Dysfunction In Cardiomyopathy Research Articles

The interplay between cardiac dyads and mitochondria regulated the calcium handling in cardiomyocytes.

Calcium mishandling and mitochondrial dysfunction have been increasingly recognized as significant factors involved in the progression procedure of cardiomyopathy. Ca2+ mishandling could cause calcium-triggered arrhythmias, which could enhance force development and ATP consumption. Mitochondrial disorganization and dysfunction in cardiomyopathy could disturb the balance of energy catabolic and anabolic procedure. Close spatial localization and arrangement of structural among T-tubule, sarcoplasmic reticulum, mitochondria are important for Ca2+ handling. So that, we illustrate the regulating network between calcium handling and mitochondrial homeostasis, as well as its intracellular mechanisms in this review, which would be worthy to develop novel therapeutic strategy and restore the function of injured cardiomyocytes.

Diagnostic and prognostic implications of right ventricular-arterial coupling in cardiac amyloidosis and in genetic and non-genetic cardiomyopathies with hypertrophic phenotype

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Right ventricular (RV) dysfunction in cardiomyopathies is a consequence of chronic overload (i.e. aortic stenosis, AS) or direct involvement of systemic disorders (i.e. cardiac amyloidosis, CA). The Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure (TAPSE/sPAP) ratio has been recently proposed as a surrogate of RV-arterial coupling (RVAC). This study aims to compare RVAC between CA subgroups and between CA and other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. METHODS. We enrolled 50 patients with CA (26 AL and 24 wtATTR) and 75 cardiomyopathies with hypertrophy phenotype (LVH group) [25 pts with hypertrophic cardiomyopathy (HCM), 25 hypertensive pts(HypCM), and 25 pts with AS]. Besides routine echocardiographic measurements, we analysed right chambers dimensions and classical and novel parameters of RV function [TAPSE, TAPSE/sPAP, St wave, global (RVGLS) and free-wall (RVFWS) strain]. RESULTS. Compared to AL, the ATTR group showed higher right chambers dimensions, without differences in all RV systolic parameters. Compared to the LVH group, CA patients showed no differences in RV dimensions while RV systolic parameters, including the TAPSE/sPAP ratio, were significantly reduced in the presence of significantly higher LV filling pressures. At ROC curve analysis, TAPSE (AUC 0.877; 95% CI: 0.811-0.943; p < 0,0001) and TAPSE/sPAP ratio (AUC 0.859; 95% CI: 0.783-0.935; p < 0,0001) showed the best ability in discriminating CA among other forms of LVH (cut-off 20.5 mm for TAPSE with sensibility of 80.5% and specificity of 78.8%, respectively; cut-off 0.62 for TAPSE/sPAP ratio with sensibility of 85.4% and specificity 81.8%). At 24 months follow-up, there were 15 deaths in CA (30%) and 4 in LVH group (5%). At Kaplan-Meier estimation, the TAPSE/sPAP ratio showed progressively a significantly reduced survival in the lowest interquartile ranges. Moreover, at multivariate analysis, TAPSE/sPAP was the only independent prognostic factor (β -5,644; 95% IC: 0,000-0,522; p < 0,027). CONCLUSIONS. The RVAC is significantly impaired in CA compared to the LVH group but not between CA subgroups. Its reduction seems attributable to both increase LV filling pressure, due to the restrictive nature of the infiltrative cardiomyopathy, and reduced RV systolic function, due to either indirect RV chronic overload and direct myocardial infiltration. The TAPSE/sPAP ratio is a surrogate of RVAC and proved to be a novel echocardiographic parameter useful in both discriminating CA among genetic and non-genetic forms of LVH, and stratifying the prognosis. Abstract Table 1 Abstract Figure 1

The role of right ventricular-arterial coupling in cardiac amyloidosis: a comparison between subtypes and with other genetic and non-genetic hypertrophic cardiomyopathies and prognostic consequences

Abstract Background Right ventricular (RV) dysfunction in cardiomyopathies is a consequence of chronic overload (i.e. aortic stenosis) or direct involvement of systemic disorders (i.e. cardiac amyloidosis, CA). The Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure ratio (TAPSE/sPAP) has been recently proposed as a surrogate of RV-arterial coupling (RVAC) in many cardiac disorders. Purpose This study aims to compare RVAC between CA subgroups and between CA and other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. Methods We enrolled 50 patients with CA (26 pts with AL and 24 pts with wild type ATTR form), 75 patients with LV hypertrophy (LVH) [25 patients with HCM, 25 with hypertensive cardiomyopathy (HypCM), and 25 with aortic stenosis]. We analysed right chambers dimensions and classical and novel parameters of RV function [TAPSE, TAPSE/sPAP, St (S' wave at RV TDI), global (RVGLS) and free-wall (RVFWS) strain]. Results The ATTR group showed higher right dimensions than AL, without differences in all RV systolic parameters (see Table 1). Compared to the LVH group, CA patients showed no differences in RV dimensions while RV systolic parameters, included the TAPSE/sPAP ratio, were significantly reduced. At ROC curve analysis TAPSE (AUC 0.877; 95% CI: 0.811–0.943; p<0,0001) and TAPSE/sPAP ratio (AUC 0.859; 95% CI: 0.783–0.935; p<0,0001) showed the best ability in discriminating CA among other forms of LVH (cut-off 20,5 mm for TAPSE with a sensibility of 80,5% and specificity of 78,8%; cut-off 0,62 for TAPSE/sPAP ratio with a sensibility of 85,4% and a specificity 81,8%). At Kaplan-Meier estimation, the TAPSE/sPAP ratio showed a significantly reduced survival in the lowest interquartile ranges. Moreover, at multivariate analysis TAPSE/sPAP was the only independent prognostic factor (β −5,644; 95% IC: 0,000–0,522; p<0,027). Discussion The RVAC is significantly impaired in CA compared to the LVH group but not between CA subgroups. TAPSE/sPAP proved to be a novel echocardiographic parameter useful in discriminating CA among genetic and non-genetic forms of LVH, and that also show prognostic significance. Funding Acknowledgement Type of funding sources: None. Figure 1. K-M for TAPSE/sPAP ratio IQ rangesTable 1

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice.

Rationale: Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM).Methods: Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed.Results: In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets.Conclusion: Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.

5162Novel insights into desminopathy in the era of next generation sequencing

Abstract Aims The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. This disease of intermediate filaments causes not only a contractile dysfunction in cardiomyopathy and skeletal myopathy, but also a secondary mitochondrial dysfunction. We aimed to describe prevalence, phenotypic expression and mitochondrial function in desmin mutation carriers identified in a large cohort of patients with unexplained cardiomyopathy. Methods and results A representative cohort of 327 Czech patients with unexplained cardiomyopathy underwent whole exome sequencing. The cohort consisted of cases with familial and sporadic dilated cardiomyopathy (81%), left ventricular noncompaction cardiomyopathy (LVNC) (13%), and less frequently of restrictive (3%) or arrhythmogenic cardiomyopathy (3%). Clinical and laboratory data of desmin mutation carriers were collected. Morphology, desmin expression and mitochondrial function were studied in available myocardial and skeletal muscle specimens. Rare, conserved and possibly pathogenic desmin variants were identified in 6 (1.8%) probands. Two desmin mutations previously classified as variants of uncertain significance (p.K43E, p.S57L), one novel desmin variant (p.A210D) and two known pathogenic desmin mutations (p.R406W, p.R454W) were in affected individuals associated with characteristic pathological desmin aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel desmin variant p.Q364H had decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal biopsy and presented with familial left ventricular non-compaction cardiomyopathy, a novel phenotype of desminopathy. Assessment of mitochondrial function in four carriers of desmin mutations with fresh-frozen skeletal and/or myocardial muscle specimens confirmed decreased metabolic capacity of mitochondrial respiratory chain complexes, which was in case of myocardial succinate respiration more profound than in end-stage heart failure of other etiologies. Genetic testing corrected an inappropriate clinical diagnosis in two probands previously diagnosed with mitochondrial disease and inflammatory cardiomyopathy. During a median follow-up of 56 months, 5 (83%) probands developed end-stage heart failure. Conclusions Desminopathy is a rare cause of cardiomyopathy and/or skeletal muscle myopathy with a pleomorphic clinical presentation and poor prognosis. The presence of desminopathy should be considered also in individuals with left ventricular non-compaction cardiomyopathy, and in the differential diagnosis of mitochondrial diseases and inflammatory cardiomyopathy. Acknowledgement/Funding Research grant of the Ministry of Health, Czech Republic [MZ 15-27682A], No. 00023001 (IKEM, Prague, CZ), the Czech Science Foundation [14-36804G].

Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation.

Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy. In vivo expression of cofilin-1, phosphorylated on Thr25 by endogenous ERK1/2 signaling, leads to alterations in left ventricular function and cardiac actin. These results demonstrate a novel role for cofilin-1 on actin dynamics in cardiac muscle and provide a rationale on how increased ERK1/2 signaling leads to LMNA cardiomyopathy.

Proteasome dysfunction in cardiomyopathies.

The ubiquitin-proteasome system (UPS) plays a critical role in removing unwanted intracellular proteins and is involved in protein quality control, signalling and cell death. Because the heart is subject to continuous metabolic and mechanical stress, the proteasome plays a particularly important role in the heart, and proteasome dysfunction has been suggested as a causative factor in cardiac dysfunction. Proteasome impairment has been detected in cardiomyopathies, heart failure, myocardial ischaemia, and hypertrophy. Proteasome inhibition is also sufficient to cause cardiac dysfunction in healthy pigs, and patients using a proteasome inhibitor for cancer therapy have a higher incidence of heart failure. In this Topical Review we discuss the experimental data which suggest UPS dysfunction is a common feature of cardiomyopathies, with an emphasis on hypertrophic cardiomyopathy caused by sarcomeric mutations. We also propose potential mechanisms by which cardiomyopathy-causing mutations may lead to proteasome impairment, such as altered calcium handling and increased oxidative stress due to mitochondrial dysfunction.

An experimental approach to study the function of mitochondria in cardiomyopathy.

Cardiomyopathy is an inherited or acquired disease of the myocardium, which can result in severe ventricular dysfunction. Mitochondrial dysfunction is involved in the pathological process of cardiomyopathy. Many dysfunctions in cardiac mitochondria are consequences of mutations in nuclear or mitochondrial DNA followed by alterations in transcriptional regulation, mitochondrial protein function, and mitochondrial dynamics and energetics, presenting with associated multisystem mitochondrial disorders. To ensure correct diagnosis and optimal management of mitochondrial dysfunction in cardiomyopathy caused by multiple pathogenesis, multidisciplinary approaches are required, and to integrate between clinical and basic sciences, ideal translational models are needed. In this review, we will focus on experimental models to provide insights into basic mitochondrial physiology and detailed underlying mechanisms of cardiomyopathy and current mitochondria-targeted therapies for cardiomyopathy. [BMB Reports 2015; 48(10): 541-548]

Myocardial strain imaging: how useful is it in clinical decision making?

Myocardial strain is a principle for quantification of left ventricular (LV) function which is now feasible with speckle-tracking echocardiography. The best evaluated strain parameter is global longitudinal strain (GLS) which is more sensitive than left ventricular ejection fraction (LVEF) as a measure of systolic function, and may be used to identify sub-clinical LV dysfunction in cardiomyopathies. Furthermore, GLS is recommended as routine measurement in patients undergoing chemotherapy to detect reduction in LV function prior to fall in LVEF. Intersegmental variability in timing of peak myocardial strain has been proposed as predictor of risk of ventricular arrhythmias. Strain imaging may be applied to guide placement of the LV pacing lead in patients receiving cardiac resynchronization therapy. Strain may also be used to diagnose myocardial ischaemia, but the technology is not sufficiently standardized to be recommended as a general tool for this purpose. Peak systolic left atrial strain is a promising supplementary index of LV filling pressure. The strain imaging methodology is still undergoing development, and further clinical trials are needed to determine if clinical decisions based on strain imaging result in better outcome. With this important limitation in mind, strain may be applied clinically as a supplementary diagnostic method.

Regional rotation of the left ventricle in healthy and cardiomyopathic subjects measured with radial myocardial tagging

Background Left ventricular rotational deformation, which arises from contraction of myofibers arranged in a helical structure, plays a crucial role in cardiac mechanics. Myocardial dysfunction in cardiomyopathies is usually associated with altered diastolic rotation [1-3]. However, regional myocardial abnormalities in various cardiomyopathies may result in regional alterations of both systolic and diastolic rotational motion. The regional variation of LV rotation in healthy subjects has been previously studied [4-7]. We hypothesize that LV regional rotation abnormalities may be a sensitive marker in heart diseases where myocardial structure is disordered. In this regard, we investigate the regional rotation pattern of the mid LV wall in both healthy subjects and patients with cardiomyopathies. In this study, LV regional rotation is assessed through dense radial tagging [8], which facilitates analysis of the rotational motion and provides detailed regional measurement by increasing the achievable circumferential resolution. Methods LV tagging in a dense radial pattern was performed at the mid LV short axis level in twelve healthy subjects and nine cardiomyopathic patients at 1.5T or 3.0T. Number of radial taglines was set to 22 per circle. Corresponding short axis cine images were available in all subjects. The mid LV short axis was divided into 6 circumferential segments according to the AHA 17-segment model. To compute rotation of each specific segment, the tag points located on the segment were automatically detected and traced through successive frames. Finally, the rotation of each LV sector was estimated using the spatial coordinate of the tag points plus that of the LV center of mass. Results The resulting mid ventricular rotation values and rotation rates in myopathic patients were decreased relative to healthy subjects in most circumferential segments (table 1 & Figure 1). Moreover, as is shown in Figure 1, the homogeneity of regional rotations at the mid level is more pronounced in healthy subjects compared with cardiomyopathic patients. Conclusions Initial results with high density radial tagging suggest a heterogeneous and diminished pattern of regional rotation in patients with cardiomyopathy. This may potentially reflect an imbalance in LV mechanical function and lead to decreased global rotation. Regional heterogeneity of rotation may merit further study as a myocardial functional marker. The simple and rapid calculation of regional

Oxidative modification leads to the left ventricular dysfunction in cardiomyopathy

Oxidative modification leads to the left ventricular dysfunction in cardiomyopathy

Reference values of mitral and tricuspid annular plane systolic excursion for the evaluation of left and right ventricular performance

Background Mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) correlate with the left and right ventricular (LV,RV) ejection fraction as well as with the prognosis of patients with heart failure. Furthermore, M/TAPSE are sensitive markers for impaired longitudinal function which can be the earliest marker of myocardial dysfunction in cardiomyopathies with preserved ejection fraction. Cardiac MRI is the reference method for ventricular function and morphology and both M/TAPSE can be easily obtained from cine images. To date, there are no age and gender specific reference values for M/TAPSE derived from a healthy collective of normal volunteers. In this study we want to provide reference values for M/TAPSE for cardiac MRI with regard to age and gender. Methods 60 male and 59 female healthy volunteers were divided into three age groups (I=20-34yrs, II=35-49yrs, III≥50yrs). Images were acquired on a 1.5T whole body MRI scanner (Philips Achieva) using a SSFP sequence of short axis slices covering the entire left ventricle as well as two-, three- and four-chamber views. M/TAPSE were measured on 4-chamber SSFP images. Two separate reference lines were drawn in diastole and systole from the basal lateral tricuspid (TAPSE) and the basal anterior mitral leaflet (MAPSE) to a reference point on the left chest surface. The lengths differences of the reference lines between diastole and systole were measured and represent both M/TAPSE. P<0.05 was considered significant. Results The normal values for MAPSE and TAPSE are shown in table 1 and 2. Collectively, there were no significant differences between the different age and gender groups. Only in the subgroup analyses of the MAPSE values, the difference between men of group I and II and the discrepancy between men and women in group II were significant (p<0.05). Conclusions In this study, we present age and gender specific reference values of longitudinal LV and RV function in a large group of normal volunteers. Interestingly, in healthy volunteers the values of M/TAPSE are only marginally influenced by age or gender. However, further investigations are needed to confirm these findings and to provide quantification of pathological values.

Diastolic dysfunction in cardiomyopathies

Abstract Introduction Cardiomyopathies are diseases of the heart muscle, with frequent genetic component, characterized by a strong heterogeneity concerning clinical presentation and echocardiographic profile. Diastolic dysfunction can affect all forms of cardiomyopathy, often being an expression of a more advanced state of the disease. Objectives To analyze the role of diastolic dysfunction in cardiomyopathies. Conclusions Echo-Doppler analysis is therefore very helpful, as it may give important information concerning the clinical stage of disease progression and could provide a prognostic stratification tool in order to orient the clinician toward early specific treatment.

Is atrial function in Chagas dilated cardiomyopathy more impaired than in idiopathic dilated cardiomyopathy?

Atrial function is an important component in overall cardiovascular performance. However, information on atrial function in dilated cardiomyopathy is limited. This study aimed to assess atrial function in dilated cardiomyopathy and to investigate if parameters of atrial function are more impaired in Chagas dilated cardiomyopathy (CDC) than in idiopathic dilated cardiomyopathy (IDC). Seventy-two patients with dilated cardiomyopathy (36 with CDC and 36 with IDC) and 32 healthy controls were evaluated by tissue Doppler, Doppler-based strain and strain rate (SR) imaging of the left atrium (LA) and right atrium (RA). Peak atrial strain during systole and SR during systole, early and late diastolic SR, were measured at the interatrial septum, LA inferior wall and at the lateral wall of the RA. The clinical characteristics and the parameters of LV function were similar between patients with CDC and IDC. Myocardial deformation indices during the reservoir phase of both RA and LA were lower in patients with dilated cardiomyopathy than in controls, suggesting atrial dysfunction in cardiomyopathies. However, LA and RA deformation parameters did not differ between CDC and IDC patients (interatrial septal strain during the reservoir phase: -25.2 ± 14.8 vs. -24.9 ± 16.0%, P = NS; strain rate during the reservoir phase: -1.3 ± 0.7 vs. -1.5 ± 0.9/s, P = NS). Atrial myocardial deformation properties are abnormal in patients with dilated cardiomyopathy. CDC does not seem to have more atrial involvement than IDC.

Activated expression of cardiac adenylyl cyclase 6 reduces dilation and dysfunction of the pressure-overloaded heart

Background and objective Cardiac-directed adenylyl cyclase 6 (AC6) expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy, but its effects in the pressure-overloaded heart are unknown. Methods Mice with cardiac-directed and regulated expression of AC6 underwent transaortic constriction (TAC) to induce LV pressure overload. Ten days prior to TAC, and for the duration of the 4 week study, cardiac myocyte AC6 expression was activated in one group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 4 week after TAC, and LV samples assessed for alterations in Ca 2+ signaling. Results LV contractility, as reflected in the end-systolic pressure–volume relationship ( E max), was increased ( p = 0.01) by activation of AC6 expression. In addition, diastolic function was improved ( p < 0.05) and LV dilation was reduced ( p < 0.05). LV samples from AC-On mice showed reduced protein expression of sodium/calcium exchanger (NCX1) ( p < 0.05), protein phosphatase 1 (PP1) ( p < 0.01), and increased phosphorylation of phospholamban (PLN) at Ser16 ( p < 0.05). Finally, sarcoplasmic reticulum (SR) Ca 2+ content was increased in cardiac myocytes isolated from AC-On mice ( p < 0.05). Conclusions Activation of cardiac AC6 expression improves function of the pressure-overloaded and failing heart. The predominant mechanism for this favorable adaptation is improved Ca 2+ handling, a consequence of increased PLN phosphorylation, reduced NCX1, reduced PP1 expression, and increased SR Ca 2+ content.

A novel chymase inhibitor, 4-[1-([bis-(4-methyl-phenyl)-methyl]-carbamoyl)3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB), suppressed cardiac fibrosis in cardiomyopathic hamsters.

Previously, we reported that levels of chymase activity and its mRNA in cardiac tissues were significantly increased along with progression of cardiac fibrosis in cardiomyopathic hamsters, but the involvement of chymase in the progression of fibrosis has been unclear. In cultured human fibroblasts, the concentration of transforming growth factor-beta in the supernatant of medium was significantly increased after injection of human chymase. Furthermore, human chymase dose dependently increased cell proliferation, and this chymase-dependent proliferation was completely suppressed by a chymase inhibitor, Suc-Val-Pro-Phe(p)(OPh)(2) (10 micro M) or an anti-transforming growth factor-beta antibody (100 micro g/ml). In this study, we used Bio14.6 and F1B hamsters as cardiomyopathic and control hamsters, respectively. Cardiomyopathic hamsters were orally administered a novel chymase inhibitor, 4-[1-([bis-(4-methylphenyl)-methyl]-carbamoyl)-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB; 100 mg/kg per day), or placebo from 5- to 45-week-old. In the placebo-treated group, the cardiac chymase activity in cardiomyopathic hamsters 45 weeks old was significantly increased compared with that in control hamsters. BCEAB significantly reduced the cardiac chymase activity. The indexes (+dP/dt and -dP/dt) of cardiac function were significantly improved by treatment with BCEAB. The mRNA levels of collagen I and collagen III in the placebo-treated hamsters were significantly reduced to 69.6 and 76.5% by treatment with BCEAB, respectively. The fibrotic area in cardiac tissues in the BCEAB-treated hamsters was significantly suppressed to 50.7% compared with that in the placebo-treated treated hamsters. Therefore, the activation of transforming growth factor-beta by chymase may play an important role in the progression of cardiac fibrosis and cardiac dysfunction in cardiomyopathy.

Left ventricular and biventricular pacing in congestive heart failure.

Dual-chamber pacing improved hemodynamics acutely in a subset of patients with left ventricular (LV) dysfunction but conveyed no long-term symptomatic benefit in most. More recently, LV pacing and biventricular (multisite) pacing have been used to improve systolic contractility by altering the electrical and mechanical ventricular activation sequence in patients with severe congestive heart failure (CHF) and intraventricular conduction delay or left bundle branch block (LBBB). Intraventricular conduction delay and LBBB cause dyssynchronous right ventricular and LV contraction and worsen LV dysfunction in cardiomyopathies. Both LV and biventricular cardiac pacing are thought to improve cardiac function in this situation by effecting a more coordinated and efficient ventricular contraction. Short-term hemodynamic studies have shown improvement in LV systolic function, which seems more pronounced with monoventricular LV pacing than with biventricular pacing. Recent clinical studies in limited numbers of patients suggest long-term clinical benefit of biventricular pacing in patients with severe CHF symptoms. Continuing and future studies will demonstrate whether and in which patients LV and biventricular pacing are permanently effective and equivalent and which pacing site within the LV produces the most beneficial hemodynamic results.

Clinical Pharmacology of Prazosin and Phentolamine in Patients with Heart Failure

In a controlled crossover study we assessed the effects of an initial single oral dose of 150 mg phentolamine or 2 mg prazosin on the haemodynamics and plasma concentrations of noradrenaline in 12 patients with mild to moderate cardiac dysfunction in cardiomyopathy (NYHA Classes I-III). Nine of these patients continued chronic oral treatment with either 300-450 mg phentolamine or 7.5-15 mg prazosin for a period of 4-6 weeks each in randomised order. The effects on both haemodynamics and plasma noradrenaline were essentially the same under the treatment with both drugs. The acute effect on reduction of exercise-induced elevation of diastolic pulmonary artery pressure was abolished after chronic treatment. However, significant increase in stroke volume—on average, from 83 ± 7.2 to 100 ± 6.0 ml (phentolamine) and 99 ± 6.7 ml (prazosin)—occurred only after chronic treatment. Increased sympathetic activity, as expressed in plasma noradrenaline concentrations, was similar under both phentolamine and prazosin. There was no direct evidence for the clinical relevance of the more pronounced presynaptic α-blockade with phentolamine as compared with the almost pure postsynaptic α-blocking properties of prazosin. Development of tolerance seemed to occur with both drugs; however, haemodynamic benefit in terms of increased stroke volume could only be achieved after chronic treatment.