Concurrent Primary Cardiac Tumors of Differing Histology and Origin: Case Report with Literature Review

Primary cardiac tumors are rare and are diverse in histology and anatomic origin. Approximately 75% are benign, and nearly 50% of these are myxomas. Herein, we report concurrent myxoma and papillary fibroelastoma, which tumors were found attached to the left atrial septum and aortic valve, respectively. Concurrent primary cardiac tumors of differing histology and origin are rare, and, to our knowledge, this is one of the few such cases reported in the medical literature.Key words: Echocardiography, fibroma, heart neoplasms/primary/diagnosis/surgery, myxoma, neoplasms, multiple primary/diagnosis/surgeryPrimary cardiac tumors are rare, with an incidence ranging from 0.0017% to 0.19% in autopsy series in unselected patients.^1–3 Myxomas are the most common cardiac neoplasm, accounting for as many as 50% of all benign tumors.⁴ Papillary fibroelastoma, the 3rd most common cardiac neoplasm, occurs in adults and is frequently diagnosed postmortem.⁵ Concurrent primary cardiac tumors of differing histology and origin are rare, and few cases have been reported in the medical literature. We are reporting a case of concurrent intracardiac myxoma and papillary fibroelastoma.     

Left Main Coronary Artery Embolus: Unusual Presentation of Papillary Fibroelastoma of the Aortic Valve

The usual cause of left main coronary artery obstruction is atherosclerotic occlusion resulting from plaque rupture and subsequent thrombus formation. In previously reported cases, tumor embolization into the coronary arteries caused sudden death and was detected only at autopsy. Herein, we report an unusual presentation of cardiac papillary fibroelastoma of the aortic valve in a 62-year-old man. The fibroelastoma caused a left main coronary artery embolus and symptoms of acute coronary syndrome. The fibroelastoma was successfully excised during a valve-sparing surgical procedure. We believe that this is the 1st report of tumor embolization to the left main coronary artery—and in a living patient.Key words: Aortic valve/pathology/surgery, coronary disease/etiology, fibroma/complications/diagnosis/pathology/surgery/ultrasonography, heart neoplasms/physiopathology/surgery, heart valve diseases/pathology, incidental findings, papilloma/pathology, treatment outcomePapillary fibroelastomas are histologically benign neoplasms. These avascular tumors are small (mean diameter, 3–10 mm) and almost always occur singly. Often, they are mobile and have a thin stalk.¹ They have multiple papillary fronds, so that they resemble sea anemones. Papillary fibroelastomas consist of a core of dense connective tissue, an intermediate layer of loose connective tissue, and a covering of hyperplastic endothelial cells. Although cardiac papillary fibroelastoma is rare, it is the 2nd most common primary benign cardiac tumor (myxoma has been reported more often),² and it is the most common primary tumor of the heart valves. As with myxoma, its origin is not clear. Papillary fibroelastomas can develop on any cardiac valve or cardiac endothelial surface.³ Most are diagnosed incidentally.Clinical manifestations of cardiac papillary fibroelastomas include syncope, angina pectoris, transient ischemic attack, stroke, myocardial infarction, pulmonary embolism, congestive heart failure, and sudden death. Coronary ischemia has been caused by the prolapse of pedunculated coronary cusp tumors into the coronary ostia,⁴ and, alternatively, by the direct embolization of organized thrombus from a cusp lesion to a coronary artery.^3,5 In previously reported cases,^5-7 tumor embolization into the coronary arteries caused sudden death and was detected only at autopsy. Here, we present the case of a patient who presented with symptoms of acute coronary syndrome. The diagnosis was a left main coronary artery (LMCA) embolus from a cardiac papillary fibroelastoma.     

Atrial Myxoma in a Patient with Hypertrophic Cardiomyopathy

Atrial myxoma is the most common primary cardiac tumor. Patients with atrial myxoma typically present with obstructive, embolic, or systemic symptoms; asymptomatic presentation is very rare. To our knowledge, isolated association of atrial myxoma with hypertrophic cardiomyopathy has been reported only once in the English-language medical literature. We report the case of an asymptomatic 71-year-old woman with known hypertrophic cardiomyopathy in whom a left atrial mass was incidentally identified on cardiac magnetic resonance images. After surgical excision of the mass and partial excision of the left atrial septum, histopathologic analysis confirmed the diagnosis of atrial myxoma. The patient was placed on preventive implantable cardioverter-defibrillator therapy and remained asymptomatic. The management of asymptomatic cardiac myxoma is a topic of debate, because no reports definitively favor either conservative or surgical measures.Key words: Abnormalities, multiple/diagnosis; cardiomyopathy, hypertrophic/diagnosis/physiopathology; heart atria/pathology; heart neoplasms/diagnosis/pathology/surgery; myxoma/diagnosis/pathology/surgery; risk factorsPrimary cardiac tumors are rare entities, with a prevalence on autopsy of less than 1%.¹ Approximately three quarters of primary heart tumors are benign, and approximately 75% of those are myxomas. The remainder are lipomas, papillary fibroelastomas, and rhabdomyomas.² Cardiac myxomas usually develop in the atria—the vast majority in the left atrium, specifically from the interatrial septum at the border of the fossa ovalis.³ Patients with atrial myxoma typically present with cardiovascular symptoms such as heart failure and pulmonary hypertension, secondary to mitral valve obstruction. They can also present with neurologic deficits, transient or permanent visual loss, or involvement of internal viscera secondary to embolic phenomena. Constitutional symptoms include fatigue, fever, erythematous rash, arthralgia, myalgia, and weight loss.³ An asymptomatic presentation is extremely rare. Hypertrophic cardiomyopathy (HCM) is often diagnosed incidentally, and it can also present with obstructive symptoms similar to those of myxoma.⁴ We describe and discuss the case of an asymptomatic elderly patient with known HCM and an incidentally diagnosed atrial myxoma.     

Ultrafast four-dimensional imaging of cardiac mechanical wave propagation with sparse optoacoustic sensing

Propagation of electromechanical waves in excitable heart muscles follows complex spatiotemporal patterns holding the key to understanding life-threatening arrhythmias and other cardiac conditions. Accurate volumetric mapping of cardiac wave propagation is currently hampered by fast heart motion, particularly in small model organisms. Here we demonstrate that ultrafast four-dimensional imaging of cardiac mechanical wave propagation in entire beating murine heart can be accomplished by sparse optoacoustic sensing with high contrast, ∼115-µm spatial and submillisecond temporal resolution. We extract accurate dispersion and phase velocity maps of the cardiac waves and reveal vortex-like patterns associated with mechanical phase singularities that occur during arrhythmic events induced via burst ventricular electric stimulation. The newly introduced cardiac mapping approach is a bold step toward deciphering the complex mechanisms underlying cardiac arrhythmias and enabling precise therapeutic interventions.

The first observation of irregular spikes in electrocardiogram (ECG) signals in the early 1900s (1) has fostered vast research efforts to unravel the fundamental mechanisms underlying cardiac arrhythmias (2–4). The information encoded in ECG signals corresponds to the integrated electrical activity of cardiac cells. Point-by-point ECG mapping combined with modeling of tissue electrical properties has enabled localizing the onset and propagation paths of irregular electric signaling in the heart (5). Electrocardiographic imaging further combined multiple ECG body-surface readings with full-body X-ray computed tomography (CT) or MRI scans to map the electrical activity on the epicardial heart surface (6, 7). While delivering excellent contrast for imaging cardiac anatomy and blood flow (8–10), the temporal resolution of CT and MRI is insufficient for three-dimensional (3D) visualization of transient nonperiodic events in the heart. Models linking the electrophysiology of single cells to the propagation of electric signals in cardiac muscles have subsequently been developed, yet complete depiction of the entire heart motion in real-time and 3D remains challenging without employing cardiac gating (11). Progress in ultrasound (US) imaging recently enabled attaining millisecond-scale temporal resolutions, leading to major advances in characterization of the cardiac motion. Particularly, visualization of electromechanical and shear waves in the heart was possible with ultrafast US (12, 13). In parallel, development of optical probes of transmembrane voltage (14, 15) and intracellular calcium (16, 17) has provided unprecedented insights into cardiovascular physiology and the mechanisms of electrical activity (18, 19). A combination between US and optical mapping has further enabled the multimodal characterization of scroll waves in an isolated Langendorff pig heart model (20), a pivotal step toward better understanding of the heart rhythm disorders.Despite major technical advances, the spatiotemporal resolution and penetration of the currently available cardiac imaging modalities hinders the transmural visualization of fast electromechanical phenomena across the entire beating heart, particularly in small model organisms. The effective spatiotemporal resolution of ultrafast volumetric US is ultimately limited by the need for compounding multiple plane-wave transmissions in order to achieve sufficient image contrast (21, 22). While offering important benefits, such as fast response times (23) and accurate spatial mapping capacity (24), the strong photon scattering in biological tissues fundamentally confines optical mapping to surface-weighted two-dimensional (2D) observations (25, 26), whereas motion artifacts associated with the myocardial contractions further lead to out-of-focus artifacts complicating action potential readings (18, 27–29). Other common impediments of extrinsic cardiac labeling approaches include phototoxicity (30), photobleaching (31), and nonphysiological changes in the heart (32).Recent progress in the development of optoacoustic (OA) tomography methods have attained a unique combination between fast volumetric imaging speed, deep-tissue penetration, and high molecular sensitivity (26, 33–35), making this modality particularly attractive for studying cardiac function. Whole-heart OA imaging at 50-Hz volumetric frame rates was demonstrated for the Langendorff-perfused model (36) as well as in vivo by capturing bulk perfusion of optical contrast agents (37, 38). Healing of infarcted myocardium in models of coronary occlusion and c-kit mutants has further been studied using this approach (39), highlighting its unique capacity for multiparametric characterization of morphological and functional changes in murine models of myocardial infarction.Yet, accurate mapping of microscopic tissue deformations in a rapidly beating murine heart implies 3D imaging at significantly faster frame rates on a submillisecond temporal resolution scale (39, 40). Here, we demonstrate that ultrafast four-dimensional imaging of cardiac mechanical wave propagation in the entire beating murine heart can be accomplished using sparse OA sensing (SOS) of volumetric cardiac motion. Our approach is based on a rapid compressed acquisition of OA responses from randomized subsets of US detection channels followed by iterative reconstruction of the entire image sequence with infimal convolution of the total variation (ICTV) functional. In this way, we were able to efficiently delineate the multiscale spatiotemporal information encoded in the volumetric heart motion with high-contrast, ∼115-µm spatial, and submillisecond temporal resolution.     

Posterobasal Left Ventricular Aneurysms: Surgical Treatment and Long-Term Outcomes

This retrospective study analyzes short- and long-term outcomes in 18 patients who underwent repair of posterobasal left ventricular aneurysm from January 1993 through December 2009. As concomitant procedures, mitral reconstruction was performed in 4 patients, ventricular septal defect repair in 2 patients, and coronary artery bypass grafting in 17 patients. In regard to surgical technique, 10 patients underwent patch repair and 8 underwent closure by linear suture.The in-hospital mortality rate was 11% (2 patients). An intra-aortic balloon pump was placed postoperatively in 1 patient. One patient underwent reoperation for mediastinitis and 2 for bleeding. The 1-, 5-, and 10-year survival rates were 82%, 76%, and 52%, respectively.Posterobasal left ventricular aneurysm repair can be performed with low short-term mortality rates and good long-term outcomes. It must be judged whether a linear repair or patch repair is better, in accordance with aneurysm size and the concomitant operative procedure, if any.Key words: Aneurysm, left ventricular; aneurysmectomy; cardiac surgical procedures/mortality; heart aneurysm/mortality/surgery; heart ventricle/surgery; myocardial infarction; retrospective studiesPosterior left ventricular (LV) aneurysms are less common than anterior aneurysms.^1–3 Their prevalence in large series has usually been reported as less than 10%.^2–4 The posterobasal part of the heart is supplied by the left circumflex coronary artery and by terminal branches of the right coronary artery.⁵ Pathologic states of these branches cause inferoposterior or posterolateral LV aneurysm.³ Posterior aneurysms can be accompanied by various degrees of mitral insufficiency⁶ and by ventricular septal defects (VSD).⁷ A 2004 study reported mitral insufficiency of grade 2/4 or higher in all 13 patients who underwent repair of aneurysm due to posterior myocardial infarction (MI).⁶ Our study investigates operative results among patients who underwent surgery for posterior LV aneurysm. Our surgical approach is discussed in terms of short- and long-term outcomes.     

Factors Contributing to Suboptimal Vaccination against Influenza: Results of a Nationwide Telephone Survey of Persons with Cardiovascular Disease

Vaccination against influenza averts cardiovascular events and is recommended for all patients with coronary heart disease. Because data were unavailable regarding vaccination rates among such patients'' household contacts, we sought to estimate the rate of influenza vaccination in persons with cardiovascular disease and their contacts.In 2004, we conducted a random, nationwide telephone survey of 1,202 adults (age, ≥18 yr) to ascertain knowledge, attitudes, and behaviors regarding influenza vaccination. Of the interviewees, 134 (11.1%) had histories of heart disease or stroke. Of these 134, 57% were men, and 45% were ≥65 years of age. Overall, 57% were inoculated against influenza in 2003–2004, and 68% intended the same during 2004–2005. Vaccination rates increased with age: 48% (ages, 18–49 yr), 68% (ages, 50–64 yr), and 75% (age, ≥65 yr). Forty of 69 respondents (58%) reported that their spouses were vaccinated, and 7 of 21 (33%) reported the inoculation of children ≤17 years old in their household. Only 65% of the 134 patients considered themselves to be of high-risk status. Chief reasons for remaining unvaccinated were disbelief in being at risk and fear of contracting influenza from the vaccine.Although seasonal influenza vaccination is recommended for all coronary heart disease patients and their household contacts, the practice is less prevalent than is optimal. Intensified approaches are needed to increase vaccination rates. These findings suggest a need to increase vaccination efforts in high-risk subjects, particularly amidst the emerging H1N1 pandemic.Key words: Advisory committees/statistics & numerical data/trends, age factors, cardiovascular diseases/etiology/prevention & control/virology, cost of illness, health care surveys, health policy, infectious disease transmission, influenza vaccines/administration & dosage/economics/supply & distribution/therapeutic use, influenza, human/complications/epidemiology/immunology/mortality/prevention & control/transmission, risk factors, United States/epidemiology, vaccination/economics/standards/statistics & numerical data/utilizationCoronary heart disease (CHD) is the leading cause of death in the Western world. It claims more than 700,000 American lives each year and accounts for 29% of all deaths in the United States, costing the nation $193.8 billion per year.¹ Influenza, the 7th leading cause of death, was responsible for 64,684 deaths in 1999 and an average of 36,000 deaths per year in the United States during the 1990s.² Annual estimates of influenza-associated deaths have increased substantially over the last 2 decades. Influenza is associated with preventable hospitalizations (especially in the elderly population) and with increased healthcare costs that amount to millions of dollars.³ Outbreaks of variable extent and severity, which occur nearly every winter, result in substantial morbidity in the general population and in increased mortality rates among certain high-risk patients, chiefly from cardiovascular and pulmonary complications.⁴ As we have shown earlier, a considerable number of coronary events are triggered by influenza infection.^5–7 Moreover, physicians tend to underreport influenza cases, especially when the illness is complicated by myocardial infarction (MI). Therefore, the true incidence in the United States may exceed 36,000 deaths per year.⁷Vaccination—currently the most effective action against influenza—reduces the occurrence of the illness by 70% to 90% in healthy adults younger than 65 years of age^8,9 and reduces the all-cause mortality rate by 50% to 68% in healthy persons of age 65 and older.^10,11 Vaccination is also efficacious in reducing healthcare costs and the losses in productivity that are associated with influenza illness.¹²Inoculation against influenza has been shown to prevent the occurrence of cardiovascular events in high-risk patients.⁷ We have previously shown that, in patients with chronic CHD, vaccination reduces the risk of developing recurrent MI during the peak influenza season¹³ of September through February. Other researchers have confirmed our findings by showing a post-vaccination decrease in hospitalization for primary cardiac arrest^14,15; death and ischemic events after MI and angioplasty¹⁶; the composite endpoint of cardiovascular death, MI, or unplanned revascularization or hospitalization for ischemia¹⁷; and stroke and transient ischemic attacks.^18,19 One study determined no benefit.²⁰The inoculation of all persons who have chronic cardiovascular conditions, and of anyone in close contact with these persons, is recommended by the Centers for Disease Control (CDC).²¹ Close contacts include household members (spouses and children) and in-home healthcare workers. Despite the recommendations, it was found that only 38.8% of persons with CHD in the 18-to 49-year age group and 83.1% in the 50-to 64-year age group with CHD had received the influenza vaccine in 2001.²² Another study reported similar findings.²³ Moreover, a lack of data concerning the vaccination rates in household contacts of CHD patients potentially forebodes greater challenges in attaining the CDC-recommended goals regarding vaccination against influenza. Children are the primary source for transmitting influenza infection to adults: previous studies have shown that inoculating children reduces all-cause death in the elderly and influenza-related illnesses in all adults.^24,25In light of these factors, we commissioned a nationwide telephone survey in order to investigate the rate of influenza vaccination among CHD patients and their household contacts. Our aim was to identify patients with cardiovascular disease (CVD) and evaluate why large numbers of them fail to avail themselves of vaccination against influenza.     

Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress

Heart failure is accompanied by a loss of the orderly disposition of transverse (T)-tubules and a decrease of their associations with the junctional sarcoplasmic reticulum (jSR). Junctophilin-2 (JP2) is a structural protein responsible for jSR/T-tubule docking. Animal models of cardiac stresses demonstrate that down-regulation of JP2 contributes to T-tubule disorganization, loss of excitation-contraction coupling, and heart failure development. Our objective was to determine whether JP2 overexpression attenuates stress-induced T-tubule disorganization and protects against heart failure progression. We therefore generated transgenic mice with cardiac-specific JP2 overexpression (JP2-OE). Baseline cardiac function and Ca²⁺ handling properties were similar between JP2-OE and control mice. However, JP2-OE mice displayed a significant increase in the junctional coupling area between T-tubules and the SR and an elevated expression of the Na⁺/Ca²⁺ exchanger, although other excitation-contraction coupling protein levels were not significantly changed. Despite similar cardiac function at baseline, overexpression of JP2 provided significantly protective benefits after pressure overload. This was accompanied by a decreased percentage of surviving mice that developed heart failure, as well as preservation of T-tubule network integrity in both the left and right ventricles. Taken together, these data suggest that strategies to maintain JP2 levels can prevent the progression from hypertrophy to heart failure.In working ventricular myocytes, normal excitation-contraction (E-C) coupling requires precise communication between voltage-gated L-type Ca²⁺ channels (Cav1.2) located in clusters within transverse (T)-tubules and, less frequently, on the plasmalemma, and Ca²⁺ release channels/ryanodine receptor channels (RyRs) that are also clustered on the junctional sarcoplasmic reticulum (jSR) membrane (1–4). In normal hearts, flat jSR cisternae containing a continuous row of polymerized calsequestrin (CsQ2) either wrap around a T-tubule segment or abut against the plasmalemma (5, 6) and are coupled to the surface membranes via apposed clusters of RyR2 and Cav1.2 (7). These junctional sites are called dyads. However, although the jSR cisternae constitute a single continuous compartment, the clusters of RyR2 do not occupy the whole jSR surface but are in smaller groups (8, 9). Hence, each dyad is composed of several smaller RyR2/Cav1.2 complexes, also called couplons. Functional interaction between Cav1.2 and RyR2 at these sites ensure synchronous SR Ca²⁺ release and coordinated contraction (1, 10, 11). There is evidence that impaired cardiac E-C coupling/Ca²⁺ handling is a key mediator of heart failure (12, 13). One underlying mechanism for the defective Ca²⁺ release is the progressive loss of T-tubule network organization and of the relationship between RyR2 and Cav1.2 (14–16). Therefore, preventing loss of jSR/T-tubule junctions and of T-tubule organization may represent a new strategy for therapeutic intervention in heart failure.In normal cardiomyocytes, the formation of dyads requires junctophilin 2 (JP2), a structural protein that provides a physical connection between the T-tubule and SR membranes (17). JP2’s eight N-terminal “membrane occupation and recognition nexus” domains bind to the plasmalemma (T-tubules), and its C-terminal transmembrane domain tethers the opposite end to the SR membrane (17). Decreased JP2 levels have been observed in human heart failure patients and in failing hearts from animal models of cardiac disease (16, 18–22). Knockdown of JP2 results in acute heart failure that is associated with the loss of junctional membrane complex, disrupted T-tubule organization, and Ca²⁺ handling dysfunction (23). In addition, embryonic myocytes with JP2 deficiency have defective cardiac dyads, including more SR segments with no T-tubule couplings as well as reduced intracellular Ca²⁺ transients (17). These data collectively suggest that loss of JP2 contributes to the functional defects in heart failure. Therefore, interesting questions are: Is the JP2 deficiency effect linked to the resultant disruption of jSR/T-tubule junctions and of T-tubule network integrity, as suggested by previous findings (16–18, 23)? Conversely, could exogenous overexpression of JP2 in cardiomyocytes improve Ca²⁺ handling and protect against the development of heart failure?To answer this question, we generated transgenic mice with cardiac-specific overexpression of JP2. Moderate overexpression of JP2 led to a significant increase in the junctional coupling area between T-tubule and SR membrane, but surprisingly, it did not enhance cardiac function or increase SR Ca²⁺ release at baseline. However, interestingly, JP2-overexpressing mice were resistant to left ventricular pressure overload-induced heart failure, demonstrating that JP2 overexpression is protective. These data suggest that preventing the loss of JP2 could be a potential therapeutic strategy for heart failure treatment.     

Rhesus monkeys have an interoceptive sense of their beating hearts

The sensation of internal bodily signals, such as when your stomach is contracting or your heart is beating, plays a critical role in broad biological and psychological functions ranging from homeostasis to emotional experience and self-awareness. The evolutionary origins of this capacity and, thus, the extent to which it is present in nonhuman animals remain unclear. Here, we show that rhesus monkeys (Macaca mulatta) spend significantly more time viewing stimuli presented asynchronously, as compared to synchronously, with their heartbeats. This is consistent with evidence previously shown in human infants using a nearly identical experimental paradigm, suggesting that rhesus monkeys have a human-like capacity to integrate interoceptive signals from the heart with exteroceptive audiovisual information. As no prior work has demonstrated behavioral evidence of innate cardiac interoceptive ability in nonhuman animals, these results have important implications for our understanding of the evolution of this ability and for establishing rhesus monkeys as an animal model for human interoceptive function and dysfunction. We anticipate that this work may also provide an important model for future psychiatric research, as disordered interoceptive processing is implicated in a wide variety of psychiatric conditions.

Signals from the body form a rich landscape that grounds the complex mental lives of humans and nonhuman animals. The capacity to sense^* these signals and the physiological state of the body more generally, referred to as “interoception” (1, 2), are understood to underlie human processes as diverse as, but not limited to, energy regulation (3), subjective emotional experience (4, 5), decision-making (6, 7), and self-awareness (8). In humans, interoceptive capacities have long been characterized with measures that index people’s ability to sense when their own hearts are beating, typically by counting the number of heartbeats that occur over a span of time (9) or discriminating between auditory, visual, or audiovisual stimuli presented synchronously or asynchronously with heartbeats (10, 11). Performance on these tasks is then quantified in terms of accuracy or sensitivity and, together with interoceptive sensibility (i.e., metacognitive self-assessment of interoceptive ability) and interoceptive awareness (i.e., coherence of accuracy and self-assessment), constitute the core of the multidimensional construct of interoception (12). Individual differences in cardiac interoception have trait-like stability which has been correlated with interoceptive capacity in other physiological domains, like gastric interoception (13, 14), as well as with a variety of psychological functions [e.g., emotional experience (4), metacognition (15), memory (16)] and dysfunctions [e.g., psychiatric disorders, broadly (17), anxiety (18) depression (19)].Alterations and deficits in interoceptive processing are increasingly recognized to impact both physical and mental health (20–22). Animal models—and nonhuman primate models, specifically—of interoceptive function and dysfunction are therefore likely to be important for advancing our understanding of the etiology of such disorders and supporting the development of treatments and interventions for them, just as nonhuman primate models have proven critical for the advancement of other subfields of biomedical research (23–25). Evaluating interoceptive capacity in nonhuman primates also allows testing hypotheses about its evolution. Decades of neuroanatomical research demonstrates that, unlike rodents, primates have a phylogenetically new anatomical system for processing interoceptive information, which includes the lamina I spinothalamic tract, ventromedial nucleus of the thalamus, and insula, allowing for the direct projection of signals representing the physiological condition of the body onto thalamocortical circuits (9, 26). The rodent interoceptive pathway also includes direct projections from the parabrachial nucleus to the insula and ventromedial prefrontal cortex (27), a pathway that is notably absent in nonhuman primates (28), and a difference which likely means that interoceptive processing in primates (including humans and monkeys) is radically different from that in rodents (29). Additionally, the nonhuman primate insula, like the human insula, has baroreceptor-sensitive neurons, providing evidence for the direct representation of cardiac cycle-related information in cortex (30, 31), is far more complex than rodent insula (32) and has different brain-wide connections than the rodent insula (33). The limited behavioral evidence that exists from monkeys suggests that, at the very least, monkeys can learn to alter their cardiac function. For example, rhesus monkeys (Macaca mulatta) have been classically conditioned to alter both their heart rate and blood pressure in response to the presentation of a light after pairing it with an electric shock (34, 35) as well as to raise and lower their heart rate to avoid an electric shock (36).Despite this evidence from the early learning studies related to cardiac control (34–36) and decades of neuroanatomical studies (8, 26, 30–32), summarized above, it remains unclear whether nonhuman primates share an innate capacity to integrate interoceptive and exteroceptive sensory information in order to influence behavioral measures of psychological functions, as has long been established in humans (9, 10). To test this hypothesis, we capitalized upon the recent development of an implicit behavioral measure for assessing cardiac interoceptive capacity in human infants [Infant Heartbeat Task or iBEAT  (37)] to assess the impact of spontaneous sensation and integration of cardiac interoceptive signals on visual attention in the rhesus monkey.     

From the Cover: Mitochondrial calcium overload is a key determinant in heart failure

Calcium (Ca²⁺) released from the sarcoplasmic reticulum (SR) is crucial for excitation–contraction (E–C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca²⁺ is essential for optimal function of these organelles. However, Ca²⁺ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca²⁺ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca²⁺ leak causes mitochondrial Ca²⁺ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca²⁺ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca²⁺ leak, we found that leaky RyR2 channels result in mitochondrial Ca²⁺ overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca²⁺ overload and dysfunction in HF.Type 2 ryanodine receptor/Ca²⁺ release channel (RyR2) and type 2 inositol 1,4,5-trisphosphate receptor (IP3R2) are the major intracellular Ca²⁺ release channels in the heart (1–3). RyR2 is essential for cardiac excitation–contraction (E–C) coupling (2), whereas the role of IP3R2 in cardiomyocytes is less well understood (3). E–C coupling requires energy in the form of ATP produced primarily by oxidative phosphorylation in mitochondria (4–8).Both increased and reduced mitochondrial Ca²⁺ levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) (6, 7, 9–17). Albeit Ca²⁺ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle (18, 19), excessive mitochondrial Ca²⁺ uptake has been associated with cellular dysfunction (14, 20). Furthermore, the exact source of mitochondrial Ca²⁺ has not been clearly established. Given the intimate anatomical and functional association between the sarcoplasmic reticulum (SR) and mitochondria (6, 21, 22), we hypothesized that SR Ca²⁺ release via RyR2 and/or IP3R2 channels in cardiomyocytes could lead to mitochondrial Ca²⁺ accumulation and dysfunction contributing to oxidative overload and energy depletion.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Synergistic regulation of nonbinary molecular switches by protonation and light

We report a molecular switching ensemble whose states may be regulated in synergistic fashion by both protonation and photoirradiation. This allows hierarchical control in both a kinetic and thermodynamic sense. These pseudorotaxane-based molecular devices exploit the so-called Texas-sized molecular box (cyclo[2]-(2,6-di(1H-imidazol-1-yl)pyridine)[2](1,4-dimethylenebenzene); 1⁴⁺, studied as its tetrakis-PF₆ ⁻ salt) as the wheel component. Anions of azobenzene-4,4′-dicarboxylic acid (2H⁺•2) or 4,4′-stilbenedicarboxylic acid (2H⁺•3) serve as the threading rod elements. The various forms of 2 and 3 (neutral, monoprotonated, and diprotonated) interact differently with 1⁴⁺, as do the photoinduced cis or trans forms of these classic photoactive guests. The net result is a multimodal molecular switch that can be regulated in synergistic fashion through protonation/deprotonation and photoirradiation. The degree of guest protonation is the dominating control factor, with light acting as a secondary regulatory stimulus. The present dual input strategy provides a complement to more traditional orthogonal stimulus-based approaches to molecular switching and allows for the creation of nonbinary stimulus-responsive functional materials.

Multifactor regulation of biomolecular machines is essential to their ability to carry out various biological functions (1 –11). Construction of artificial molecular devices with multifactor regulation features may allow us to understand and simulate biological systems more effectively (12 –31). However, creating and controlling such synthetic constructs remains challenging (16, 32 –37). Most known systems involving multifactor regulation, including most so-called molecular switches and logic devices (38 –43), have been predicated on an orthogonal strategy wherein the different control factors that determine the distribution of accessible states do not affect one another (20, 44 –56). However, in principle, a greater level of control can be achieved by using two separate regulatory inputs that operate in synergistic fashion. Ideally, this could lead to hierarchical control where different states are specifically accessed by means of appropriately selected nonorthogonal inputs. However, to our knowledge, only a limited number of reports detailing controlled hierarchical systems have appeared (57). Furthermore, the balance between specific effects (e.g., kinetics vs. thermodynamics) under conditions of stimulus regulation is still far from fully understood (54). There is thus a need for new systems that can provide further insights into the underlying design determinants. Here we report a set of pseudorotaxane molecular shuttles that act as multimodal chemical switches subject to hierarchical control.     

Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin

In this study, we investigated the role of the super-relaxed (SRX) state of myosin in the structure–function relationship of sarcomeres in the hearts of mouse models of cardiomyopathy-bearing mutations in the human ventricular regulatory light chain (RLC, MYL2 gene). Skinned papillary muscles from hypertrophic (HCM–D166V) and dilated (DCM–D94A) cardiomyopathy models were subjected to small-angle X-ray diffraction simultaneously with isometric force measurements to obtain the interfilament lattice spacing and equatorial intensity ratios (I₁₁/I₁₀) together with the force-pCa relationship over a full range of [Ca²⁺] and at a sarcomere length of 2.1 μm. In parallel, we studied the effect of mutations on the ATP-dependent myosin energetic states. Compared with wild-type (WT) and DCM–D94A mice, HCM–D166V significantly increased the Ca²⁺ sensitivity of force and left shifted the I₁₁/I₁₀-pCa relationship, indicating an apparent movement of HCM–D166V cross-bridges closer to actin-containing thin filaments, thereby allowing for their premature Ca²⁺ activation. The HCM–D166V model also disrupted the SRX state and promoted an SRX-to-DRX (super-relaxed to disordered relaxed) transition that correlated with an HCM-linked phenotype of hypercontractility. While this dysregulation of SRX ↔ DRX equilibrium was consistent with repositioning of myosin motors closer to the thin filaments and with increased force-pCa dependence for HCM–D166V, the DCM–D94A model favored the energy-conserving SRX state, but the structure/function–pCa data were similar to WT. Our results suggest that the mutation-induced redistribution of myosin energetic states is one of the key mechanisms contributing to the development of complex clinical phenotypes associated with human HCM–D166V and DCM–D94A mutations.

Inherited cardiomyopathies are a class of heart diseases caused by variations in multiple genetic loci, mostly originating from point mutations in sarcomeric proteins (1). The majority of hypertrophic cardiomyopathy (HCM)–causing mutations reside in human β-cardiac myosin (∼35%) and cardiac myosin-binding protein C (∼35%); however, according to recent genetic studies, mutations in the human cardiac regulatory light chain (RLC, MYL2 gene) are more common than previously reported, and they are often associated with adverse clinical outcomes (reviewed in refs. 2 and 3). In this study, we focused on the D166V (aspartate166 → valine)-RLC mutation shown to result in HCM (4) and the D94A (aspartate94 → alanine)–RLC mutation associated with dilated cardiomyopathy (DCM) in patients (5). Two “humanized” mouse models were explored, expressing human ventricular HCM–D166V and DCM–D94A MYL2 variants in mice (6, 7), and they served as model systems for investigating the mechanisms underlying human HCM and DCM.The myosin RLC is a major subunit of striated-muscle myosin and a modulator of Ca²⁺ and tropomyosin–troponin-regulated cardiac muscle contraction (8). Together with the myosin essential light chain (ELC), the RLC binds to the lever arm domain of the myosin head, suggesting important roles for both light chains in maintaining the structural and functional integrity of the lever arm during the power stroke and sarcomere shortening (9, 10). Structurally, the RLC belongs to the EF-hand calcium-binding protein family and contains a homologous helix–loop–helix region composed of a 12-amino-acid Ca²⁺-binding loop flanked by two perpendicular α-helices (EF-hand motif) (8). The human cardiac RLC also contains a highly conserved N-terminal phosphorylatable serine (Ser-15), a target of cardiac myosin light chain kinase (11). Our previous investigations implied that both properties of the RLC, Ca²⁺ binding and Ser-15 phosphorylation, determine the role that RLC plays in cardiac muscle contraction in healthy and cardiomyopathic muscle (12, 13). The phosphorylation of cardiac RLC was shown to directly modulate the Ca²⁺-dependent force development and the kinetics of attachment and detachment of cycling myosin cross-bridges (14–16), and RLC phosphorylation-mediated sensitization to calcium was attributed to the switch between the OFF and ON conformations of myosin motors and a movement of myosin heads toward the thin filaments (17, 18).Considering the importance of myosin RLC for the actin–myosin interaction and force production in the heart, it is not surprising that genetic mutations in MYL2 can result in structural and functional alterations and lead to cardiomyopathy in humans. To better understand the interplay between the mutation-induced molecular insult and heart dysfunction, we examined the effect of HCM–D166V and DCM–D94A mutations expressed in mouse models of HCM and DCM (6, 7) on sarcomeric structure, force production, and myosin energetic states using left ventricular (LV) papillary muscles (PM) from the hearts of mutant versus wild-type (WT) mice expressing a nonmutated human ventricular RLC. Importantly, we monitored the structural determinants of muscle contraction simultaneously with force development over the full range of Ca²⁺-activated force from relaxed through submaximal to maximum Ca²⁺ activation.Small-angle X-ray diffraction is the technique of choice to obtain structural information concerning the sarcomere under physiological or disease-like conditions. The equatorial diffraction patterns yield two structural parameters, the interfilament lattice spacing (d₁₀) that is proportional to the center-to-center distance between two adjacent thick and thin filaments (19) and the equatorial intensity ratio (I₁₁/I₁₀). I₁₁/I₁₀ is the ratio of the integrated intensity of the 1,1 equatorial reflections originating from the myosin and actin filaments to the 1,0 equatorial reflections arising from the myosin-containing thick filaments. These two parameters have been extensively used to characterize the normal sarcomere structure, but they also enable the assessment of the effects of various mutations in sarcomeric proteins on the proximity of myosin heads to actin, providing insights into the structural basis of disease phenotypes (18, 20, 21). I₁₁/I₁₀ reveals information about the proximity of myosin heads to the actin-containing thin filaments and is directly proportional to the number of attached cross-bridges in both cardiac (22) and skeletal (23) muscles. A relatively high value of I₁₁/I₁₀ indicates that myosin heads are more closely associated with the actin filaments, and a low value depicts myosin heads more closely associated with the thick filament backbone, apparently reflecting the formation of the “interacting-heads motif” (IHM) (22, 24). The IHM is thought to be, but not yet proven, the structural basis of the recently discovered super-relaxed (SRX) state of myosin (25, 26) that is considered central to modulating sarcomeric force production and energy utilization in cardiac muscle (27–29). The SRX is an energy-conserving state in which myosin cross-bridges cycle with a highly inhibited ATP turnover rate (25, 26). It has 10- to 100-fold slower ATPase than the already known non-actin–bound, disordered relaxed (DRX) state in which myosin heads protrude into the interfilament space but are restricted from binding to actin compared with SRX heads that are neatly ordered around the thick filament backbone (30). Structurally, the SRX state is associated with the IHM, comprised of the primary head–head interaction site of the “blocked” head and the converter domain of the “free” head, with both heads locked into the thick filament backbone, thus inhibiting ATP hydrolysis and withdrawing both heads from thin filament interaction and force production (1, 28, 31). This asymmetric IHM formation is presumed to define the SRX state of thick filaments in the heart (22) and could explain the structural origin of the slow (250 to 300 s) versus fast (<30 s) ATP turnover time in cardiac muscle (30, 31).Under resting conditions, myosin heads can exist in a wide range of structural states and proximities to actin filaments, each associated with different rates of energy consumption (1). The relaxation phase of the cardiac cycle is critically important for normal heart function, and the disruption of IHM structures may contribute to energetically compromised myocardium and inefficient heart performance (24, 27, 29). The SRX conformation is supported by protein–protein interactions of myosin heads with the ELC and RLC that serve as scaffolding proteins, and mutations in these structural components of the IHM may lead to destabilization of SRX and unbalanced SRX ↔ DRX equilibrium. We thus tested whether the SRX state is affected by the two pathogenic variants of RLC and explored the mutation-specific redistribution of myosin energetic states in the hearts of HCM–D166V and DCM–D94A versus WT mice.     

Pericardial Fat Necrosis: A Review and Update

A previously healthy middle-aged person presents with excruciating left-sided chest pain of 6 hours'' duration. The pain has come on abruptly, without warning, and is located in the lower part of the chest anteriorly. It radiates to the neck and left shoulder and worsens on deep inspiration. The patient appears seriously ill, with tachypnea, tachycardia, and diaphoresis. Otherwise, the physical examination is unremarkable. The electrocardiogram shows sinus tachycardia. Results of conventional blood studies and the chest radiograph are within normal limits. Three days later, a follow-up chest radiograph shows a 3.5 × 4-cm mass adjacent to the left side of the heart near the diaphragm.This hypothetical case illustrates the typical presentation of a rare but important benign disease—pericardial fat necrosis (PFN). At least 23 cases of PFN have been documented in the English-language medical literature since Jackson, Clagett, and McDonald described the condition in 1957.^1–17 Textbooks of internal medicine^18–22 and cardiology^23–25 offer nothing on this ailment, and only 1²⁶ of 3^26–28 books devoted solely to the pericardium mentions it. As a result, PFN remains little known and poorly appreciated. Yet, early in its course, PFN characteristically is mistaken for a serious disease, particularly myocardial infarction^1–3,10 or pulmonary embolism.^1,8,10,13 Later, it uniformly mimics a pericardial cyst or a pericardial or pulmonary neoplasm. Misdiagnosis and mismanagement are inevitable, therefore, if one is not familiar with this unique clinicoradiologic entity. Hence, this review.

Clinical Features

Pericardial fat necrosis classically strikes suddenly, without warning. All of the victims reported to date—15 men and 8 women—were in good health at the time PFN began. They ranged in age from 23 to 67 years (mean age, 49.2 yr). Five of the men^1–3,6 and 2 of the women^11,12 were white and 1 of the women was black.¹³ Race was not recorded for the remaining 15 patients.Severe chest pain, typically pleuritic, is the initial manifestation. It was left-sided in 15 patients,^{1–3,5–7,9–11,13,14,16} right-sided in 5,^1,4,8,10,12 present but not further described in 1,¹⁶ absent in 1,¹⁷ and not mentioned in 1.¹⁵ The pain is located anteriorly near the diaphragm and radiates at times to the neck, shoulder, upper arm, axilla, or back. It lasts several days to a week or so, but can recur with less intensity for up to a year.^1,10 Fever and cough are not features of PFN.If examined soon after onset of the chest pain, the patient is dyspneic, with tachypnea, tachycardia, and diaphoresis. One patient was hypotensive at admission,³ 2 had a pericardial friction rub,^3,7 and 3 others had marked tenderness to palpation over or near the precordium.^5,6,10 By contrast, if several days or more elapse before the patient comes under observation, the physical examination usually gives normal findings.Electrocardiographic Observations. The electrocardiogram characteristically is normal. Occasionally, it shows tachycardia, nonspecific ST- or T-wave changes suggesting ischemia, or findings consistent with resolving pericarditis.^8,13,14 In 1 case, it showed right bundle branch block.¹¹

Imaging Results

Chest radiographs obtained during the first few days of the illness may show no abnormality. Thereafter, a mass invariably appears in or near the cardiophrenic angle on the side of the chest pain. The mass is always located anteriorly and is almost always contiguous with the cardiac silhouette. In 1 case, however, it extended between the lingula and left lower lobe¹⁰; in another, it overlay the left hemidiaphragm in the area of the interlobar fissure¹; and in another, it was distinctly separate from the heart.⁷ Finding such a mass on the chest radiograph always raised concern for a pericardial cyst or a pericardial or pulmonary neoplasm.Computed tomography (CT) helps determine the nature and exact location of the chest mass.^12–16,17 From density measurements, one can infer that the mass consists of fat; but CT cannot always distinguish between a benign and malignant fatty tumor, especially when stranding is present within the fat.^13,16 In such cases, operative intervention might still be indicated to establish the precise diagnosis.Magnetic resonance imaging performed in 2 patients confirmed the CT findings of fat with dense stranding.^14,16Gallium-67 scintigraphy in a patient with unexplained hemoptysis incidentally showed increased gallium uptake in the pericardial fat.¹⁵ Subsequent biopsy of the pericardial fat showed necrosis but no evidence of malignancy.

Miscellaneous Studies

Pleural effusion occurred in 4 patients. Thoracentesis yielded only a small amount of bloody fluid in 1 case,¹ “did not demonstrate any evidence of malignancy and the bacterial culture was negative” in another case,¹⁴ and was not mentioned in the third case.¹⁵ In the fourth case, thoracentesis disclosed a pH of 7.58; erythrocytes, 13,600/mm³; leukocytes, 5,000/mm³ (64% segmented neutrophils, 13% lymphocytes, and 24% monocytes); glucose, 139 mg/dL; protein, 4.6 g/dL; and lactate dehydrogenase, 167 U/mL.¹³Transthoracic and transesophageal echocardiography performed in 1 patient¹⁷ demonstrated a 5-cm, ovoid, solid pericardial mass compressing the right side of the heart.Other investigations that were noncontributory included the total and differential leukocyte counts, erythrocyte sedimentation rate, serum amylase and electrolytes, cardiac enzymes, barium swallow and barium enema, complete metastatic workup, arterial blood gas determination, ventilation/perfusion lung scan, bronchography, bronchoscopy with cytologic washings, pulmonary function tests, and pulmonary angiography.^{4,7,8,12,13,17}

Diagnosis

In 22 of the 23 cases, histologic examination of biopsied or (most often) resected tissue proved PFN. The sole exception was a case reported 5 years ago, in which the clinical, radiographic, and CT findings prompted a tentative diagnosis of PFN.¹⁶ With symptomatic treatment, the chest pain resolved at 1 week, and the chest radiograph 2 months later showed that the paracardiac density had disappeared. A follow-up chest CT at 2 months also showed a marked decrease in size and thickness of the pericardial lesion.

Surgical and Histologic Findings

After nondiagnostic workups, sometimes extensive, 21 of the 23 patients underwent exploratory thoracotomy. At operation, the typical finding was an inflammatory mass involving the parietal pericardial fat pad; masses varied from 1.5 cm in size⁹ to 10 × 7.5 × 3 cm in size.³ The pathologic features bore close resemblance to those of infarcted epiploic appendices and to fat necrosis in the breast.⁸ Lesions removed early in the clinical course showed a central focus of necrotic fat cells encompassed by macrophages with intense neutrophilic infiltration.¹² Specimens removed later in the clinical course showed considerable fibrosis as well. In 1 case, calcifications were also present.¹⁷ Resection of the diseased tissue effected a cure in every case, with follow-ups for as long as 19 years.¹⁰

Pathogenesis

The cause of PFN remains speculative. In 2 patients, the mass was attached to the heart by a pedicle, acute torsion of which might have triggered the necrosis.^1,5 A pre-existing structural abnormality of the adipose tissue, such as lipoma or hamartoma, might make the tissue vulnerable to the trauma of a beating heart and moving diaphragm.^4,6,17 Two cases lend credence to this possibility: in 1, lipomatosis abutted the right atrium¹⁷; in the other, the resected specimen was histologically consistent with a lipoma showing fat necrosis.⁴ In the circumstance of extreme lifting efforts before⁶ or during³ onset of the chest pain, rapid changes in intravascular pressure associated with the Valsalva maneuver might cause hemorrhage into the loosely supported adipose tissue of the pericardium. The hemorrhage might, in turn, initiate the necrosis.⁶ Although the original report on PFN listed obesity as a probable prerequisite for the disease,¹ only 8 of the 20 patients in subsequent reports were said to be obese.^8–11,14 Evidence of recent or concomitant infection, acute pancreatitis, or any other disease has been absent in every case.     

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

Homozygous cardiac myosin binding protein C-deficient (Mybpc^t/t) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc^t/t myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc^t/t myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc^t/t mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3^+/− individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3^−/− mice is primarily myocyte hyperplasia.Dilated cardiomyopathy (DCM) leads to heart failure and is a leading cause of morbidity and mortality (1, 2). DCM is generally diagnosed as left ventricular (LV) dilation with associated reduction in cardiac contraction measured as impaired fractional shortening (3). Hearts from affected individuals frequently demonstrate myocyte elongation, myocyte death, and fibrosis, in addition to LV dilation. DCM results from a variety of environmental factors, such as viral infection and alcohol abuse, as well as from mutations in a number of genes including titin, lamin A/C, cardiac actin, cardiac myosin heavy chain, and phospholamban (reviewed in refs. 4–6). Whether all of these DCM-inducing factors activate the same or different cellular pathways to produce similar clinical features remains uncertain. The mechanisms by which mutations in the cardiac myosin binding protein C (MYBPC3) gene and other sarcomere protein genes lead to cardiac dilatation are under investigation.MYBPC is a thick filament accessory protein component of the striated muscle sarcomere A band that constitutes 2–4% of the myofibril (discussed in ref. 7). Although there are four Mybpc genes in the mammalian genome, only cardiac Mybpc (Mybpc3) is expressed in embryonic, neonatal, and adult hearts (8, 9). Cardiac MYBPC interacts with at least four sarcomere components: myosin heavy chain, actin, myosin light chain 2, and titin (10–12). More than 400 cardiac MYBPC3 gene mutations have been identified in patients as a cause of hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder resulting from defective sarcomeres (for reviews, see refs. 12, 13). Due to an ancient founder mutation, 4% of the population of India carries a truncating MYBPC3 mutation (14, 15). The majority of cardiac MYBPC3 mutations are predicted to encode truncated proteins that lack portions of either the carboxyl myosin and/or titin binding domains (7, 13). These truncating MYBPC3 mutations are thought to cause cardiac hypertrophy by inducing myocyte hypertrophy (increased cell size), rather than myocyte hyperplasia.We and other researchers have created mice that carry a mutant cardiac Mybpc3 gene to create murine HCM models (16–18). Heterozygous mice, designated Mybpc^t/+, like humans bearing the same mutation, develop adult onset HCM. Homozygous MYBPC3 mutations are a much rarer cause of human DCM than autosomal dominant mutations in other sarcomere protein genes. However, homozygous Mybpc^t/t mice that express two mutant alleles and no wild-type cardiac Mybpc3 develop LV dilation by 3 d postbirth and have all of the features of DCM, including LV chamber dilation, albeit mildly impaired fractional shortening (16). Unlike most humans with DCM, homozygous mutant cardiac Mybpc^t/t mice have normal survival despite their cardiac disease. Other homozygous null cardiac Mybpc3 mice develop an identical phenotype (7, 17, 18). Hence, for the studies described here, we assume that the phenotype of the Mybpc^t/t mice is due to lack of MYBPC protein, rather than to small amounts of truncated protein. Recently, two groups have demonstrated that delivery of MYBPC to Mybpc3-null hearts restores cardiac function and morphology (19, 20). Here, we have begun to dissect the mechanism by which homozygous Mybpc^t/t hearts develop DCM.Because Mybpc^t/t mice begin LV dilation within a few days postbirth (16), we hypothesized that this reflected abnormal development of neonatal myocytes. During fetal and early perinatal development in wild-type hearts, cardiomyocytes divide rapidly, producing hyperplastic cardiac growth (21). However, at 10 d postbirth, cardiomyocytes cease to divide and all subsequent increases in myocardial mass result from myocyte hypertrophy (22). Despite the importance of this phenomenon, little is known about the molecular basis for the transition from hyperplasic to hypertrophic-based myocardial growth. We hypothesized that abnormal cardiomyocyte growth, either hyperplastic or hypertrophic, in the perinatal period accounted for the LV dilation of Mybpc^t/t mouse hearts. To address this question, we have counted and measured cardiomyocytes from Mybpc^t/t and wild-type mice. We have also studied the consequences of reducing MYBPC levels by injecting Mybpc3-specific shRNA at birth. Neonatal cardiomyocytes lacking cardiac MYBPC, due to Mybpc3-specific shRNA knockdown, undergo an additional round of cytokinesis. We conclude that dramatic reductions in the amount of cardiac MYBPC leads to aberrant cell cycle regulation at the G1/S checkpoint, resulting in at least one extra round of myocyte division and DCM.     

Management of Intra-Aortic Balloon Pump Entrapment: A Case Report and Review of the Literature

An intra-aortic balloon pump is one of the most valuable tools in the cardiac surgeon''s armament to assist in the management of the failing heart. Despite its widespread use, there are associated risks and complications, one of which is balloon rupture with associated entrapment. Numerous approaches for dealing with this complication have been described; here we review the previous experience with intra-aortic balloon pump entrapment and discuss potential management, with particular reference to a recent case of our own.Key words: Assisted circulation/adverse effects, counterpulsation/mortality, entrapment, intra-aortic balloon pumping/adverse effects/methods/mortality/rupture/standards/statistics & numerical data, risk assessmentCardiac surgery offers myriad interventions for possible use in an aging population that has a high prevalence of heart disease. This abundance of options has led to more complex cardiac surgery and to higher public expectations of successful outcomes.¹ Against this background, any mechanism that facilitates survival is welcome.The intra-aortic balloon pump (IABP), first used by Kantrowitz in 1967 in a patient with cardiogenic shock, provides mechanical cardiac support via insertion of an inflatable balloon into the descending aorta; it is the most commonly used supportive tool for temporary cardiac assistance.^1,2 The IABP works by reducing afterload and actively increasing coronary perfusion.² The indications are varied but include ongoing ischemia refractory to medical therapy, a need for prophylaxis in high-risk patients before cardiac surgery, and postoperative ischemia and low cardiac output despite inotropic support.³ Intra-aortic balloon pump use, although priceless in improving postoperative survival in high-risk cardiac surgical patients and those with ventricular dysfunction, is not without risks.^1,2 Balloon rupture, aortic or iliac artery dissection, thromboembolism, distal ischemia, and thrombocytopenia due to the mechanical action of the balloon on platelets are all potential complications of IABP use.^1,4 Despite these risks, there are over 70,000 insertions annually in the United States alone. Of all cardiac surgical patients, 5% to 10% undergo IABP placement.⁵ Intra-aortic balloon pump rupture with associated entrapment of the balloon within the arterial tree is very rare. Because numerous approaches to deal with this complication have been described, we review the previous experience and discuss the potential management of IABP entrapment, with specific reference to a case of our own.     

Thermodynamics of formation of coffinite,USiO4

Coffinite, USiO₄, is an important U(IV) mineral, but its thermodynamic properties are not well-constrained. In this work, two different coffinite samples were synthesized under hydrothermal conditions and purified from a mixture of products. The enthalpy of formation was obtained by high-temperature oxide melt solution calorimetry. Coffinite is energetically metastable with respect to a mixture of UO₂ (uraninite) and SiO₂ (quartz) by 25.6 ± 3.9 kJ/mol. Its standard enthalpy of formation from the elements at 25 °C is −1,970.0 ± 4.2 kJ/mol. Decomposition of the two samples was characterized by X-ray diffraction and by thermogravimetry and differential scanning calorimetry coupled with mass spectrometric analysis of evolved gases. Coffinite slowly decomposes to U₃O₈ and SiO₂ starting around 450 °C in air and thus has poor thermal stability in the ambient environment. The energetic metastability explains why coffinite cannot be synthesized directly from uraninite and quartz but can be made by low-temperature precipitation in aqueous and hydrothermal environments. These thermochemical constraints are in accord with observations of the occurrence of coffinite in nature and are relevant to spent nuclear fuel corrosion.In many countries with nuclear energy programs, spent nuclear fuel (SNF) and/or vitrified high-level radioactive waste will be disposed in an underground geological repository. Demonstrating the long-term (10⁶–10⁹ y) safety of such a repository system is a major challenge. The potential release of radionuclides into the environment strongly depends on the availability of water and the subsequent corrosion of the waste form as well as the formation of secondary phases, which control the radionuclide solubility. Coffinite (1), USiO₄, is expected to be an important alteration product of SNF in contact with silica-enriched groundwater under reducing conditions (2–8). It is also found, accompanied by thorium orthosilicate and uranothorite, in igneous and metamorphic rocks and ore minerals from uranium and thorium sedimentary deposits (2, 4, 5, 8–16). Under reducing conditions in the repository system, the uranium solubility (very low) in aqueous solutions is typically derived from the solubility product of UO₂. Stable U(IV) minerals, which could form as secondary phases, would impart lower uranium solubility to such systems. Thus, knowledge of coffinite thermodynamics is needed to constrain the solubility of U(IV) in natural environments and would be useful in repository assessment.In natural uranium deposits such as Oklo (Gabon) (4, 7, 11, 12, 14, 17, 18) and Cigar Lake (Canada) (5, 13, 15), coffinite has been suggested to coexist with uraninite, based on electron probe microanalysis (EPMA) (4, 5, 7, 11, 13, 17, 19, 20) and transmission electron microscopy (TEM) (8, 15). However, it is not clear whether such apparent replacement of uraninite by a coffinite-like phase is a direct solid-state process or occurs mediated by dissolution and reprecipitation.The precipitation of USiO₄ as a secondary phase should be favored in contact with silica-rich groundwater (21) [silica concentration >10⁻⁴ mol/L (22, 23)]. Natural coffinite samples are often fine-grained (4, 5, 8, 11, 13, 15, 24), due to the long exposure to alpha-decay event irradiation (4, 6, 25, 26) and are associated with other minerals and organic matter (6, 8, 12, 18, 27, 28). Hence the determination of accurate thermodynamic data from natural samples is not straightforward. However, the synthesis of pure coffinite also has challenges. It appears not to form by reacting the oxides under dry high-temperature conditions (24, 29). Synthesis from aqueous solutions usually produces UO₂ and amorphous SiO₂ impurities, with coffinite sometimes being only a minor phase (24, 30–35). It is not clear whether these difficulties arise from kinetic factors (slow reaction rates) or reflect intrinsic thermodynamic instability (33). Thus, there are only a few reported estimates of thermodynamic properties of coffinite (22, 36–40) and some of them are inconsistent. To resolve these uncertainties, we directly investigated the energetics of synthetic coffinite by high-temperature oxide melt solution calorimetry to obtain a reliable enthalpy of formation and explored its thermal decomposition.     

Primary Cardiac Pleomorphic Sarcoma Presenting as Back Pain in an 18-Year-Old Man

Soft-tissue sarcoma is the most prevalent primary malignant cardiac tumor. This sarcoma usually presents with cardiac manifestations secondary to local obstruction or arrhythmias; very rarely does it present with initial symptoms of distant metastasis. We discuss the unusual case of an 18-year-old man who emergently presented with acute-on-chronic back pain. Imaging revealed a lesion on the 12th thoracic vertebra and a large mass arising from the left atrium. The cardiac mass was resected, and immunohistochemical analysis revealed it to be a pleomorphic sarcoma that had metastasized to the spine. The patient died 2 years later of diffuse metastases. In addition to the patient''s case, we discuss the nature and treatment of cardiac sarcoma.Key words: Bone neoplasms/secondary, heart neoplasms/diagnosis/pathology/surgery, sarcoma/complications/diagnosis/surgeryPrimary cardiac tumors are rare and usually benign. Approximately 15% to 20% of cardiac neoplasms are malignant.^1,2 Chief among these is soft-tissue sarcoma, the second-most prevalent of all primary cardiac tumors.^3,4 The typical presentation of cardiac sarcoma results from an anatomic obstruction of blood flow. Initial presentation in the form of occult distant metastasis is highly unusual, and only sporadic cases have been described.⁵ We report the case of a young man in whom a metastatic cardiac sarcoma presented as back pain, and we discuss the nature and treatment of these neoplasms.