Single-beat estimation of the left ventricular end-systolic pressure–volume relationship in patients with heart failure

Aim: The end-systolic pressure–volume relationship (ESPVR) constructed from multiple pressure–volume (PV) loops acquired during load intervention is an established method to asses left ventricular (LV) contractility. We tested the accuracy of simplified single-beat (SB) ESPVR estimation in patients with severe heart failure. Methods: Nineteen heart failure patients (NYHA III-IV) scheduled for surgical ventricular restoration and/or restrictive mitral annuloplasty and 12 patients with normal LV function scheduled for coronary artery bypass grafting were included. PV signals were obtained before and after cardiac surgery by pressure-conductance catheters and gradual pre-load reductions by vena cava occlusion (VCO). The SB method was applied to the first beat of the VCO run. Accuracy was quantified by the root-mean-square-error (RMSE) between ESPVR_SB and gold-standard ESPVR_VCO. In addition, we compared slopes (E_ES) and intercepts (end-systolic volume at multiple pressure levels (70–100 mmHg: ESV₇₀–ESV₁₀₀) of ESPVR_SB vs. ESPVR_VCO by Bland–Altman analyses. Results: RMSE was 1.7 ± 1.0 mmHg and was not significantly different between groups and not dependent on end-diastolic volume, indicating equal, high accuracy over a wide volume range. SB-predicted E_ES had a bias of −0.39 mmHg mL⁻¹ and limits of agreement (LoA) −2.0 to +1.2 mmHg mL⁻¹. SB-predicted ESVs at each pressure level showed small bias (range: −10.8 to +9.4 mL) and narrow LoA. Two-way anova indicated that differences between groups were not dependent on the method. Conclusion: Our findings, obtained in hearts spanning a wide range of sizes and conditions, support the use of the SB method. This method ultimately facilitates less invasive ESPVR estimation, particularly when coupled with emerging noninvasive techniques to measure LV pressures and volumes.     

Radiofrequency ablation can reverse the structural remodeling caused by frequent premature ventricular contractions originating from the right ventricular outflow tract even in a “normal heart”

OBJECTIVE:

The aim of this study was to evaluate whether frequent premature ventricular contractions originating from the right ventricular outflow tract remodel the cardiac structure and function in patients with a “seemingly normal heart” and whether radiofrequency ablation can reverse this remodeling.

METHODS:

Sixty-eight patients with idiopathic frequent premature ventricular contractions originating from the right ventricular outflow tract and normal heart structure and function were enrolled in this study. The patients were divided into three groups according to the therapeutic method: radiofrequency ablation group (24 cases), anti-arrhythmia drug group (26 cases), and control group (18 cases without any treatment). Clinical Registration number: ChiCTR-ONRC-12002834

RESULTS:

The basic patient characteristics were comparable between the three groups, except for the premature ventricular contraction rate, which was significantly lower in the control group. After six months of follow up, the premature ventricular contraction rate was significantly reduced in the radiofrequency ablation group, which was accompanied by a significant decrease in the following cardiac cavity inner diameters, as determined by echocardiography: right atrium (33.33±3.78 vs. 30.05±2.60 mm, p = 0.001), right ventricle (23.24±2.40 vs. 21.05±2.16 mm, p = 0.020), and left ventricle (44.76±4.33 vs. 41.71±3.44 mm, p = 0.025). These results were similar in the anti-arrhythmia drug group, although this group exhibited a smaller extent of change (right atrium: 33.94±3.25 vs. 31.27±3.11 mm, p = 0.024; right ventricle: 22.97±3.09 vs. 21.64±2.33 mm, p = 0.049; left ventricle: 45.92±6.38 vs. 43.84±5.67 mm, p = 0.039), but not in the control group (p>0.05). There was a tendency toward improvement in the cardiac functions in both the radiofrequency ablation and anti-arrhythmia drug groups. However, these differences were not statistically significant (p>0.05).

CONCLUSIONS:

These results indicate that radiofrequency ablation can potentially reverse the cardiac remodeling caused by frequent premature ventricular contractions even in structurally normal hearts and that frequent premature ventricular contractions should be abated even in structurally normal hearts.     

The effect of 18 h of simulated high altitude on left ventricular function

High altitude produces increased pulmonary capillary pressure by hypoxia induced pulmonary vasoconstriction. It is also possible that hypoxia results in mildly elevated left ventricular (LV) filling pressures that may contribute to the elevated capillary pressures. This study investigates the impact of simulated high altitude on global and regional echocardiographic measures of LV performance and filling pressure. Seventeen healthy individuals underwent transthoracic echocardiography, including tissue Doppler of the septal mitral annulus and basal segments before and after an 18-h overnight stay in a high altitude simulation tent with a FiO₂ of 12%, simulating an altitude of approximately 4,000 m above sea level. In simulated high altitude, the ratio of early transmitral flow velocity to early myocardial relaxation velocity increased 22%, P < 0.001, and the Index of Myocardial Performance increased 30%, P < 0.01 due to an 58% increase in the isovolumic relaxation time (IVRT), P < 0.001. Simulated high altitude leads to a reduction in LV performance with an accompanying increase in markers of LV filling pressure. The significant changes in filling pattern and IVRT in the setting of normal and unchanged systolic function, indicates that hypoxia induces mild diastolic dysfunction in young healthy individuals.     

β-Adrenergic stimulation does not regulate Na pump function in voltage-clamped ventricular myocytes of the rat heart

Summary Na pump current was measured in rat ventricular myocytes to determine if -adrenergic stimulation can directly modulate Na,K-ATPase activity. Enzymatically-isolated heart cells were voltage-clamped with a single patch electrode and Na pump current was briefly activated by rapidly increasing extracellular [K⁺] from 0 to 15 mM for 3–5 s after other ionic currents were blocked or inactivated. The salt solution in the voltage-clamping electrode included (in mM): (1) 100 Na⁺, 10 EGTA, (2) 5 Na⁺, 10 EGTA, or (3) 100 Na⁺, 7.5 Ca²⁺, 10 EGTA (free [Ca²⁺]=480 nM). With all three electrode solutions, Na pump current was not significantly changed after 2–4 min in the presence of 10 M isoprenaline. -adrenergic pathways were still intact as evidenced by the two-fold increase in Cd²⁺-sensitive Ba²⁺ current through calcium channels that was observed in the presence of isoprenaline. Thus, -adrenergic stimulation does not appear to directly regulate Na,K-ATPase activity in rat ventricular myocytes.     

Sleep on the right side—Get cancer on the left?

Breast cancer frequently occurs in the left breast among both women and men [R. Roychoudhuri, V. Putcha, H. Møller, Cancer and laterality: a study of the five major paired organs (UK), Cancer Causes Control 17 (2006) 655–662; M.T. Goodman, K.H. Tung, L.R. Wilkens, Comparative epidemiology of breast cancer among men and women in the US, 1996 to 2000, Cancer Causes Control 17 (2006) 127–136; C.I. Perkins, J. Hotes, B.A. Kohler, H.L. Howe, Association between breast cancer laterality and tumor location, United States, 1994–1998, Cancer Causes Control 15 (2004) 637–645; H.A. Weiss, S.S. Devesa, L.A. Brinton, Laterality of breast cancer in the United States, Cancer Causes Control 7 (1996) 539–543; A. Ekbom, H.O. Adami, D. Trichopoulos, M. Lambe, C.C. Hsieh, J. Pontén, Epidemiologic correlates of breast cancer laterality (Sweden), Cancer Causes Control 5 (1994) 510–516]. Moreover, recent results showed that the left side of the body is more prone to melanoma than the right side [D.H. Brewster, M.J. Horner, S. Rowan, P. Jelfs, E. de Vries, E. Pukkala, Left-sided excess of invasive cutaneous melanoma in six countries, Eur. J. Cancer 43 (2007) 2634–2637]. Current explanations for left-sided breast cancer include handedness [L. Titus-Ernstoff, P.A. Newcomb, K.M. Egan, et al., Left-handedness in relation to breast cancer risk in postmenopausal women, Epidemiology 11 (2000) 181–184; M.A. Kramer, S. Albrecht, R.A. Miller, Handedness and the laterality of breast cancer in women, Nurs. Res. 34 (1985) 333–337; M.K. Ramadhani, S.G. Elias, P.A. van Noord, D.E. Grobbee, P.H. Peeters, C.S. Uiterwaal, Innate left handedness and risk of breast cancer: case-cohort study, BMJ 331 (2005) 882–883], size difference, nursing preference, and brain structure. However, men are affected even more by left laterality than women, thus many of these explanations are unconvincing. Increasing rates of skin melanoma have been associated with immune-disruptive radiation from FM/TV transmitters [Ö. Hallberg, A theory and model to explain the skin melanoma epidemic, Melanoma Res. 16 (2006) 115–118; Ö. Hallberg, A reduced repair efficiency can explain increasing melanoma rates, Eur. J. Cancer Prev. 17 (2008) 147–152; Ö. Hallberg, O. Johansson, Melanoma incidence and frequency modulation (FM) broadcasting, Arch. Environ. Health 57 (2002) 32–40; Ö. Hallberg, O. Johansson, FM broadcasting exposure time and malignant melanoma incidence, Electromagn. Biol. Med. 24 (2005) 1–8; Ö. Hallberg, Radio TV towers linked to increased risk of melanoma, Report, available at: http://foodconsumer.org/7777/8888/C_ancer_31/120907442007_Exclusive_report_Radio_TV_towers_linked_to_increased_risk_of_melanoma.shtml, 2007 (accessed 2007)]. Geographical areas covered by several transmitters show higher incidences of melanoma than areas covered by one transmitter. Here we show that a high prevalence of breast cancer and melanoma on the left side of the body may be a logical consequence of sleeping in beds having mattresses containing wave-reflecting metal springs. We found that people tend to sleep for longer periods on their right side, apparently to avoid disturbance by the heartbeat. This puts the left side farther away from the field-attenuating influence of the metal springs in the mattress; thus the left side will spend, on average, more time exposed to stronger combined fields from incident and reflected waves. This hypothesis may also explain why body parts farthest away from the mattress (trunk and upper arms for men; lower limbs and hips for women) have higher melanoma rates than the sun-exposed face area. The implications of this study should promote a critical consideration of population exposure to electromagnetic fields, especially during the night.     

Hypertension-induced changes in the rat myocardium during the development of cardiac hypertrophy – a comparison between the left and the right ventricle

The hypertrophy of the cardiac muscle is one of the most significant maladaptive mechanisms activated in response to increased workload. It is associated with histological and ultrastructural alterations, changes in the quantitative parameters and the expression of different enzymes. While the structural and functional consequences of systemic hypertension on the left ventricle have been well evaluated, the right ventricle has received less attention. The aim of the present study was to analyse and compare the changes in the left and right ventricle during the development of cardiac hypertrophy initiated by systemic hypertension in different age groups of spontaneously hypertensive rats. Therefore, we studied the histology and ultrastructure of the cells of the myocardium, evaluated the immunohistochemical expression of the enzyme neuronal nitric oxide synthase and conducted a quantitative analysis of several morphometric parameters. We used three groups of spontaneously hypertensive rats. For the quantitative analysis we also used three age groups of age- and weight-matched control animals (normotensive Wistar rats). In both ventricles, we described cardiomyocytic hypertrophy, focal myocytolysis and increased collagen deposition in the interstitial space. Our observations on the ultrastructural level were associated with changes in the cardiomyocytic nuclei, the arrangement, maturity and organisation of the myofibrils, the localisation and ultrastructure of the mitochondria, the development and maturity of the intercalated discs, as well as changes in the components of the interstitium. The immunohistochemical expression of neuronal nitric oxide synthase in the left ventricle was stronger than that in the right ventricle across all age groups. The comparative quantitative analysis revealed that changes in the studied morphometric parameters in the two ventricles occurred disproportionately. In conclusion, the present study characterised the development of cardiac hypertrophy in response to systemic hypertension in both ventricles and demonstrated the involvement of the right ventricle.     

Patient-specific finite element modeling of the Cardiokinetix Parachute® device: effects on left ventricular wall stress and function

The Parachute^® (Cardiokinetix, Inc., Menlo Park, California) is a catheter-based device intended to reverse left ventricular (LV) remodeling after antero-apical myocardial infarction. When deployed, the device partitions the LV into upper and lower chambers. To simulate its mechanical effects, we created a finite element LV model based on computed tomography (CT) images from a patient before and 6 months after Parachute^® implantation. Acute mechanical effects were determined by in silico device implantation (VIRTUAL-Parachute). Chronic effects of the device were determined by adjusting the diastolic and systolic material parameters to better match the 6-month post-implantation CT data and LV pressure data at end-diastole (ED) (POST-OP). Regional myofiber stress and pump function were calculated in each case. The principal finding is that VIRTUAL-Parachute was associated with a 61.2 % reduction in the lower chamber myofiber stress at ED. The POST-OP model was associated with a decrease in LV diastolic stiffness and a larger reduction in myofiber stress at the upper (27.1 %) and lower chamber (78.4 %) at ED. Myofiber stress at end-systole and stroke volume was little changed in the POST-OP case. These results suggest that the primary mechanism of Parachute^® is a reduction in ED myofiber stress, which may reverse eccentric post-infarct LV hypertrophy.     

The effects of anxiety on the interpretation of emotion in the face�Cvoice pairs

Anxious individuals have been shown to interpret others' emotional states negatively. Since most studies have used facial expressions as emotional cues, we examined whether trait anxiety affects the recognition of emotion in a dynamic face and voice that were presented in synchrony. The face and voice cues conveyed either matched (e.g., happy face and voice) or mismatched emotions (e.g., happy face and angry voice). Participants with high or low trait anxiety were to indicate the perceived emotion using one of the cues while ignoring the other. The results showed that individuals with high trait anxiety were more likely to interpret others' emotions in a negative manner, putting more weight on the to-be-ignored angry cues. This interpretation bias was found regardless of the cue modality (i.e., face or voice). Since trait anxiety did not affect recognition of the face or voice cues presented in isolation, this interpretation bias appears to reflect an altered integration of the face and voice cues among anxious individuals.     

The protective effects of interleukin-18 and interferon-γ on neuronal damages in the rat hippocampus following status epilepticus

To elucidate whether interleukin-18 (IL-18) or interferon-γ (IFN-γ) participates in neurodegeneartion, we investigated the changes in IL-18 and IFN-γ systems within the rat hippocampus following status epilepticus (SE). In non-SE induced animals, IL-18, IL-18 receptor α (IL-18Rα), IFN-γ and IFN-γ receptor α (IFN-γRα) immunoreactivity was not detected in the hippocampus. Following SE, IL-18 immunoreactivity was increased in CA1-3 pyramidal cells as well as dentate granule cells. IL-18 immunoreactivity was also up-regulated in astrocytes and microglia/macrophages. IL-18Rα immunoreactivity was detected in astrocytes and microglia/macrophages. IFN-γ immunoreactivity was detected only in astrocytes within all regions of the hippocampus. IFN-γRα immunoreactivity was increased in neurons as well as astrocytes. Intracerebroventricular infusions of recombinant rat IL-18 or IFN-γ alleviated SE-induced neuronal damages, while neutralization of IL-18, IFN-γ or their receptors aggravated them, as compared to saline-infused animals. These findings suggest that astroglial-mediated IFN-γ pathway in response to IL-18 induction may play an important role in alleviation of SE-induced neuronal damages.     

Hypoplastic left heart syndrome: Rheumatic heart disease of the fetus?

Hypoplastic left heart syndrome (HLHS) accounts for nearly 25% of deaths among neonates with congenital heart disease. The essential feature of HLHS is a small left ventricle (LV) incapable of supporting the circulation. The etiology of HLHS is unknown. A hypothesis is proposed implicating an immune mechanism involving maternal antibodies produced in response to pharyngitis caused by group A beta-hemolytic streptococci (GABHS) ("strep throat"). After crossing the placenta, the antibodies injure the developing fetal heart, leading to HLHS either because of direct injury to the LV or secondary to reduced blood flow through affected aortic and mitral valves. Analogy is drawn to rheumatic heart disease (RHD), a known sequela of strep throat. In RHD a misdirected immune response originally intended for GABHS leads to cardiac injury through "molecular mimicry"; the normal heart antigens supposedly mimic the GABHS antigens. A similar pathogenesis is proposed for HLHS and related heart defects. HLHS may represent an extreme form of injury, while a milder insult may present as only mild aortic stenosis or a bicuspid aortic valve, conditions with wide prevalence among the general population. The injury may indeed superimpose on many other congenital heart defects, leading to a variable presentation of these other diseases. Beside remarkable likenesses between HLHS and RHD, the hypothesis is also supported by increasing evidence for the role of deleterious transplacental antibodies in the pathogenesis of other fetal diseases. Implications for other congenital heart diseases and the broader picture of global public health are discussed.     

Arrhythmogenic right ventricular cardiomyopathy: use of a left ventricular assist device as a bridge to transplantation?

The principal characteristic of arrhythmogenic right ventricular cardiomyopathy (ARVC) is the tendency for ventricular arrhythmia and sudden death to occur without overt ventricular dysfunction. Current recommendations for management of patients with ARVC include insertion of an automated implantable cardioverter–defibrillator (AICD) to prevent sudden cardiac death. However, despite the use of AICD and/or anti-arrhythmic drugs some patients suffer recurrent ventricular arrhythmias unresponsive to optimum medical management. We present two cases of ARVC with refractory recurrent ventricular arrhythmias that were successfully managed by left ventricular assist device (LVAD) implantation, as a bridge to transplant (BTT). These two cases are unconventional examples of use of LVAD, given the predominant right ventricular pathology of ARVC and the arrhythmogenic nature of their presentation. The novelty of these cases should be taken in the context of increasing pressure to standardize indications for use of mechanical circulatory support.     

The effects of APOE-ε4 on the BOLD response

In the last decade, functional magnetic resonance imaging (fMRI) has emerged as a tool to study changes in brain function associated with a genetic risk for Alzheimer's disease (AD), with a particular focus on the effects of the APOE-ε4 allele. This review compiles the existing literature concerning the effects of APOE genotype on the blood oxygen level dependent (BOLD) response, measured during task-based functional magnetic resonance imaging. While most studies report a significant difference in brain activity between carriers and noncarriers of the ε4 allele, there are inconsistencies in the direction and location of change. These inconsistencies were addressed by examining the effect of task, family history of Alzheimer's disease, and age on the relationship between APOE genotype and the BOLD response, but no clear pattern emerged. The review discusses the interpretation of BOLD differences between ε4 carriers and noncarriers, provides suggestions for future studies, and highlights important limitations of this type of research.     

The effect of BMP-2 on the osteoconductive properties of β-tricalcium phosphate in rat calvaria defects

Bone formation in critical-sized calvaria defects is strongly dependent on the osteoconductive properties of grafts. It remains a matter of controversy whether biomaterials can replace autografts and whether the supplementation of biomaterials with Bone Morphogenetic Proteins (BMPs) is necessary to enhance bone formation. We examined rat calvaria critical-sized defects (5-mm-diameter) treated with β-tricalcium phosphate (TCP; Cerasorb? M), polylactic and polyglycolic acid gel (PLA/PGA; Fisiograft?) and calcium phosphate cement (CPC; Norian? CRS?), either alone or in the presence of 5 μg of BMP-2 after 45 days. Autografts and untreated defects served as controls. Bone formation was evaluated based on μCT analysis, histomorphometric analysis and fluorescence analysis. We report that TCP supported bone formation more efficiently than did autografts. Bone formation in the presence of TCP alone reached a maximal level, as BMP-2 supplementation failed to enhance bone formation. By contrast, no significant difference in bone formation was observed when PLA/PGA and CPC were compared to autografts. Moreover, the presence of BMP-2 did not substantially change the osteoconductive properties of PLA/PGA or CPC. We conclude that the osteoconductive properties of TCP are superior to those of autografts and that TCP does not require BMP-2 supplementation. Our findings also show that the decreased osteoconductive properties of PLA/PGA and CPC cannot be overcome by BMP-2 supplementation in rat calvaria defects.     

The rise of [Na+]i during ischemia and reperfusion in the rat heart—underlying mechanisms

Intracellular Na⁺ concentration ([Na⁺]_i) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na⁺]_i contribute to ischemic and reperfusion damage through their effects on Ca²⁺ overload. Part of the rise of [Na⁺]_i during ischemia may be caused by increased activity of the cardiac Na⁺/H⁺ exchanger (NHE1), activated by the ischemic rise in [H⁺]_i. In support of this view, NHE1 inhibitors reduce the [Na⁺]_i rise during ischemia. Another possibility is that the rise of [Na⁺]_i during ischemia is caused by Na⁺ influx through channels. We have reexamined these issues by use of two different NHE1 inhibitors, amiloride, and zoniporide, in addition to tetrodotoxin (TTX), which blocks voltage-sensitive Na⁺ channels. All three drugs produced cardioprotection after ischemia, but amiloride (100 μM) and TTX (300 nM) prevented the rise in [Na⁺]_i during ischemia, whereas zoniporide (100 nM) did not. Both amiloride and zoniporide prevented the rise of [Na⁺]_i on reperfusion, whereas TTX was without effect. In an attempt to explain these differences, we measured the ability of the three drugs to block Na⁺ currents. At the concentrations used, TTX reduced the transient Na⁺ current (I _Na) by 11 ± 2% while amiloride and zoniporide were without effect. In contrast, TTX largely eliminated the persistent Na⁺ current (I _Na,P) and amiloride was equally effective, whereas zoniporide had a substantially smaller effect reducing I _Na,P to 41 ± 8%. These results suggest that part of the effect of NHE1 inhibitors on the [Na⁺]_i during ischemia is by blockade of I _Na,P. The fact that a low concentration of TTX eliminated the rise of [Na⁺]_i during ischemia suggests that I _Na,P is a major source of Na⁺ influx in this model of ischemia.     

Do cardiac neurons play a role in the intrinsic control of heart rate in the rat?

Three experiments were performed to see whether cardiac neurons contribute to the intrinsic control of heart rate in right atria of adult rats. The intrinsic heart rate response (IRR) was examined by raising right atrial pressure from 2 to 8 mmHg for 3 min. In isolated preparations of the right atrium, the IRR was not significantly altered by the addition of either 1 microM atropine (n =6; control +19+/- 3 min(-1) ; atropine+18+/-3 min(-1); (mean /+/-S.E.M.)) or 1 microM propranolol (n = 5; control +22+/- 4 min(-1); ; propranolol +21+/-3 min(-1); ).Tetrodotoxin (0.5 microm) had no effect on the IRR (n = 6; control +37+/-5 min(-1); tetrodotoxin 38+/-5 min(-1); ). In another experiment, 2-day-old rat pups were injected with capsaicin (50 mg kg(-1); treated) or with vehicle(control). There was no difference in the IRR of right atrial preparations taken from control and treated animals after they reached adulthood (control (n = 7) and treated (n = 8): +30+/- 4 and +32+/- 4 min(-1)). The influence of right atrial pressure on the efficacy of vagal stimulation was examined. The rate response to vagal stimulation was reduced similarly in control and treated preparations when pressure was elevated from 2 to 4 mmHg (control and treated: -34+/- 5% and -33+/- 3%). The effectiveness of the capsaicin treatment was confirmed by the depletion of substance P-immunoreactive nerve fibres in cardiac tissues. Together, these results strongly suggest that cardiac neurons are not involved in intrinsic heart rate control.     

An implantable Fabry-Pérot pressure sensor fabricated on left ventricular assist device for heart failure

Continuous flow left ventricular assist devices (LVADs) are commonly used as bridge-to-transplantation or destination therapy for heart failure patients. However, non-optimal pumping speeds can reduce the efficacy of circulatory support or cause dangerous ventricular arrhythmias. Optimal flow control for continuous flow LVADs has not been defined and calls for an implantable pressure sensor integrated with the LVAD for real-time feedback control of pump speed based on ventricular pressure. A MEMS pressure sensor prototype is designed, fabricated and seamlessly integrated with LVAD to enable real-time control, optimize its performance and reduce its risks. The pressure sensing mechanism is based on Fabry-Pérot interferometer principle. A biocompatible parylene diaphragm with a silicon mirror at the center is fabricated directly on the inlet shell of the LVAD to sense pressure changes. The sensitivity, range and response time of the pressure sensor are measured and validated to meet the requirements of LVAD pressure sensing.