to 134 ± 32 ms ( p = 0.029). At 6 months, QTc was found to be 372 ± 56 ms ( p = 0.046 versus baseline, 15% shortening) and QRS 118 ± 25 ms ( p = 0.028 versus baseline, 11% shortening). A strong correlation was found between QTc shortening and increase in left ventricular ejection fraction and decrease in left ventricular filling pressures. After 2 months of LVAD support, premature ventricular contractions had decreased from 3,507 ± 4,252 to 483 ± 417 in 24 hours ( p = 0.043), ventricular couplets from 82 ± 99 to 29 ± 25 in 24 hours ( p = 0.05), and ventricular runs from 9 ± 8 to 10 ± 9 (not significant). No patient died suddenly or suffered a symptomatic arrhythmic event during follow-up. No significant electrocardiographic, functional, or hemodynamic change was observed in the 7 patients untreated with LVAD. Conclusions The LVAD support caused progressive shortening of QTc and QRS intervals, consistent with reverse remodeling of the failing heart's electrical properties, accompanied by a decrease in frequency of ventricular arrhythmias.

Hypertrophic cardiomyopathy (HCM), a heterogeneous genetic heart disease with global distribution, is an important cause of heart failure disability at any age. For 50 years, surgical septal myectomy has been the preferred and primary treatment strategy for most HCM patients with progressive, drug refractory functional limitation due to left ventricular (LV) outflow tract obstruction. With very low surgical mortality at experienced centres, septal myectomy reliably abolishes impedance to LV outflow and heart failure-related symptoms, restores quality of life, and importantly is associated with long-term survival similar to that in the general population. Nevertheless, alternatives to surgical management are necessary for selected HCM patients. For example, after a brief flirtation with dual-chamber pacing 20 years ago, percutaneous alcohol septal ablation has garnered a large measure of enthusiasm and a dedicated following in the interventional cardiology community, achieving benefits for patients, paradoxically, by virtue of producing a transmural myocardial infarct. However, an unintended consequence has been the virtual obliteration of the surgical option for HCM patients in Europe, where several robust myectomy programmes once existed. Therefore, clear differences are now evident internationally regarding management strategies for symptomatic obstructive HCM. The surgical option is now unavailable to many patients based solely on geography, including some who would likely benefit more substantially from surgical myectomy than from catheter-based alcohol ablation. It is our aspiration that this discussion will generate reconsideration and resurgence of interest in surgical septal myectomy as a treatment option for severely symptomatic obstructive HCM patients within Europe.

Background— We have previously shown that a specific combination of drug therapy and left ventricular assist device unloading results in significant myocardial recovery, sufficient to allow pump removal, in two thirds of patients with dilated cardiomyopathy receiving a Heartmate I pulsatile device. However, this protocol has not been used with nonpulsatile devices. Methods and Results— We report the results of a prospective study of 20 patients who received a combination of angiotensin-converting enzymes, β-blockers, angiotensin II inhibitors, and aldosterone antagonists followed by the β 2 -agonist clenbuterol and were regularly tested (echocardiograms, exercise tests, catheterizations) with the pump at low speed. Before left ventricular assist device insertion, patient age was 35.2±12.6 years (16 male patients), patients were on 2.0±0.9 inotropes, 7 (35) had an intra-aortic balloon pump, 2 were hemofiltered, 2 were ventilated, 3 had a prior Levitronix device, and 1 had extracorporeal membrane oxygenation. Cardiac index was 1.39±0.43 L · min −1 · m −2 , pulmonary capillary wedge pressure was 31.5±5.7 mm Hg, and heart failure history was 3.4±3.5 years. One patient was lost to follow-up and died after 240 days of support. Of the remaining 19 patients, 12 (63.2) were explanted after 286±97 days. Eight had symptomatic heart failure for ≤6 months and 4 for >6 months (48 to 132 months). Before explantation, at low flow for 15 minutes, ejection fraction was 70±7, left ventricular end-diastolic diameter was 48.6±5.7 mm, left ventricular end-systolic diameter was 32.3±5.7 mm, mV̇ o 2 was 21.6±4 mL · kg −1 · min −1 , pulmonary capillary wedge pressure was 5.9±4.6 mm Hg, and cardiac index was 3.6±0.6 L · min −1 · m −2 . Estimated survival without heart failure recurrence was 83.3 at 1 and 3 years. After a 430.7±337.1-day follow-up, surviving explants had an ejection fraction of 58.1±13.8, left ventricular end-diastolic diameter of 59.0±9.3 mm, left ventricular end-systolic diameter of 42.0±10.7 mm, and mV̇ o 2 of 22.6±5.3 mL · kg −1 · min −1 . Conclusions— Reversal of end-stage heart failure secondary to nonischemic cardiomyopathy can be achieved in a substantial proportion of patients with nonpulsatile flow through the use of a combination of mechanical and pharmacological therapy.

Collagen fibers are essential components of tissues, which are highly conserved across the animal kingdom and could be extremely useful in tissue engineering. The formation of these macromolecular fibers depends on molecular interactions-based self-assembly of the basic building blocks of collagen called tropocollagens. Several attempts to produce biomimetic collagen have been described, however the best method to achieve the optimal material for tissue engineering has not been established. Here, we describe a bottom-up approach to design two computationally mutated molecular models that use non-covalent interactions to cross-link triple helices of tropocollagen molecules and thus promote self-association. Implementing a graph theory approach in the software FIRST reveals the hotspots that are crucial for the overall rigidity of the supramolecular helical structures and the remaining non-hotspots available for mutations. The mutated models were further decorated with GFOGER, a known collagen cell binding motif, to depict a biofunctional model. In addition to their recognized role of cell binding, the charged residues of the binding motif appeared to enhance further the supramolecular helical association. These findings could help to produce biomimetic collagen for biomedical applications.

Endomyocardial fibrosis (EMF) is a cardiomyopathy with high prevalence in Sub-Saharan Africa with unclear etiology, pathogenesis and natural history. Most pathological abnormalities can potentially be diagnosed by echocardiography allowing surgery in some cases. With increasing availability of echocardiography in endemic areas for EMF we designed a study aiming at assessing its accuracy in defining EMF structural abnormalities pre-operatively, and describe pathological findings through detailed intraoperative examination and evaluation of histopathological changes in tissue obtained from excisional biopsies. Transthoracic echocardiography was performed pre-operatively to 29 patients with chronic severe EMF. All patients were submitted to excisional endomyocardial biopsies during surgery and careful standardized intra-operative evaluation was also done. Surgical and histopathological findings were compared to those obtained by echocardiography. Of the 29 patients studied, 16 had moderate lesions while 13 had severe disease. Their mean age was 12 (±4.6) years and 17 were males. All but one patient were in NYHA functional class III or IV at time of surgery. All patients had severe atrioventricular valve regurgitation with valves considered suitable for repair. We evaluated tissue from 25 left ventricles and 12 right ventricles. Endocardial thickening was the most prominent abnormality due to deposition of hyaline and cellular collagen underneath a layer of apparently normal endocardial endothelial cells. The mean endocardial thickness was 2,541 ± 1,707 μm. There was high agreement between echocardiographic and intraoperative findings, with the findings coinciding completely in 24 patients. Severe EMF assessed by echocardiography was associated with intense endocardial fibrosis on histology. In contrast, the presence of inflammation in peripheral blood was not associated with tissue inflammation. Structural abnormalities of chronic severe EMF are accurately diagnosed by transthoracic echocardiography, allowing this non-invasive technique to be used as the gold standard for diagnosis and surgical management of chronic EMF in endemic areas.

IMPORTANCE: The ideal aortic valve substitute in young and middle-aged adults remains unknown. OBJECTIVE: To compare long-term outcomes between the Ross procedure and mechanical aortic valve replacement in adults. DATA SOURCES: The Ovid versions of MEDLINE and EMBASE classic (January 1, 1967, to April 26, 2018; search performed on April 27, 2018) were screened for relevant studies using the following text word search in the title or abstract: (“Ross” OR “autograft”) AND (“aortic” OR “mechanical”). STUDY SELECTION: All randomized clinical trials and observational studies comparing the Ross procedure to the use of mechanical prostheses in adults undergoing aortic valve replacement were included. Studies were included if they reported any of the prespecified primary or secondary outcomes. Studies were excluded if no clinical outcomes were reported or if data were published only as an abstract. Citations were screened in duplicate by 2 of the authors, and disagreements regarding inclusion were reconciled via consensus. DATA EXTRACTION AND SYNTHESIS: This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. Data were independently abstracted by 3 reviewers and pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was all-cause mortality. RESULTS: The search identified 2919 reports, of which 18 studies (3516 patients) met inclusion criteria, including 1 randomized clinical trial and 17 observational studies, with a median average follow-up of 5.8 (interquartile range, 3.4-9.2) years. Analysis of the primary outcome showed a 46% lower all-cause mortality in patients undergoing the Ross procedure compared with mechanical aortic valve replacement (incidence rate ratio [IRR], 0.54; 95% CI, 0.35-0.82; P = .004; I(2) = 28%). The Ross procedure was also associated with lower rates of stroke (IRR, 0.26; 95% CI, 0.09-0.80; P = .02; I(2) = 8%) and major bleeding (IRR, 0.17; 95% CI, 0.07-0.40; P

Optimal function of the aortic root relies upon the ability of its component structures to move in a coordinated fashion. Some of the cells that make up the structures of the aortic root have been shown to contain nerves, receptors, and contractile elements. The ability to contract or relax may contribute to the successful function of the valve by allowing it to move in a coordinated manner in response to biological stimuli. It is known that cusp tissue receives primary, sensory, and autonomic nerves, suggesting a role for neuronal regulation of cusp function. In addition, cusp tissue has been shown to express a wide variety of receptors and to contract to a range of common vasoactive agents. The cells that constitute the valve have also shown secretory and proliferative responses. The biological signals that mediate the cross-talk between the different parts of the root have not been established. This review will examine the mechanisms that have been documented to be present and to assess their potential contribution in affecting aortic valve function.

Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease.

Clinical observation in patients with heart disease indicates that reduced activity of AMP deaminase could be protective in heart failure and ischemic heart disease. This study evaluated the effect of 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo [4,5-d][1,3]diazepin-8-ol, an AMP deaminase inhibitor (AMPDI) in the mouse heart subjected to hypoxia. ApoE/LDLR knock-out mice were subjected to reduced oxygen tension in breathing air. AMPDI was infused before hypoxia in the treated group. We observed amelioration of elcetrocardiographic changes during hypoxia in the treated group that are consistent with a protective effect.

AMP deaminase could be a potential target for treatment of heart disease but experimental evaluation of this concept is difficult due to limited availability of inhibitors with proven efficiency in biological systems. This study evaluated the effect of 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo [4,5-d][1,3]diazepin-8-ol, an AMP deaminase inhibitor (AMPDI) on the pathways of nucleotide metabolism in perfused rat heart. We show that AMPDI at 0.3 mM concentration effectively inhibits AMP deaminase in this experimental model.

Peak cardiac power output (CPO), as a direct measurement of overall cardiac function, has been shown to be a most powerful predictor of prognosis for patients with chronic heart failure. The present study assessed CPO and exercise performance in patients implanted with a left ventricular assist device (LVAD), those explanted due to myocardial recovery, and those with moderate to severe heart failure. Hemodynamic and respiratory gas exchange measurements were undertaken at rest and at peak graded exercise. These were performed in 54 patients-20 with moderate to severe heart failure, 18 with implanted LVADs, and 16 with explanted LVADs. At rest there was a nonsignificant difference in CPO among groups (p >0.05). Peak CPO was significantly higher in the explanted LVAD than in the heart failure and implanted LVAD groups (heart failure 1.90 +/- 0.45 W, implanted LVAD 2.37 +/- 0.55 W, explanted LVAD 3.39 +/- 0.61 W, p

Prolonged mechanical unloading (UN) of the heart is associated with detrimental changes to the structure and function of cardiomyocytes. The mechanisms underlying these changes are unknown. In this study, we report the influence of UN on excitation-contraction coupling, Ca2+-induced Ca2+ release (CICR) in particular, and transverse (t)-tubule structure. UN was induced in male Lewis rat hearts by heterotopic abdominal heart transplantation. Left ventricular cardiomyocytes were isolated from the transplanted hearts after 4 wk and studied using whole-cell patch clamping, confocal microscopy, and scanning ion conductance microscopy (SICM). Recipient hearts were used as control (C). UN reduced the volume of cardiomyocytes by 56.5% compared with C (UN, n=90; C, n=59; P

Currently, the arterial switch operation (ASO) is the treatment of choice for the majority of patients with TGA. However, in low and middle-income countries, a significant number of patients present too late for ASO. A new modified Mustard operation (MMO) designed to improve contractile and

The field of myocardial regeneration (angiogenesis and myogenesis) might prove to play an important role in the future management of cardiovascular disease. Stem cells are currently undergoing testing in Phase I and Phase II clinical trials. Methods of delivery will affect the outcome of such therapies, perhaps significantly. This document provides suggested guidance in 4 methods of delivery: endocardial, intracoronary, coronary sinus, and epicardial.

The introduction of the heart lung machine more than 50 years ago proved in principle that heart function can be replaced, albeit for short periods. This was followed by attempts to produce total or partial artificial hearts that could function for prolonged periods of time. Progress in this field has been intermittent but has accelerated considerably in the past 10 years, with ventricular assist devices (VADs) reaching an impressive degree of sophistication and complexity owing to the contributions from clinicians, engineers, scientists, industrialists, and others. This review describes the currently available types of VADs, their current clinical use, the patient selection process, the trend toward use of VADs in patients with less severe heart failure, and the use of VADs for myocardial recovery in combination with novel pharmacological strategies, gene therapy, and cell therapy.

BACKGROUND We hypothesized that genetic variation of ATP-binding cassette subfamily B member 1 (ABCB1) that encodes P-glycoprotein (involved in the uptake of cyclosporin A [CsA]) contributes to trough drug concentrations and thereby to CsA's immunosuppressive and toxic effects. METHODS Three hundred thirty-seven adult heart transplant recipients were studied retrospectively. White recipients receiving CsA at month 3 and years 1 to 5 after transplantation (n=192, 168, 156, 130, 95, and 74, respectively) were then studied with respect to ABCB1 genotype or haplotype and CsA disposition. Genotyping was performed using a gel-based polymerase chain reaction method. Dose- and weight-adjusted CsA trough concentrations ([microg/L]/[mg/kg]), time to first endomyocardial biopsy-proven acute rejection episode (grade>or=3A), weaning from steroids at 1 year, and renal function at 1 year posttransplant were measured. RESULTS An association between dose- and weight-adjusted CsA trough concentrations and ABCB1 haplotypes was found, with 12/1236, 21/2677, 26/3435 CC/GG/CC individuals having significantly higher concentrations than TT/TT/TT individuals at years 1 and 5 (68.9+/-26.9 vs. 54.9+/-19.5 and 70.6+/-35 vs. 50.0+/-12.2 [microg/L]/[mg/kg] P

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 x 10(-15)) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10(-5) to 10(-20)). SCN10A encodes Na(V)1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a(-/-) mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.

Objectives The aims of this study were to compare long-term results after homograft versus Freestyle (Medtronic Inc., Minneapolis, Minnesota) aortic root replacement. Background The ideal substitute for aortic root replacement remains undetermined. Methods Between 1997 and 2005, 166 patients (age 65 ± 8 years) undergoing total aortic root replacement were randomized to receive a homograft (n = 76) or a Freestyle bioprosthesis (n = 90). Six patients randomly assigned to homograft crossed over to Freestyle because of unavailability of suitably sized homografts. Median follow-up was 7.6 years (maximum 11 years; 1,035 patient-years). “Evolving” aortic valve dysfunction was defined as aortic regurgitation ≥2/4 and/or peak gradient >20 mm Hg. Results Patient characteristics were comparable between groups. Concomitant procedures were performed in 44% and 47% of Freestyle and homograft patients, respectively (p = 0.5). Overall hospital mortality was 4.8% (1% for isolated root replacement). Eight-year survival was 80 ± 5% in the Freestyle group versus 77 ± 6% in the homograft group (p = 0.9). Freedom from need for reoperation at 8 years was significantly higher after Freestyle root replacement (100 ± 0% vs. 90 ± 5% after homograft replacement; p = 0.02). All reoperations were secondary to structural valve deterioration (n = 6). At last echocardiographic follow-up, actuarial freedom from evolving aortic valve dysfunction was 86 ± 5% for Freestyle bioprostheses versus 37 ± 7% for homografts (p Conclusions In this patient group, late survival is similar after homograft versus Freestyle root replacement. However, Freestyle aortic root replacement is associated with significantly less progressive aortic valve dysfunction and a lower need for reoperations.

Objectives The purpose of this study was to analyze the effects of left ventricular assist devices (LVADs) on myocardial sympathetic innervation of the failing heart. Background Ventricular unloading by LVADs seems to cause reverse remodeling of the failing heart, but little is known about the sympathetic nerve activity during long-term mechanical unloading. Methods We studied the effects of LVADs on myocardial sympathetic innervation, by iodine 123-meta-iodobenzylguanidine (123I-mIBG) scintigraphy performed before and 3 months after LVAD implantation in 12 end-stage heart failure patients. We calculated the: 1) heart-to-mediastinum (H/M) uptake ratio on early and delayed images, indicating myocardial accumulation of 123I-mIBG; and 2) rate of 123I-mIBG washout after initial accumulation. Similar 123I-mIBG imaging and functional and hemodynamic measurements were made 3 months apart in 6 other heart failure patients not treated with an LVAD. Results After 3 months of LVAD support, the mean left ventricular ejection fraction had increased from 19 ± 6% to 29 ± 9% (p = 0.006), peak oxygen consumption increased from 9 ± 4 ml/kg/min to 13 ± 3 ml/kg/min (p = 0.058), serum sodium increased from 135 ± 4 mEq/l to 140 ± 2 mEq/l (p = 0.014), whereas the left ventricular end-diastolic diameter decreased from 72 ± 7 mm to 56 ± 3 mm (p = 0.002), pulmonary capillary wedge pressure decreased from 30 ± 6 mm Hg to 5 ± 3 mm Hg (p = 0.012), serum creatinine decreased from 1.5 ± 0.6 mg/dl to 1.0 ± 0.4 mg/dl (p = 0.011), and B-type natriuretic peptide decreased from 2,279 ± 1,900 pg/ml to 102 ± 5 pg/ml (p = 0.003). After 3 months of LVAD, the H/M ratio increased on delayed images from 1.25 ± 0.18 to 1.43 ± 0.13 (p = 0.01) and on early images from 1.35 ± 0.19 to 1.44 ± 0.11 (p = 0.028), and the washout rate decreased from 51.0 ± 23.2% to 30.6 ± 8.7%, (p = 0.015). There was a significant correlation between the late H/M mIBG ratio and B-type natriuretic peptide (R = 0.77, p = 0.01) and systolic pulmonary pressure (R = 0.7, p = 0.05). No significant scintigraphic, functional or hemodynamic change was observed between the 2 evaluations in the 6 patients not treated with an LVAD. Conclusions Ventricular unloading caused clinical, functional, and hemodynamic improvements accompanied by improvements in sympathetic innervation in the failing heart.

The aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure. Recent evidence suggests that the aortic valve performs highly sophisticated functions as a result of its unique microscopic structure. These functions allow it to adapt to its hemodynamic and mechanical environment. Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease. We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysiological and clinical implications.

Genetic mutations in bone morphogenetic protein receptor 2 (BMPR2) have been shown to occur in patients with familial and idiopathic pulmonary arterial hypertension (PAH). However the interactions between ligands for this receptor and other mediators implicated in heritable PAH have not been investigated. This study examines the regulation of endothelin-1 (ET-1), a potent vasoconstrictor and comitogen that is implicated in the pathogenesis of heritable PAH, by ligands for the BMPR2. Immunohistochemical studies showed that pulmonary artery segments removed from normotensive human lungs express BMPR2 and bone morphogenetic proteins 2, 4 and 7 (BMP2, BMP4 and BMP7). In the presence of BMP7 and BMP4 there was a significant inhibition of ET-1 release, induced by cytokines, from cultured pulmonary artery smooth muscle cells. Fresh ring segments of pulmonary artery were assessed for their response to ET-1 in the presence and absence of BMP2, BMP4 and BMP7. BMP7 inhibited contraction in response to ET-1 in a concentration-dependent manner. BMP2 and BMP4 had no significant effect on the response to ET-1. These results suggest that BMP7 has the ability to regulate the effects of endothelin-1 in the pulmonary circulation. Genetic mutations in BMPR2 may lead to a loss of these regulatory mechanisms and contribute to the pathogenesis of pulmonary hypertension.

Hypertrophic cardiomyopathy (HCM) is an epidemiologically relevant, worldwide spread condition which is frequently perceived as a rare disease. This misconception might be supported by some characteristics of HCM such as its incomplete penetrance and variable age at onset and by the fact that many patients remain asymptomatic for a long course of the disease and are thus unlikely to seek for medical evaluation. Multiple evidences suggest that early diagnosis of HCM is important, not only because it allows the patients to be addressed to appropriate diagnostic work-out and to adequate therapeutical options but because it may trigger the screening of family members with the potential of further, new diagnosis of HCM in previously unsuspected individuals. Increased awareness of the disease among physicians working in community-based hospitals and in outpatients facilities, and a facilitated communication and access to tertiary referral centers, will result into a wider knowledge of the spectrum of the disease, a better access to the state-of-the-art management options for patients, and to a more diffuse practice of genetic evaluation of HCM families.

Cell transplantation is an emerging therapy for treating post-infarction heart failure. Although the paracrine effect has been proposed to be an important mechanism for the therapeutic benefits, details remain largely unknown. This study compared various aspects of the paracrine effect after transplantation of either bone marrow mononuclear cells (BMC) or skeletal myoblasts (SMB) into the post-infarction chronically failing heart. Three weeks after left coronary artery ligation, adult rats received intramyocardial injection of either BMC, SMB or PBS only. Echocardiography demonstrated that injection of either cell type improved cardiac function compared to PBS injection. Interestingly, BMC injection markedly improved neovascularization in the border areas surrounding infarcts, while SMB injection decreased fibrosis in both the border and remote areas. Injection of either cell type similarly reduced hypertrophy of cardiomyocytes as assessed by cell-size planimetry using isolated cardiomyocytes. Quantitative RT-PCR revealed that, among 15 candidate mediators of paracrine effects studied, Fgf2 and Hgf were upregulated only after BMC injection, while Mmp2 and Timp4 were modulated after SMB injection. Additional investigations of signalling pathways relevant to heart failure by western blotting showed that p38 and STAT3 were temporarily activated after BMC injection, in contrast, ERK1/2 and JNK were activated after SMB injection. There was no difference in activation of Akt, PKD or Smad3 among groups. These data suggest that paracrine effects observed after cell transplantation in post-infarction heart failure were noticeably different between cell types in terms of mediators, signal transductions and consequent effects.

Using low microwave frequencies (up to 2 GHz) through a monostatic analysis, the signature of a metallic target behind a thick brick wall is detected and resolved. An alternative approach using cepstral analysis is introduced for resolving the target's signature from that of the wall, which is particularly beneficial at close proximity when both signatures merge in the time domain. The use of lower frequencies combined with the monostatic analysis provides for greater flexibility in operational requirements, frequency spectrum constraints, and cost of transceivers, as well as a better wall penetration of the electromagnetic waves. Additionally, the introduction of the cepstrum-domain analysis opens a new window for detection and identification research in the field of through-wall remote sensing.

The C34T T allele of the adenosine monophosphate deaminase-1 (AMPD1) gene has been associated with improved outcome in patients with cardiac dysfunction. We hypothesized that possession of this allele by donor hearts plays a role in the outcome of cardiac transplantation; 262 cardiac donors and 190 of their recipients were studied. AMPD1 C34T genotype was determined using 5' exonuclease chemistry. Requirement for inotropic agents before organ donation, 1-year post-transplantation survival, cause of death, and factors known to affect survival after transplantation were also studied. Multiple regression models for factors affecting survival were constructed. A significant yearly increase in frequency of the T allele in donors was noted (0.06 to 0.18 from 1994 to 1999). Donors with the CT or TT genotype required less inotropic support than those with the CC genotype (mean number of inotropes per donor with CT or TT genotype 0.27 compared with 0.47 per donor with CC genotype, n = 206, p = 0.03). Recipients of T-allele-carrying organs showed worse 1-year survival after transplantation (59% vs 79%, p0.001). Excess deaths in these patients was due to early graft dysfunction (odds ratio for early graft dysfunction 6.6, 95% confidence interval 2 to 21.6, p = 0.0001). Multivariate analysis showed donor AMPD1 genotype, recipient age, and pretransplantation anemia to independently affect 1-year post-transplantation survival (adjusted hazard ratios 3.7, 1.06, and 2.6, respectively). In conclusion, possession of the AMPD1 T allele is associated with decreased inotropic requirements before heart donation. The incidence of early graft dysfunction, however, was significantly higher in recipients who received AMPD1 T-allele-possessing organs resulting in worse 1-year survival.

The majority of genetic mutations associated with hypertrophic cardiomyopathy (HCM) occur in genes encoding sarcomeric proteins, which are expressed only in cardiomyocytes. However, some manifestations of the HCM phenotype, such as myocardial disarray, interstitial fibrosis, mitral valve abnormalities, and microvascular remodeling, indicate the involvement of other cell lineages. The link between sarcomeric gene defects and these 'extended' HCM phenotypes remains elusive. Based on novel insights provided by cardiac developmental biology, we propose that a common lineage ancestry of the diverse HCM phenotypes not involving the cardiomyocyte can be traced to the pluripotent epicardium-derived cells (EPDCs). During cardiac colonization, EPDCs differentiate into interstitial fibroblasts, coronary smooth-muscle cells, and atrioventricular endocardial cushions as mesenchymal cells. We propose that the cross-talk between healthy EPDCs and abnormally contracting cardiomyocytes might account for the diverse manifestations of HCM, by a putative mechanism of mechanotransduction leading to abnormal gene expression and differentiation.

Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either 107 green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 × 106 GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, Ca2+ handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the Ca2+ transient observed in failing cardiomyocytes. The smaller and slower L-type Ca2+ current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca2+ sparks suggested a normalization of sarcoplasmic reticulum Ca2+ leak after skeletal myoblast transplantation. The increased Ca2+ wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation.

The purpose of this study was to determine the effects of chronic treatment with the beta 2 adrenergic receptor agonist clenbuterol on endothelial progenitor cells (EPC) in a well-characterized model of heart failure, the muscle LIM protein knockout (MLP(-/-)) mouse. MLP(-/-) mice were treated daily with clenbuterol (2 mg/kg) or saline subcutaneously for 6 weeks. Clenbuterol led to a 30% increase in CD31(+) cells in the bone marrow of MLP(-/-) heart failure mice (p < 0.004). Clenbuterol did not improve ejection fraction. Clenbuterol treatment in MLP(-/-) mice was associated with significant changes in the following circulating factors: tissue inhibitor of metalloproteinase-type 1, leukemia inhibitory factor 1, C-reactive protein, apolipoprotein A1, fibroblast growth factor 2, serum glutamic oxaloacetic transaminase, macrophage-derived chemokine, and monocyte chemoattractant protein-3. Clenbuterol treatment in the MLP(-/-) model of heart failure did not rescue heart function, yet did increase CD31(+) cells in the bone marrow. This is the first evidence that a beta 2 agonist increases EPC proliferation in the bone marrow in a preclinical model of heart failure.

Background Abnormalities in the extracellular matrix (ECM) can occur in heart failure. In this study we analyzed ECM gene expression in patients with advanced dilated cardiomyopathy who did and did not develop sustained myocardial recovery after left ventricular asst device (LVAD) unloading combined with pharmacologic therapy. Methods Myocardial gene expression of collagens (COL1A1 and COL3A1), fibronectin (FN), matrix metalloproteinases (MMPs 1 to 14), tissue inhibitors of metalloproteinases (TIMPs 1 to 4), connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-β1) and THY1 was measured by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) at LVAD implantation and again at explantation (recovery, n = 11) or transplantation (non-recovery, n = 5). Results The non-recovery group had higher levels of pro-fibrotic markers (COL1A1, TGF-β1 and THY1) at implantation compared with the recovery group (1.82 ± 0.74-, 1.81 ± 0.69- and 3.01 ± 1.70-fold, respectively; p ≤ 0.05). Both recovery and non-recovery groups showed no significant difference in gene expression after treatment, but levels of pro-fibrotic genes (COL1A1, COL3A1, FN and THY1) correlated negatively with post-explant ejection fraction in the recovery group. Of all genes analyzed only TIMP4 showed a significant change, with expression reduced during recovery (0.55 ± 0.25-fold at explant vs implant, p = 0.001). All other genes showed complex patterns between individuals with both increased and decreased expression of pro-fibrotic markers, MMPs and TIMPs in recovery patients. Conclusions Patients who did not recover had higher myocardial expression of pro-fibrotic genes at LVAD implantation, and in recovered patients higher levels at explant were negatively associated with subsequent ejection fraction. However, individual patients showed complex expression patterns and a decrease in pro-fibrotic markers was not required for recovery.

Clenbuterol, a compound classified as a β2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca2+ transients, and L-type Ca2+ current and compared these effects to two other clinically used β2-AR agonists: fenoterol and salbutamol. Clenbuterol (30 μM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca2+ transient amplitude and L-type Ca2+ current. Selective β1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol ( P < 0.05). Incubation with 2 μg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 μM clenbuterol. In addition, overexpression of inhibitory G protein (Gi) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the Gi protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through Gi, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

The 4.1 proteins are a family of multifunctional adaptor proteins. They promote the mechanical stability of plasma membranes by interaction with the cytoskeletal proteins spectrin and actin and are required for the cell surface expression of a number of transmembrane proteins. Protein 4.1R is expressed in heart and upregulated in deteriorating human heart failure, but its functional role in myocardium is unknown. To investigate the role of protein 4.1R on myocardial contractility and electrophysiology, we studied 4.1R-deficient (knockout) mice (4.1R KO). ECG analysis revealed reduced heart rate with prolonged Q-T interval in 4.1R KO. No changes in ejection fraction and fractional shortening, assessed by echocardiography, were found. The action potential duration in isolated ventricular myocytes was prolonged in 4.1R KO. Ca 2+ transients were larger and slower to decay in 4.1R KO. The sarcoplasmic reticulum Ca 2+ content and Ca 2+ sparks frequency were increased. The Na + /Ca 2+ exchanger current density was reduced in 4.1R KO. The transient inward current inactivation was faster and the persistent Na + current density was increased in the 4.1R KO group, with possible effects on action potential duration. Although no major morphological changes were noted, 4.1R KO hearts showed reduced expression of NaV1.5α and increased expression of protein 4.1G. Our data indicate an unexpected and novel role for the cytoskeletal protein 4.1R in modulating the functional properties of several cardiac ion transporters with consequences on cardiac electrophysiology and with possible significant roles during normal cardiac function and disease.

Objectives We investigated in vivo in aortic valve stenosis (AVS) whether there is: 1) thermal heterogeneity within the valve leaflets; 2) temperature difference between the leaflets and the ascending aortic wall; and 3) a possible correlation between heat production, inflammation, and neoangiogenesis. Background Histological studies have demonstrated a potential role of inflammation and neoangiogenesis in AVS. Methods We examined 96 leaflets scheduled for aortic valve replacement. Twenty-five patients had AVS, and 7 had aortic valve insufficiency (AVI). Temperature measurements were performed right before hypothermic cardioplegia. Temperature difference (ΔT) was assigned as the mean temperature of each leaflet minus the temperature of the aortic wall. Histological, immunohistological analysis, and vascular endothelial growth factor (VEGF) immunoreactivity was performed. Results Significant thermal heterogeneity was recorded within the leaflets of AVS, compared with AVI (1.52 ± 1.35°C vs. 0.13 ± 0.11°C, p Conclusions Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors.

The R403Q mutation in β-myosin heavy chain was the first mutation to be identified as responsible for familial hypertrophic cardiomyopathy (FHC). In spite of extensive work on the functional sequelae of this mutation, the mechanism by which the mutant protein causes the disease has not been definitely identified. Here we directly compare contraction and relaxation mechanics of single myofibrils from left ventricular samples of one patient carrying the R403Q mutation to those from a healthy control heart. Tension generation and relaxation following sudden increase and decrease in [Ca2+] were much faster in the R403Q myofibrils with relaxation rates being the most affected parameters. The results show that the R403Q mutation leads to an apparent gain of protein function but a greater energetic cost of tension generation. Increased energy cost of tension generation may be central to the FHC disease process, help explain some unresolved clinical observations, and carry significant therapeutic implications.