Chronic amlodipine treatment during the development of heart failure

BACKGROUND: This study examined the effects of chronic amlodipine treatment on left ventricular (LV) pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF) both at rest and with treadmill exercise. In an additional series of in vitro studies, LV myocyte contractile function was examined. METHODS AND RESULTS: Sixteen pigs were studied under normal control conditions and after the development of chronic pacing-induced CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5 mg . kg-1 . d-1, n=8). Under ambient resting conditions, LV stroke volume (mL) was reduced with CHF compared with the normal control state (16+/-2 versus 31+/-2, P<0.05) and increased with concomitant amlodipine treatment (29+/-2, P<0.05). At rest, systemic and pulmonary vascular resistance (dyne . s-1 . cm-5) increased with CHF compared with the normal control state (3102+/-251 versus 2156+/-66 and 1066+/-140 versus 253+/-24, respectively, both P<0.05) and were reduced with amlodipine treatment (2108+/-199 and 480+/-74, respectively, P<0.05). With CHF, LV stroke volume remained reduced and was associated with a 40% reduction in myocardial blood flow during treadmill exercise, whereas chronic amlodipine treatment normalized LV stroke volume and improved myocardial blood flow. Resting and exercise-induced plasma norepinephrine levels were increased by >5-fold in the CHF group and were reduced by 50% from CHF values with chronic amlodipine treatment. Resting plasma endothelin (fmol/mL) increased with CHF compared with the normal state (10.4+/-0.9 versus 3.1+/-0.3, P<0.05) and was reduced with amlodipine treatment (6.6+/-1.1, P<0.5). With CHF, LV myocyte velocity of shortening ( microm/s) was reduced compared with normal controls (39+/-1 versus 64+/-1, P<0.05) and was increased with chronic amlodipine treatment (52+/-1, P<0.05). CONCLUSIONS: Chronic amlodipine treatment in this model of developing CHF produced favorable hemodynamic, neurohormonal, and contractile effects in the setting of developing CHF.     

Myosin heavy chain gene expression in human heart failure

Two isoforms of myosin heavy chain (MyHC), alpha and beta, exist in the mammalian ventricular myocardium, and their relative expression is correlated with the contractile velocity of cardiac muscle. Several pathologic stimuli can cause a shift in the MyHC composition of the rodent ventricle from alpha- to beta-MyHC. Given the potential physiological consequences of cardiac MyHC isoform shifts, we determined MyHC gene expression in human heart failure where cardiac contractility is impaired significantly. In this study, we quantitated the relative amounts of alpha- and beta-MyHC mRNA in the left ventricular free walls (LVs) of 14 heart donor candidates with no history of cardiovascular disease or structural cardiovascular abnormalities. This group consisted of seven patients with nonfailing (NF) hearts and seven patients with hearts that exhibited donor heart dysfunction (DHD). These were compared with 19 patients undergoing cardiac transplantation for chronic end-stage heart failure (F). The relative amounts of alpha-MyHC mRNA to total (i.e., alpha + beta) MyHC mRNA in the NF- and DHD-LVs were surprisingly high compared with previous reports (33.3+/-18.9 and 35.4+/-16.5%, respectively), and were significantly higher than those in the F-LVs, regardless of the cause of heart failure (2.2+/-3.5%, P < 0.0001). There was no significant difference in the ratios in NF- and DHD-LVs. Our results demonstrate that a considerable amount of alpha-MyHC mRNA is expressed in the normal heart, and is decreased significantly in chronic end-stage heart failure. If protein and enzymatic activity correlate with mRNA expression, this molecular alteration may be sufficient to explain systolic dysfunction in F-LVs, and therapeutics oriented towards increasing alpha-MyHC gene expression may be feasible.     

Alterations in skeletal muscle gene expression in the rat with chronic congestive heart failure

Congestive heart failure is often associated with skeletal muscle abnormalities that contribute to early fatigue and acidosis. Up to the present time, however, the mechanisms responsible for these changes are unclear. Myocardial infarctions were produced by coronary ligation in adult Sprague-Dawley rats. At 20 weeks, 10 control rats, and 15 animals with heart failure [defined by elevated LVEDP (26.1 +/- 3.1 v 2.5 +/- 0.5 mmHg) and RV hypertrophy (300 +/- 21 g v 158 +/- 9 mg)] underwent in vivo measurements of total body, and soleus total protein and myosin heavy chain (MHC) synthesis by [3H]leucine constant infusion. Soleus muscle was also analysed for protein content, and MHC isoenzyme content by SDS-PAGE. Northern blotting also was used to determine levels of the mRNA's encoding type I, IIa, IIb, and IIx MHC, alpha-skeletal actin, COX III, SDH and GAPDH. Soleus muscles in heart failure rats were smaller than controls (112 +/- 6 v 126 +/- 5 mg) and the degree of atrophy was significant when corrected for body mass (0.38 +/- 0.02 v 0.46 +/- 0.02 mg/g. P = 0.007). Although there was no significant difference in plasma leucine flux (an index of whole-body protein synthesis), soleus muscle total and MHC synthesis was reduced in heart failure animals. Whereas the Type I MHC isoenzyme (beta MHC) was the only MHC detected in the soleus of control animals, type II MHC isoenzyme comprised 11.8 +/- 3.1% of the MHC in the heart failure group. Furthermore, steady-state mRNA levels encoding beta MHC were significantly depressed in the heart failure rats, where those encoding Types IIb and IIx MHC were increased. Steady-state mRNA levels of alpha-skeletal actin, cytochrome C oxidase (COX III) and succinate dehydrogenase (SDH) were also significantly depressed. This animal model of chronic heart failure is associated with quantitative and qualitative alterations in skeletal muscle gene expression that are similar to those reported in skeletal muscle of patients with chronic heart failure. The altered phenotype and impaired metabolic capacity may contribute to exercise intolerance in CHF.     

Swelling-activated chloride current is persistently activated in ventricular myocytes from dogs with tachycardia-induced congestive heart failure

The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) anion channels was tested. Digital video microscopy and amphotericin-perforated-patch voltage clamp were used to measure cell volume and ion currents in ventricular myocytes isolated from normal dogs and dogs with rapid ventricular pacing-induced CHF. In normal myocytes, osmotic swelling in 0.9T to 0.6T solution (T, relative osmolarity; isosmotic solution, 296 mOsmol/L) was required to elicit ICl,swell, an outwardly rectifying swelling-activated Cl- current that reversed near -33 mV and was inhibited by 1 mmol/L 9-anthracene carboxylic acid (9AC), an anion channel blocker. Block of ICl,swell by 9AC simultaneously increased the volume of normal cells in hyposmotic solutions by up to 7%, but 9AC had no effect on volume in isosmotic or hyperosmotic solutions. In contrast, ICl,swell was persistently activated under isosmotic conditions in CHF myocytes, and 9AC increased cell volume by 9%. Osmotic shrinkage in 1.1T to 1.5T solution inhibited both ICl,swell and 9AC-induced cell swelling in CHF cells, whereas osmotic swelling only slightly increased ICl,swell. The current density for fully activated 9AC-sensitive ICl,swell was 40% greater in CHF than normal myocytes. In both groups, 9AC-sensitive current and 9AC-induced cell swelling were proportional with changes in osmolarity and 9AC concentration, and the effects of 9AC on current and volume were blocked by replacing bath Cl- with methanesulfonate. CHF thus altered the set point and magnitude of ICl,swell and resulted in its persistent activation. We previously observed analogous regulation of mechanosensitive cation channels in the same CHF model. Mechanosensitive anion and cation channels may contribute to the electrophysiological and contractile derangements in CHF and may be novel targets for therapy.     

Problems and pitfalls in evaluating studies for pacing in heart failure

The objectives of this study were to investigate clinical and patho-histological characteristics of childhood hepatoblastoma on their value as prognostic factors, and to evaluate the predictive impact of different staging systems for liver tumors on 72 patients treated in the German Pediatric Liver-Tumor Study HB89. Statistical analysis was performed by comparing patients' disease-free survival with characteristics and stages. Multivariate analysis was done by the Cox proportional-hazards model, the recursive partitioning and amalgamation model (RECPAM) and the model of clustering by response (CBR). The following characteristics were significantly related with prognosis: tumor involvement of one vs. both liver lobes, multifocal disseminated vs. unifocal growth pattern in the liver, distant metastases, vascular invasion, fetal vs. embryonal differentiation, and serum alpha-fetoprotein; patients with values of < or = 100 ng/ml or > or = 1,000,000 ng/ml had a worse outcome than those with 100 to 1,000,000 ng/ml. Multivariate analysis with the 3 models revealed that tumor-growth pattern, serum alpha-fetoprotein and, in the Cox and CBR models, vascular invasion also are independent prognostic factors, permitting the allocation of hepatoblastoma patients to 1 of 2 prognostic groups for differential therapy. Post-surgical staging and the conventional TNM system for liver carcinoma had a high predictive value, in contrast to a TNM system proposed by the UICC for testing on childhood liver tumors. We therefore propose that the TNM system for liver carcinoma be applied for comparison of treatment results in hepatoblastoma.     

Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure

OBJECTIVES: The aim of this study was to assess the potential acute benefit of multisite cardiac pacing with optimized atrioventricular synchrony and simultaneous biventricular pacing in patients with drug-refractory congestive heart failure (CHF). BACKGROUND: Prognosis and quality of life in severe CHF are poor. Various nonpharmacological therapies have been evaluated but are restricted in their effectiveness and applications. In the early 1990s, dual chamber pacing (DDD) pacing was proposed as primary treatment of refractory CHF but results were controversial. Recently, tests to evaluate the effect of simultaneous pacing of both ventricles have elicited a significant improvement of cardiac performance. METHODS: Acute hemodynamic study was conducted in 18 patients with severe CHF (New York Heart Association class III and IV) and major intraventricular conduction block (IVCB) (QRS duration = 170+/-37 ms). Using a Swan-Ganz catheter, pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were measured in different pacing configurations: atrial pacing (AAI) mode, used as reference, single-site right ventricular DDD pacing and biventricular pacing with the right ventricular lead placed either at the apex or at the outflow tract. RESULTS: The CI was significantly increased by biventricular pacing in comparison with AAI or right ventricular (RV). DDD pacing (2.7+/-0.7 vs. 2+/-0.5 and 2.4+/-0.6 l/min/m2, p < 0.001). The PCWP also decreased significantly during biventricular pacing, compared with AAI (22+/-8 vs. 27+/-9 mm Hg; p < 0.001). CONCLUSIONS: This acute hemodynamic study demonstrated that biventricular DDD pacing may significantly improve cardiac performance in patients with IVCB and with severe heart failure, in comparison with intrinsic conduction and single-site RV DDD pacing.     

Changes in gene expression during post-eclosional development in the olfactory system of Drosophila melanogaster

We have found that the expression of some genes in Drosophila melanogaster changes during the life of the adult fly. These changes can be illustrated by the use of enhancer trap lines which mark the expression of particular genes in the adult fly. Although the fly is considered able to perform most necessary adult functions within the first 72 h after eclosion from the pupal case, we find changes in expression over the first 10 days of life in the antennae of several of the genes we have examined. Some genes change by increasing from an initially low level of expression of the marked gene, while other lines, which we have termed 'late-onset' genes, show no expression of the marked gene until 4-5 days following eclosion. In contrast, some genes decrease their expression during the first 10 days of life. The changes in gene expression seen over the first 10 days of the fly's adult life provides molecular evidence of the many maturational changes occurring during the early life of the adult fly.     

Captopril and angiotensin II receptor antagonist therapy in a pacing model of heart failure

Twenty-four splenectomized dogs were subjected to rapid right ventricular pacing (RRVP) at 250 beats/min for five weeks. During the final three weeks, four groups six dogs were untreated or treated with captopril alone, with the angiotensin II type 1 (AT1) receptor antagonist L158,809 alone or with the two drugs combined by constant intravenous infusion. Hemodynamic studies were carried out during light anesthesia at baseline, and after two and five weeks of pacing. Total vascular capacitance and stressed blood volume were calculated from the mean circulatory filling pressure during transient circulatory arrest after acetylcholine administration at three different circulating volumes. Central blood volume and cardiac output were measured by thermodilution. Severe heart failure was present in the untreated group after five weeks of RRVP, characterized by low cardiac output and total vascular capacitance, high right atrial and pulmonary capillary wedge and mean circulatory filling pressure, plus increased stressed and central blood volumes. While L158,809 had not effect, captopril alone or combined with L158,809 ameliorated the reduction in total vascular capacitance, and reduced right atrial and mean circulatory pressure and stressed blood volumes. Combined therapy reduced pulmonary capillary wedge pressure. Thus, angiotensin-converting enzyme inhibition with captopril was effective in this model of chronic low output heart failure, whereas AT1 receptor antagonism was not.     

Endomyocardial biopsy in heterotopic heart transplant recipients via the femoral vein

The treatment of recurrent anterior shoulder dislocation with the rotational humeral osteotomie by Weber showed best results in the follow-up of 53 operations when combined with a shortening of the capsule and the musculus subscapularis. Rotational humeral osteotomie alone showed in 20% redislocations. The rate of redislocation could significantly be reduced by additional shortening of the soft tissue.     

The role of myocardial apoptosis in the development of heart failure

Heart failure can result from a variety of causes, including volume or pressure overload and contractile disturbances of the myocardium. Loss of myocytes is an important mechanism in the development of cardiac failure. In general, myocyte death resulting in progressive deterioration of myocardial function is attributed to necrosis, but recently the involvement of programmed cell death (mainly apoptosis) has been suggested. The authors review the possible role of myocardial apoptosis in developing of heart failure. Subcellular genetic regulatory processes as well as the pharmacological susceptibility of programmed cell death are also discussed. In heart failure, significant amount of cardiac myocytes undergoes apoptosis, that unlike necrosis can be prevented. Specific inhibition of this process could mean a considerable part of cardioprotection after thorough understanding of the underlying cellular mechanisms.     

Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure

To verify that atrioventricular (AV) synchronous pacing (DDD) with short AV delay improves the condition of patients with severe congestive heart failure, we implanted DDD pacemakers in 10 patients with severe heart failure (New York Heart Association [NYHA] class III to IV). One day after pacemaker implantation, the AV delay was optimized by Doppler echocardiographic measurements over the aortic outflow tract. Patients were evaluated regarding NYHA class, stroke volume, cardiac output, ejection fraction, and quality of life at 1, 3, and 6 months after pacemaker implantation. Although the optimized AV delay was associated with short-term improvement in stroke volume and cardiac output (baseline stroke volume = 22 +/- 7 ml, day 1 = 28 +/- 12 ml; p = 0.03: baseline cardiac output = 1.9 +/- 0.6 L/min, day 1 = 2.2 +/- 1.1 L/min; p = 0.10), the mean stroke volume, cardiac output, NYHA class, and ejection fraction did not change significantly after 1, 3, and 6 months of pacing compared with baseline values. Three patients improved in NYHA class during the follow-up. A consistent improvement in stroke volume, cardiac output, NYHA class, and ejection fraction was observed in only 1 patient. In conclusion, we found no beneficial effects of AV-synchronous pacing with optimized AV delay in patients with severe heart failure.     

Calcium transients in single myocytes and membranous ultrastructures during the development of cardiac hypertrophy and heart failure in rats

1. We examined changes in intracellular calcium transients of separated single myocytes from the right ventricle (RV) of the rat heart during the change from adaptation to maladaptation in response to a pressure overload. 2. Right ventricular hypertrophy (RVH) secondary to pulmonary hypertension was induced by a subcutaneous injection of monocrotaline. Developed tensions of the RV-free wall were decreased as RVH progressed. Single myocytes were separated from the RV during different stages of RVH. Fura-2/AM-loaded cells were field stimulated, and changes in calcium transients were measured by Olympus OSP-3 system. We also examined membranous ultrastructures (sarcoplasmic reticulum, mitochondria, surface caveolae) involved in calcium metabolism in the hearts using scanning electron microscopy. 3. We observed characteristic changes in calcium transients during the change from adaptation to maladaptation, and also found that one parameter (amplitude) of calcium transients appeared to be correlated with the changes in the number of sarcoplasmic reticulum. 4. These results provided some insights into the mechanism of calcium handling of hypertrophied heart in response to a pressure overload from adaptation to maladaptation especially when stimulatory frequency was high, and suggested that heart rate control is a very important factor for the treatment of patients with congestive heart failure.     

Retinoid-regulated gene expression in neural development

The discovery and development of information surrounding the retinoic acid receptors (RAR and RXR) has ushered in a new era in understanding the molecular mechanism of action of vitamin A in embryonic development and cellular differentiation. The mechanisms involved in the regulation of gene expression by the retinoids is at least partially known and involves binding of the RAR and RXR to retinoic acid response elements. Additional factors, including coregulatory proteins, associated regulatory elements, and cell-specific factors, may also be involved in determining the specificity of retinoid-regulation of gene expression during development. During embryogenesis, retinoids are required for the development of the posterior hindbrain and its associated structures, as well as for the survival and differentiation of certain classes of neurons and neural crest cell derivatives. At least some of the effects of retinoid on hindbrain development are related to the regulation of Hox gene expression. Additional retinoid-regulated genes have been implicated in nervous system development, and the manner in which they lead to phenotypic changes during embryogenesis remains to be determined.     

Canine cardiac digitalis receptors are preserved in congestive heart failure induced by rapid ventricular pacing

In dogs, it has been reported that acute ischemia or severe and terminal heart failure results in a selective reduction of myocardial alpha 3 isoform of Na, K-ATPase activity. The aim of this study was to evaluate if a similar change in the two canine digitalis receptor isoforms occurs following 4 weeks of rapid ventricular pacing-induced heart failure without profound necrosis. Heart failure was induced in dogs by rapid ventricular pacing (240 beats x min-1). Digitalis receptors were quantitated by [3H]-ouabain binding with isolated microsomal membranes from sham-operated (n = 3) and heart failure dogs (n = 4) and by Western blot analysis using specific alpha 1 and alpha 3 polyclonal antibodies. In kinetic studies, similar dissociation rates of 19 to 22 x 10(-4) s-1 and 1.3 to 2.4 x 10(-4) s-1 corresponding to high and low affinity sites respectively, were found in sham-operated and CHF dogs. Immunoblotting showed similar abundance of alpha 1 isoform in the two groups; however, levels of alpha 3 were increased by at least 50% in pacing-induced heart failure animals. In conclusion, heart failure selectively modulates the expression of cardiac alpha 3 isoform in dogs.