May fever trigger ventricular fibrillation?

The clinical precipitants of ventricular fibrillation (VF) remain poorly understood. Clinical factors such as hypoxemia, acidosis or electrolyte imbalance, drug-related toxicity, autonomic nervous system disorders as well as viral myocarditis have been proposed to be associated with sudden cardiac death particularly in patients with structural heart disease. However, In the Brugada syndrome, concurrent febrile illness has been reported to unmask the electrocardiographic features of the Brugada syndrome and be associated with an increased propensity for VF. More recently, a febrile illnesses of infectious etiology was associated to polymorphic ventricular tachycardia or VF in patients with normal hearts and without known repolarization abnormality. In this review we detail this phenomenon and its putative mechanisms.     

The effects of right ventricular apical pacing on left ventricular function. Stimulation of the right ventricular apex: should it still be the gold standard?

Current pacing practice is undergoing continuous and substantial changes. Initially pacing had an exclusively palliative role, since it was reserved for patients developing complete heart block or severe symptomatic bradycardia. With the appearance of novel pacing indications such as pacing for heart failure and atrial fibrillation, the effect of pacing site on cardiac function has become a critically important issue and a subject for consideration. It seems that the classical pacing site in the right ventricular apex is no longer the gold standard because of possible disadvantageous effects on cardiac function. The aim of this review article is to discuss the effect of right ventricular apical pacing on cardiac function including cellular and hemodynamic changes. We also aim to discuss the role of alternative pacing sites in the light of cardiac function.     

A combination of right ventricular hypertrabeculation/noncompaction and arrhythmogenic right ventricular cardiomyopathy: a syndrome?

Background

Echocardiography is widely used in the management of patients with cardiogenic shock (CS). Left ventricular ejection fraction (EF) has been shown to be an independent predictor of survival in CS. Tissue Doppler Imaging (TDI) is a sensitive echocardiographic technique that allows for the early quantitative assessment of regional left ventricular dysfunction. TDI derived indices, including systolic velocity (S'), early (E') and late (A') diastolic velocities of the lateral mitral annulus, are reduced in heart failure patients (EF < 30%) and portend a poor prognosis. In CS patients, the application of TDI prior to revascularization remains unknown.

Objective

To characterize TDI derived indices in CS patients as compared to patients with chronic CHF.

Methods

Between 2006 and 2007, 100 patients were retrospectively evaluated who underwent echocardiography for assessment of LV systolic function. This population included: Group I) 50 patients (30 males, 57 ± 13 years) with chronic CHF as controls; and Group II) 50 patients (29 males, 58 ± 10 years) with CS. Spectral Doppler indices including peak early (E) and late (A) transmitral velocities, E/A ratio, and E-wave deceleration time were determined. Tissue Doppler indices including S', E' and A' velocities of the lateral annulus were measured.

Results

Of the entire cohort, the mean LVEF was 25 ± 5%. Cardiogenic shock patients demonstrated significantly lower lateral S', E' and a higher E/E' ratio (p < 0.01), as compared to CHF patients. The in-hospital mortality in the CHF cohort was 5% as compared to the CS group with an in hospital mortality of 40%. In the subset of CS patients (n = 30) who survived, the mean S' at presentation was higher as compared to those patients who died in hospital (3.5 ± 0.5 vs. 1.8 ± 0.5 cm/s).

Conclusion

Despite similar reduction in LV systolic function, CS patients have reduced myocardial velocities and higher filling pressures using TDI, as compared to CHF patients. Whether TDI could be a reliable tool to determine CS patients with the best chance of recovery following revascularization is yet to be determined.     

Does load-induced ventricular hypertrophy progress to systolic heart failure?

Ventricular hypertrophy develops in response to numerous forms of cardiac stress, including pressure or volume overload, loss of contractile mass from prior infarction, neuroendocrine activation, and mutations in genes encoding sarcomeric proteins. Hypertrophic growth is believed to have a compensatory role that diminishes wall stress and oxygen consumption, but Framingham and other studies established ventricular hypertrophy as a marker for increased risk of developing chronic heart failure, suggesting that hypertrophy may have maladaptive features. However, the relative contribution of comorbid disease to hypertrophy-associated systolic failure is unknown. For instance, coronary artery disease is induced by many of the same risk factors that cause hypertrophy and can itself lead to systolic dysfunction. It is uncertain, therefore, whether ventricular hypertrophy commonly progresses to systolic dysfunction without the contribution of intervening ischemia or infarction. In this review, we summarize findings from epidemiologic studies, preclinical experiments in animals, and clinical trials to lay out what is known-and not known-about this important question.     

Hypertrophic responsiveness to β2-adrenoceptor stimulation on adult ventricular cardiomyocytes

The aim of the present study was to characterize the receptor subtype and the second messenger involved in the newly discovered hypertrophic effect of -adrenoceptor stimulation in cultures of adult ventricular cardiomyocytes. Cardiomyocytes isolated from adult rats and cultured for 6 days in presence of 20% fetal calf serum (FCS) were used as experimental model. Hypertrophic responsiveness of cardiomyocytes was characterized by rate of protein synthesis, increase in protein mass, and increase in RNA content. The hypertrophic effect of the non-specific -adrenoceptor agonist isoprenaline was abolished in presence of a specific ₁-adrenoceptor antagonist (ICI 118,551), could be mimicked by use of a ₂-adrenoceptor agonist (procaterol) or direct stimulation of adenylate cyclase (forskolin) or addition of a cell-permeable analogue of cAMP (dibuytyrylcyclo-AMP). In presence of Rp-cAMPS, an inhibitor of protein kinase A, the hypertrophic effect of isoprenaline was abolished. The results indicate that the hypertrophic effect of -adrenoceptor stimulation is due to stimulation of ₂-adrenoceptors and activation of adenylate cyclase and protein kinase A.     

Markers of ventricular repolarization as an additional non-invasive electrocardiography parameters for predicting ventricular tachycardia/fibrillation in patients with Brugada Syndrome – A systematic review and meta-analysis

BackgroundControversies surrounded the management of asymptomatic Brugada syndrome. Prognostication using electrophysiology study (EPS) is disputable. Non-invasive parameters may be a valuable additional tool for risk stratification. We aim to evaluate the use markers of ventricular repolarization including Tpeak-to-Tend (TpTe), Tpe Dispersion, TpTe/QT ratio, and QTc interval as additional non-invasive electrocardiography parameters for predicting ventricular tachycardia/fibrillation in patients with Brugada syndrome.MethodsWe performed a comprehensive search on TpTe, Tpe Dispersion, TpTe/QT ratio, and QTc interval as a predictor for ventricular tachycardia(VT)/fibrillation(VF)/aborted sudden cardiac death/appropriate ICD shock in patients with Brugada syndromes up until October 2018.ResultsWe included ten studies in the qualitative synthesis and eight studies in meta-analysis. There were a total of 2126 subjects from ten studies. We found that TpTe interval (mean difference 11.97 m s [5.02–18.91]; p < 0.001; I² 80% possibly on ≥80–100 m s and maximum QTc interval (mean difference 11.42 m s [5.90–16.93], p < 0.001; I² 28%) were the most potential ECG parameters to predict VT/VF/AT/SCD. Tpe dispersion and TpTe/QT ratio have a high heterogeneity. Upon sensitivity analysis, there is no single study found to markedly affect heterogeneity of Tpe dispersion and TpTe/QT ratio. Removal of a study reduced maximum QTc interval heterogeneity to 0%.ConclusionsMeasurement of TpTe interval, Tp-e dispersion, TpTe/QT ratio, and QTc interval on ECG emerge as a promising prognostication tool which needs further investigations with a more standardized method, outcome, and cut-off points. As for now, only maximum QTc interval has a reliable result with low heterogeneity sufficiently reliable for prognostication.     

PKCε inhibits the hyperglycemia-induced apoptosis signal in adult rat ventricular myocytes

Recruitment of the protein kinase C (PKC) family of isozymes is an integral component of the signaling events that direct cardiac phenotype expressed during postnatal development and in response to pathologic stimuli. Hyperglycemia is a potent activating signal for cardiac PKC isozymes and induces the apoptosis program in cardiac muscle cells. To determine whether cardiac PKC isozymes modulate transmission of the hyperglycemia apoptosis signal, we have employed isozyme-specific peptide modulators to selectively inhibit (PKC _I/_II, and ) or activate (PKC). PKC peptides were delivered to primary cultures of serum starved adult rat ventricular myocytes (ARVM), by conjugation to the homeodomain of drosophila antennapedia. As expected, hyperglycemia induced a 35% increase in ARVM apoptosis. Peptide inhibitors of PKC _I/_II and blocked transmission of the hyperglycemia apoptosis signal, whereas the isozyme specific inhibitor of PKC (V1-2) did not alter the magnitude of glucose-induced ARVM apoptosis. Alternatively, the PKC translocation activator (RACK) abolished hyperglycemia-induced apoptosis, strongly suggesting a cardioprotective role for PKC in this system. Therefore, we conclude that cardiac PKC isozymes modulate hyperglycemia-induced apoptosis and activation of cardiac PKC protects ARVM from the hyperglycemia-induced death signal. (Mol Cell Biochem 268: 169–173, 2005)     

Reversible and irreversible damage in reoxygenated ‘ischemic’ ventricular myocytes in culture

The LDH release pattern from cardiomyocytes under ischemia-like conditions shows two phases. In the initial slow phase, reoxygenation immediately stops further enzyme release. Accelerated LDH release, which occurs concomitantly with Iysosomal enzyme release, characterizes the second phase of ischemia. Reoxygenation at this stage does not put a stop to further enzyme release.Reoxygenation during the first phase of ischemia rapidly restored ATP level, while in the second phase, ATP levels remained low even after 6 h of reoxygenation.This study as well as previous data seem to suggest that irreversible cellular damage leading to cell death, occurs by synergistic action of many effectors, each of which does not necessarily cause irreversible damage.     

Is there an A-type K+ current in guinea pig ventricular myocytes?

A unique transient outward K(+) current (I(to)) has been described to result from the removal of extracellular Ca(2+) from ventricular myocytes of the guinea pig (15). This study addressed the question of whether this current represented K(+)-selective I(to) or the efflux of K(+) via L-type Ca(2+) channels. This outward current was inhibited by Cd(2+), Ni(2+), Co(2+), and La(3+) as well as by nifedipine. All of these compounds were equally effective inhibitors of the L-type Ca(2+) current. The current was not inhibited by 4-aminopyridine. Apparent inhibition of the outward current by extracellular Ca(2+) was shown to result from the displacement of the reversal potential of cation flux through L-type Ca(2+) channels. The current was found not to be K(+) selective but also permeant to Cs(+). The voltage dependence of inactivation of the outward current was identical to that of the L-type Ca(2+) current. It is concluded that extracellular Ca(2+) does not mask an A-type K(+) current in guinea pig ventricular myocytes.     

Effects of endogenous cannabinoid anandamide on excitation–contraction coupling in rat ventricular myocytes

A role for anandamide (N-arachidonoyl ethanolamide; AEA), a major endocannabinoid, in the cardiovascular system in various pathological conditions has been reported in earlier reports. In the present study, the effects of AEA on contractility, Ca²⁺ signaling, and action potential (AP) characteristics were investigated in rat ventricular myocytes. Video edge detection was used to measure myocyte shortening. Intracellular Ca²⁺ was measured in cells loaded with the fluorescent indicator fura-2 AM. AEA (1 μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca²⁺ transients. However, the amplitudes of caffeine-evoked Ca²⁺ transients and the rate of recovery of electrically evoked Ca²⁺ transients following caffeine application were not altered. Biochemical studies in sarcoplasmic reticulum (SR) vesicles from rat ventricles indicated that AEA affected Ca²⁺-uptake and Ca²⁺-ATPase activity in a biphasic manner. [³H]-ryanodine binding and passive Ca²⁺ release from SR vesicles were not altered by 10 μM AEA. Whole-cell patch-clamp technique was employed to investigate the effect of AEA on the characteristics of APs. AEA (1 μM) significantly decreased the duration of AP. The effect of AEA on myocyte shortening and AP characteristics was not altered in the presence of pertussis toxin (PTX, 2 μg/ml for 4 h), AM251 and SR141716 (cannabinoid type 1 receptor antagonists; 0.3 μM) or AM630 and SR 144528 (cannabinoid type 2 receptor antagonists; 0.3 μM). The results suggest that AEA depresses ventricular myocyte contractility by decreasing the action potential duration (APD) in a manner independent of CB1 and CB2 receptors.     

Does atrial natriuretic factor protect against right ventricular overload? I. Hemodynamic study

We studied the effects of synthetic atrial natriuretic factor (ANF, 28-amino acid peptide) on base-line perfusion pressures and pressor responses to hypoxia and angiotensin II (ANG II) in isolated rat lungs and on the following hemodynamic and renal parameters in awake, chronically instrumented rats: cardiac output (CO), systemic (Rsa) and pulmonary (Rpa) vascular resistances, ANG II- and hypoxia (10.5% O2)-induced changes in Rsa and Rpa, and urine output. Intra-arterial ANF injections lowered base-line perfusion pressures and blunted hypoxia- and ANG II-induced pressor responses in the isolated lungs. Bolus intravenous injection of ANF (10 micrograms/kg) into intact rats decreased CO and arterial blood pressures of both systemic and pulmonary circulations and increased Rsa. ANG II (0.4 micrograms/kg) increased both Rsa and Rpa, and hypoxia increased Rpa alone in the intact rats. ANF (10 micrograms/kg) inhibited both ANG II- and hypoxia-induced increases in Rpa but did not significantly affect the ANG II-induced increase in Rsa. The antagonistic effect of ANF on pulmonary vasoconstriction was reversible and dose-dependent. The threshold doses of ANF required to inhibit pulmonary vasoconstriction were in the same range as those required to elicit diuresis and natriuresis. The data demonstrate that ANF has a preferential relaxant effect on pulmonary vessels constricted by hypoxia or ANG II. Both the renal and the pulmonary vascular effects of ANF may represent fundamental physiological actions of ANF. These actions may serve as a negative feedback control system that protects the right ventricle from excessive mechanical loads.     

Biomechanical characterization of ventricular–arterial coupling during aging: A multi-scale model study

Left ventricular–arterial (VA) coupling has been recognized to be of great significance in understanding both the global and local mechanical performance of the circulatory system. In this study, a closed-loop multi-scale model of the human cardiovascular system is established for the purpose of studying the coupled VA hemodynamic changes during aging. Obtained results show that age-associated changes in arterial properties have some negative but relatively small influences on left ventricular (LV) mechanical performance, whereas they progressively increase LV and aortic systolic pressures, and aortic pulse pressure during aging. Wave analysis reveals that increased aortic characteristic impedance and premature wave reflection induced by arterial stiffening are two coexistent factors responsible for aortic systolic hypertension and increased aortic pulse pressure at old age. In contrast, aortic dilatation can partly counteract the negative influences of arterial stiffening. Coupled LV-systolic and arterial stiffening (a constant VA coupling index) well preserves LV mechanical performance given normal LV diastolic function during aging, but with a concomitant further elevation of LV and aortic systolic pressures. Furthermore, it is found that the states of arterial, LV-systolic and diastolic stiffness can be distinguished by investigating the sensitivity of LV-systolic pressure to various cardiac indices.     

Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline

Uncontrolled pulmonary arterial hypertension (PAH) results in right ventricular (RV) hypertrophy (RVH), progressive RV failure, and low cardiac output leading to increased morbidity and mortality (McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. J Am Coll Cardiol 53: 1573-1619, 2009). Although the exact figures of its prevalence are difficult to obtain because of the diversity of identifiable causes, it is estimated that the incidence of pulmonary hypertension is seven to nine cases per million persons in the general population and is most prevalent in the age group of 20-40, occurring more commonly in women than in men (ratio: 1.7 to 1; Rubin LJ. N Engl J Med 336: 111-117, 1997). PAH is characterized by dyspnea, chest pain, and syncope. Unfortunately, there is no cure for this disease and medical regimens are limited (Simon MA. Curr Opin Crit Care 16: 237-243, 2010). PAH leads to adverse remodeling that results in RVH, progressive right heart failure, low cardiac output, and ultimately death if left untreated (Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. J Am Coll Cardiol 43: 13S-24S, 2004; Humbert M, Sitbon O, Simonneau G. N Engl J Med 351: 1425-1436, 2004. LaRaia AV, Waxman AB. South Med J 100: 393-399, 2007). As there are no direct tools to assess the onset and progression of PAH and RVH, the disease is often detected in later stages marked by full-blown RVH, with the outcome predominantly determined by the level of increased afterload (D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Ann Intern Med 115: 343-349, 1991; Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Validation of a prognostic equation Circulation 89: 1733-1744, 1994). Various studies have been performed to assess the genetic, biochemical, and morphological components that contribute to PAH. Despite major advances in the understanding of the pathogenesis of PAH, the molecular mechanism(s) by which PAH promotes RVH and cardiac failure still remains elusive. Of all the mechanisms involved in the pathogenesis, inflammation and oxidative stress remain the core of the etiology of PAH that leads to development of RVH (Dorfmüller P, Perros F, Balabanian K, Humbert M. Eur Respir J 22: 358-363, 2003).     

Heterotrisomy, a significant contributing factor to ventricular septal defect associated with Down syndrome?

Down syndrome (DS; trisomy 21) is associated with a wide range of variable clinical features, one of the most common being congenital heart defects (CHD). We used molecular genetic techniques to study the inheritance of genes on chromosome 21 in children with DS and CHD. Polymorphic markers on the long arm of chromosome 21 were analysed in 99 families who had a child with DS. Of these, 60 children had a CHD and 39 children had no CHD. Heterotrisomy describes the inheritance of an allele from each of three different grandparents. In some cases heterotrisomy will involve the inheritance of three different alleles. Heterotrisomic regions were defined as those showing retention of non-disjoining parental heterozygosity at polymorphic loci in the non-disjoined chromosomes of children with DS. Using polymorphic non-coding markers, we identified a consistent 9.6-cM minimum region (D21S167-HMG14) of heterotrisomy in children with DS and ventricular septal defect (VSD). Comparing individuals with DS and VSD to all others with DS (those either with no CHD or with any other CHD combined) shows the individuals with DS and VSD to have significantly more non-reduction or heterotrisomy in this region (P=0.006, Fisher's exact test, two-tailed). We postulate that heterotrisomy for a gene or genes in this region is a contributing factor to the pathogenesis of VSD in trisomy 21 either through the presence of three different specific alleles or through the presence of specific combinations of alleles.     

Nox2 and Nox4 mediate tumour necrosis factor-α-induced ventricular remodelling in mice

Reactive oxygen species (ROS) and pro-inflammatory cytokines are crucial in ventricular remodelling, such as inflammation-associated myocarditis. We previously reported that tumour necrosis factor-α (TNF-α)-induced ROS in human aortic smooth muscle cells is mediated by NADPH oxidase subunit Nox4. In this study, we investigated whether TNF-α-induced ventricular remodelling was mediated by Nox2 and/or Nox4. An intravenous injection of murine TNF-α was administered to a group of mice and saline injection was administered to controls. Echocardiography was performed on days 1, 7 and 28 post-injection. Ventricular tissue was used to determine gene and protein expression of Nox2, Nox4, ANP, interleukin (IL)-1β, IL-2, IL-6, TNF-α and to measure ROS. Nox2 and Nox4 siRNA were used to determine whether or not Nox2 and Nox4 mediated TNF-α-induced ROS and upregulation of IL-1β and IL-6 in adult human cardiomyocytes. Echocardiography showed a significant increase in left ventricular end-diastolic and left ventricular end-systolic diameters, and a significant decrease in the ejection fraction and fractional shortening in mice 7 and 28 days after TNF-α injection. These two groups of mice showed a significant increase in ventricular ROS, ANP, IL-1β, IL-2, IL-6 and TNF-α proteins. Nox2 and Nox4 mRNA and protein levels were also sequentially increased. ROS was significantly decreased by inhibitors of NADPH oxidase, but not by inhibitors of other ROS production systems. Nox2 and Nox4 siRNA significantly attenuated TNF-α-induced ROS and upregulation of IL-1β and IL-6 in cardiomyocytes. Our study highlights a novel TNF-α-induced chronic ventricular remodelling mechanism mediated by sequential regulation of Nox2 and Nox4 subunits.     

L-type Ca2+ channels’ involvement in IFN-γ-induced signaling in rat ventricular cardiomyocytes

Journal of Physiology and Biochemistry - The purpose of this study was to examine the effects of interferon-γ (IFN-γ) on calcium movement in rat ventricular myocytes. L-type Ca2+ currents...     

Outflow-tract ventricular tachycardia: Can 12 lead ECG during sinus rhythm identify underlying cardiac sarcoidosis?

BackgroundPatients with outflow tract ventricular tachycardia (OTVT) with normal echocardiogram are labeled as idiopathic VT (IVT). However, a subset of these patients is subsequently diagnosed with underlying cardiac sarcoidosis (CS). Objective:Whether electrocardiogram (ECG) abnormalities in sinus rhythm (SR) can differentiate underlying CS from IVT.MethodsWe retrospectively analyzed the SR-ECGs of 42 patients with OTVT/premature ventricular complexes (PVC) and normal echocardiography. All underwent advanced imaging with cardiac magnetic resonance (CMR)/¹⁸FDG PET-CT for screening of CS. Twenty-two patients had significant abnormalities in cardiac imaging and subsequently had biopsy-proven CS (Cases). Twenty patients had normal imaging and were categorized as IVT (Controls). SR-ECGs of all patients were analyzed by 2 independent, blinded observers.ResultsBaseline characteristics were comparable. Among the ECG features analyzed – fascicular (FB) or bundle branch block (BBB) was seen in 9/22 Cases vs. 1/20 controls (p = 0.01). Among patients without FB or BBB, fragmented QRS (fQRS) was present in 9/13 cases but in none of the controls (p < 0.001). Low voltage QRS was more often seen among cases as compared to controls (10/22 vs. 3/20 p = 0.03). A stepwise algorithm based on these 3 sets of ECG findings helped to diagnose CS among patients presenting with OTVT/PVC with sensitivity of 91%, specificity of 75%, a PPV of 80%, and a NPV of 88%.ConclusionsIn patients presenting with OTVT/PVC: FB/BBB, fQRS, and low QRS voltage on the baseline ECG were more often observed among patients with underlying CS as compared to true IVT. These findings may help to distinguish underlying CS among Cases presenting with OTVT/PVC.     

Apolipoprotein E gene polymorphism and the risk of left ventricular dysfunction among Egyptian β-thalassemia major

In Egypt, β-thalassemia is the most common hereditary hemolytic anemia. Cardiac dysfunction, secondary to iron overload with formation of oxygen free radicals, is the most common cause of death in β-thalassemia patients. This study was designed to determine whether the allelic genotype of apolipoprotein E (Apo E), which exhibits antioxidant properties, could represent a genetic risk factor for the development of left ventricular (LV) dysfunction in β-thalassemia major. Fifty Egyptian β-thalassemia major patients were subjected to echocardiography to assess LV function. Apo E genotyping by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was done for all patients in addition to 50 age and sex matched healthy control subjects. Patients were classified into three groups. Group I and II were clinically asymptomatic. Group II subjects had evidence of LV dilatation, while Group III patients had clinical and echocardiographic findings of LV failure. Apo E4 allele was significantly higher among Group II and III than in controls. In conclusion, Apo E4 allele can be considered as a genetic risk factor for LV dysfunctions in β-thalassemic patients. It could be used as predictive indicator for additional risk of LV failure, particularly in asymptomatic patients with LV dilatation, requiring a closer follow-up, to prevent further disease progression.