Regulation of sympathetic nerve activity in heart failure: a role for nitric oxide and angiotensin II.
The mechanisms by which sympathetic function is augmented in chronic heart failure (CHF) are not well understood. A previous study from this laboratory (Circ Res. 1998;82:496-502) indicated that blockade of nitric oxide (NO) synthesis resulted in only an increase in renal sympathetic nerve activity (RSNA) when plasma angiotensin II (Ang II) levels were elevated. The present study was undertaken to determine if NO reduces RSNA in rabbits with CHF when Ang II receptors are blocked. Twenty-four New Zealand White rabbits were instrumented with cardiac dimension crystals, a left ventricular pacing lead, and a pacemaker. After pacing at 360 to 380 bpm for approximately 3 weeks, a renal sympathetic nerve electrode and arterial and venous catheters were implanted. Studies were carried out in the conscious state 3 to 7 days after electrode implantation. The effects of a 1-hour infusion of sodium nitroprusside (SNP; 3 microgram . kg-1. min-1) on RSNA and mean arterial pressure (MAP) were determined before and after Ang II blockade with losartan (5 mg/kg) in normal and CHF rabbits. Changes in MAP were readjusted to normal with phenylephrine. Before losartan, SNP evoked a decrease in MAP and an increase in RSNA in both groups that was baroreflex-mediated, because both MAP and RSNA returned to control when phenylephrine was administered. In the normal group, losartan plus SNP caused a reduction in MAP and an increase in RSNA that was 152.6+/-9.8% of control. Phenylephrine returned both MAP and RSNA back to the control levels. However, in the CHF group, losartan plus SNP evoked a smaller change in RSNA for equivalent changes in MAP (117.1+/-4.1% of control). On returning MAP to the control level with phenylephrine, RSNA was reduced to 65.2+/-2.9% of control (P<0. 0001). These data suggest that endogenous Ang II contributes to the sympathoexcitation in the CHF state and that blockade of Ang II receptors plus providing an exogenous source of NO reduces RSNA below the elevated baseline levels. We conclude that both a loss of NO and an increase in Ang II are necessary for sustained increases in sympathetic nerve activity in the CHF state. (+info
The sarcoplasmic reticulum and the Na+/Ca2+ exchanger both contribute to the Ca2+ transient of failing human ventricular myocytes.
Our objective was to determine the respective roles of the sarcoplasmic reticulum (SR) and the Na+/Ca2+ exchanger in the small, slowly decaying Ca2+ transients of failing human ventricular myocytes. Left ventricular myocytes were isolated from explanted hearts of patients with severe heart failure (n=18). Cytosolic Ca2+, contraction, and action potentials were measured by using indo-1, edge detection, and patch pipettes, respectively. Selective inhibitors of SR Ca2+ transport (thapsigargin) and reverse-mode Na+/Ca2+ exchange activity (No. 7943, Kanebo Ltd) were used to define the respective contribution of these processes to the Ca2+ transient. Ca2+ transients and contractions induced by action potentials (AP transients) at 0.5 Hz exhibited phasic and tonic components. The duration of the tonic component was determined by the action potential duration. Ca2+ transients induced by caffeine (Caf transients) exhibited only a phasic component with a rapid rate of decay that was dependent on extracellular Na+. The SR Ca2+-ATPase inhibitor thapsigargin abolished the phasic component of the AP Ca2+ transient and of the Caf transient but had no significant effect on the tonic component of the AP transient. The Na+/Ca2+ exchange inhibitor No. 7943 eliminated the tonic component of the AP transient and reduced the magnitude of the phasic component. In failing human myocytes, Ca2+ transients and contractions exhibit an SR-related, phasic component and a slow, reverse-mode Na+/Ca2+ exchange-related tonic component. These findings suggest that Ca2+ influx via reverse-mode Na+/Ca2+ exchange during the action potential may contribute to the slow decay of the Ca2+ transient in failing human myocytes. (+info
Peripheral muscle ergoreceptors and ventilatory response during exercise recovery in heart failure.
Recent studies have suggested that the increased ventilatory response during exercise in patients with chronic heart failure was related to the activation of muscle metaboreceptors. To address this issue, 23 patients with heart failure and 7 normal subjects performed arm and leg bicycle exercises with and without cuff inflation around the arms or the thighs during recovery. Obstruction slightly reduced ventilation and gas exchange variables at recovery but did not change the kinetics of recovery of these parameters compared with nonobstructed recovery: half-time of ventilation recovery was 175 +/- 54 to 176 +/- 40 s in patients and 155 +/- 66 to 127 +/- 13 s in controls (P < 0.05, patients vs. controls, not significant within each group from baseline to obstructed recovery). We conclude that muscle metaboreceptor activation does not seem to play a role in the exertion hyperventilation of patients with heart failure. (+info
High and low pulmonary vascular resistance in heart transplant candidates. A 5-year follow-up after heart transplantation shows continuous reduction in resistance and no difference in complication rate.
BACKGROUND: In heart transplantation candidates, high pulmonary vascular resistance has been found to decrease promptly after heart transplantation without any further reduction during follow-up. Pulmonary hypertension has been described as associated with an increased peri- and postoperative complication rate and mortality. This study describes the evolution of pulmonary vascular resistance and the outcome for patients during 5 years following heart transplantation. METHODS AND RESULTS: Haemodynamic data, complication rate and mortality have been analysed during 5-year follow-up in all patients (n = 80) who were heart transplanted at Sahlgrenska University Hospital from 1988 through 1990. We found a significant and continuous reduction in pulmonary vascular resistance both in patients with a pre-operative high (> 3 Wood Units; n = 36), but reversible on nitroprusside, and pre-operative low (< or = 3 Wood Units; n = 44) pulmonary vascular resistance. A multivariate analysis showed that a pre-operative high mean pulmonary artery and low mean pulmonary capillary wedge pressure predicted the decline in pulmonary vascular resistance during 5 years after heart transplantation. The need for a postoperative assist device, complication rate, and early and late mortality were independent of the pre-operative level of pulmonary vascular resistance. CONCLUSIONS: A continuous reduction in pulmonary vascular resistance during 5 years following heart transplantation was found in patients with both high, but reversible, and low pre-operative resistance levels. The outcome and survival were independent of the pre-operative pulmonary vascular resistance level. (+info
Clinical practice guidelines for heart failure.
Development of guidelines can be a difficult process; each organization or institution must establish the rules and criteria for including specific therapies and the level of complexity needed. Specific outcomes must be incorporated, including maintenance of comfort and functionality, freedom from hospitalization, and survival. In existing guidelines for the management of heart failure, angiotensin-converting enzyme (ACE) inhibitor therapy is clearly the gold standard. However, there is still a high mortality with ACE inhibitor therapy; the key may be choosing the right patients. Current guidelines reflect the uncertainty regarding digoxin before the Digitalis Investigation Group (DIG) trial; obviously, these guidelines should be revisited. Clinical practice guidelines for the management of heart failure need to be revised to include a better consensus on beta-blockade, the new data on digoxin, emerging data on angiotensin II receptor antagonists, and current thinking on anticoagulant therapy. (+info
Cost of heart failure to the healthcare system.
From an economic, mortality, and functional standpoint, heart failure is clearly a disease that needs to be targeted. We can develop a model for heart failure to determine the impact that specific management strategies will have on the overall cost to the system, which by itself can tell us some interesting things because we're currently spending twice as much on transplantation as on digoxin therapy. We can then use this model to assess the impact of different strategies, such as greater use of angiotensin-converting enzyme (ACE) inhibitors or digoxin therapy. (+info
Heart failure and disease management.
Disease management is a comprehensive program that identifies a population of patients at risk, provides a coherent framework of coordinated care for these patients, and demonstrates improved outcomes. In applying disease management strategies to heart failure, there is clearly the technology to improve outcomes. The two main issues involved are influencing physician practice patterns and improving patient compliance. A successful disease management program in heart failure should include patient identification patient assessment, patient education and training, patient monitoring, and triage and acute intervention. With the advances in treatment of heart failure, we have the means to keep patients out of the hospital, maintain their functionality, and decrease mortality. The real issue, which is where disease management can help, is how to apply technology in an effective way to turn potential gains into real gains. The key is not to develop more technology, but to implement effectively the technology that exists. (+info
Localization and quantitation of cardiac annexins II, V, and VI in hypertensive guinea pigs.
Annexins are characterized by Ca2+-dependent binding to phospholipids. Annexin II mainly participates in cell-cell adhesion and signal transduction, whereas annexins V and VI also seem to regulate intracellular calcium cycling. Their abundance and localization were determined in left ventricle (LV) and right ventricle (RV) from hypertensive guinea pigs, during the transition from compensatory hypertrophy to heart failure. Immunoblot analysis of annexins II, V, and VI revealed an increased accumulation (2.6-, 1.45-, and 2.3-fold, respectively) in LV from hypertensive guinea pigs and no modification in RV. Immunofluorescent labeling of annexins II, V, and VI; of Na+-K+-ATPase; and of sarcomeric alpha-actinin showed that in control LV and RV, 1) annexin II is present in nonmuscle cells; 2) annexins V and VI are mainly observed in the sarcolemma and intercalated disks of myocytes; 3) annexins II, V, and VI strongly label endothelial cells and adventitia of coronary arteries; and 4) annexin VI is present in the media. At the onset of heart failure, the most striking changes are the increased protein accumulation in LV and the very strong labeling of annexins II, V, and VI in interstitial tissue, suggesting a role in fibrosis development and cardiac remodeling. (+info