Unloading Therapy Research Articles

Changes in Plasma N-Terminal proBNP Levels and Ventricular Filling Pressures During Intensive Unloading Therapy in Elderly With Decompensated Congestive Heart Failure and Preserved Left Ventricular Systolic Function

Background Plasma B-type natriuretic peptide (BNP) levels depend on left ventricular (LV) filling pressures and correlate with the state of neurohormonal modulation in patients with congestive heart failure (CHF). In these subjects, therapy of decompensated CHF can determine acute changes in BNP levels. Methods and Results We defined the sequential pattern of N-terminal (T) proBNP in elderly with decompensated CHF and preserved LV systolic function undergoing intensive unloading therapy, assessed the prevalence of patients who significantly reduced NTproBNP at the end of treatment, and verified the relations between changes in NTproBNP and ventricular filling pressures. NTproBNP was measured in 30 patients hospitalized for worsening CHF with LV ejection fraction >50% at admission and after 2 to 4 and 6 to 8 days from the start of treatment. Patients who exhibited a reduction in NTproBNP >35% from baseline to 8-day evaluation were defined as “responders.” Twelve healthy subjects matched for age and sex were used as controls. NTproBNP was significantly higher in CHF patients than controls in all time points, to a greater extent in baseline evaluation (2982 [lower/upper quartile 1273/8146] versus 235 [150/280] pg/mL). A progressive, linear reduction of NTproBNP was detected in CHF patients during unloading. At Day 8, 18 patients (60%) resulted in “responders,” whereas 12 (40%) were “nonresponders.” The former could be predicted through higher pulmonary artery wedge pressure at baseline. Surprisingly, ventricular filling pressures similarly declined in responders and non responders. At Day 8, NTproBNP was yet 7-fold higher in CHF patients than controls. Conclusion Intensive unloading therapy is associated with a significant short-term reduction in NTproBNP in elderly with CHF and preserved LV systolic function. This behavior is progressive and linear during the first week and parallels a reduction in ventricular filling pressures which, however, does not differ between patients who significantly reduce NTproBNP and those who do not. Thus the short-term changes in NTproBNP during intensive unloading therapy in our patients do not depend only on the acute improvement in hemodynamic conditions.

Serum Ferritin and Liver Iron Concentration in Patients with Iron Overload.

Despite its limitations, serum ferritin (SF) is commonly used to monitor chelation therapy in primary and secondary hemochromatosis. To better predict liver iron concentration (LIC), we prospectively investigated the relationship between SF and LIC in a total of 421 patients with primary (HFE-1 associated, n=241) or secondary hemochromatosis (n=180), consisting of chronically transfused thalassemia (Tx-Thal: n=89) or sickle cell disease patients (Tx-SCD: n=45) and transfusion independent thalassemia patients (nTx-Thal: n=26). In all patients, LIC was measured by SQUID biosusceptometry. SF correlated with LIC (RS = 0.51–0.83, p < 0.001) but was a poor predictor for LIC. SF was significantly lower (p < 0.001) in nTx-Thal and HFE-1 patients despite similar LIC (421 – 5524 μg/g-liver) and it was higher in Tx-SCD compared to Tx-Thal (p = 0.03). In order to improve the value of SF, we calculated the SF/LIC ratio for each group. SF/LIC remained stable over time in patients whose therapy did not change. In iron loaded patients without blood transfusion therapy (nTx-Thal and HFE-1), the median SF/LIC ratio was significant lower (0.32 and 0.43) as compared to transfused patients (Tx-Thal: 0.87, HCV-Thal: 0.99, Tx-SCD: 1.2), probably, indicating differences in the secretion of ferritin into plasma. We conclude that SF alone can mislead the iron unloading therapy as it underestimates LIC in nTx-Thal patients and overestimates LIC in Tx-SCD patients. Once the initial LIC value is obtained and the individual SF/LIC ratio is determined in a patient, the ratio together with SF may be more useful than SF alone to monitor iron overload and predict LIC.

Hemodynamic response to intensive unloading therapy ( furosemide and nitroprusside) in patients >70 years of age with left ventricular systolic dysfunction and decompensated chronic heart failure

In patients with decompensated chronic congesive heart failure (CHF), intensive unloading therapy allows an acute decrease in ventricular filling pressures and improves long-term prognosis. Because elderly patients do not routinely undergo invasive hemodynamic evaluation, they are generally denied such a pharmacologic approach. We prospectively characterized the acute hemodynamic response to intensive unloading and its prognostic significance in a elderly population with CHF who were hospitalized for cardiac decompensation. Fifty-nine patients aged >70 years with left ventricular systolic dysfunction underwent intensive unloading therapy (furosemide and nitroprusside) tailored to reduce ventricular filling pressures to near-normal levels. The hemodynamic parameters were monitored by Doppler echocardiography. At baseline, left and right ventricular filling pressures were 21 ± 3 and 10 ± 3 mm Hg, respectively. Although all patients experienced a relevant improvement in clinical status during hospital stay, a significant reduction of ventricular filling pressures was detected at discharge in only 40 of them (68%) (responders), whereas 19 patients (32%) had a deficient response to therapy (nonresponders). This unfavorable behavior was predicted by the presence of renal dysfunction at admission. During 19-month follow-up, death due to cardiovascular causes occurred in 8 of 40 responders (20%) and in 9 of 19 nonresponders (47%) (p <0.005). Hospitalizations for cardiovascular causes were more frequent in the nonresponders (58% vs 8%, p <0.0001). Thus, a deficient hemodynamic response to intensive unloading treatment is not infrequent in elderly patients with decompensated CHF. This behavior is predicted by renal dysfunction at admission and is associated with poorer outcome.

Axial unloading therapy device for cervical spine rehabilitation

There is an ongoing need for therapeutic cervical traction to treat chronic idiopathic neck pain. A device was designed to perform low-load cervical traction (unloading) with the patient in an upright, seated, neutral spine position. A prototype device meeting these requirements was constructed. During subsequent use, several methods for assessing the outcome of such unloading were proposed, including radiographic images, cervical range-of-motion measurements and muscle EMG activity. The prototype and measurement methods were tested on a population of normal subjects. The results demonstrated that the device design is safe and effectively transfers load into the occipital region of the skull. The use of low-load cervical unloading induced lateral rotation and posterior lengthening of the spine. Device refinements were identified. The results demonstrated that the methods described may be safely employed on a patient population

The hemodynamic effects of isotonic exercise using hand-held weights in patients with heart failure

Background: Controversy surrounds the use of resistance exercise in patients with heart failure because of concerns that increases in rate-pressure product and systemic vascular resistance might lead to increased afterload and decreased cardiac output. Methods Following pharmacologic left ventricular unloading therapy using a pulmonary artery catheter, 34 patients with advanced heart failure performed isotonic weightlifting exercise at 50%, 65%, and 80% of the calculated one repetition maximum. Measurements were made of hemodynamics, ST segment, rate-pressure product, serum norepinephrine, rating of perceived exertion, and dysrhythmias following each exercise set. Results Repeated analysis of variance showed significant increases in systolic blood pressure ( p = 0.0005), diastolic blood pressure ( p = 0.01), rate-pressure product ( p = 0.005); serum norepinephrine ( p = 0.004), and rating of perceived exertion ( p = 0.0005). However, systemic vascular resistance and cardiac output did not change significantly ( p > 0.05). Pulmonary capillary wedge pressures, the incidence of dysrhythmias, and ST segments did not significantly differ from baseline. No patients experienced angina or dyspnea during the study. Conclusions Isotonic exercise using hand-held weights was well tolerated hemodynamically and clinically, and no patients experienced adverse outcomes during exercise.

SURGICAL THERAPY FOR DILATED CARDIOMYOPATHY

As the next millennium approaches, excitement and promise characterize the future of dilated cardiomyopathy. Until recently, dilated cardiomyopathy was considered an incurable, uniformly fatal chronic disease. Epidemiologic studies have demonstrated that at least a quarter of patients with recent onset of symptoms with cardiomyopathy manifest spontaneous improvement and a sustained favorable prognosis. It is imperative that patients who present with new-onset cardiomyopathy be managed medically and closely followed. Medical treatment remains the foundation of therapy, and certainly the advent of beta-blocker use may herald further benefit beyond that observed with conventional therapy (ACE inhibitors and digoxin). Unless mechanical support is required for hemodynamic instability and end organ failure, patients should be treated medically and observed. As discussed earlier, transient mechanical support as a bridge to recovery should be considered in the appropriate clinical scenario before committing to cardiac transplantation. Patients with established disease who have been followed for extended periods (> 6 months) that have progressive symptoms despite optimal medical therapy should be considered for surgical therapies. Cardiac transplantation is available to only a minority of the diseased population. All newer modalities of surgical unloading therapy theoretically reduce wall stress. Clearly in dilated cardiomyopathy, ventricular performance is reduced; however, individual myocyte contractile function may be intact. Studies of isolated myocytes (which are unloaded) have yielded conflicting data; however, if contractile function is intact and performance is reduced primarily secondary to abnormal loading conditions, surgical unloading therapies should yield benefit. Hence the thesis of Batista that geometric alteration will improve performance assumes intrinsic integrity of the myocyte contractile function. The implication of intrinsic myocyte contractile dysfunction is that surgical remodeling does not yield improved ventricular performance. Although clinicians have learned that selection criteria appear to play a role in predicting beneficial outcomes with cardiomyoplasty and the Batista procedure, clinical techniques to assess the integrity of myocyte function are unsophisticated. Quantifying interstitial fibrosis, assays for the degree of apoptosis, and various immunologic measures currently do not provide the insight necessary to predict outcomes reliably. The future assessment of dilated cardiomyopathy and the decision to consider alternative surgical procedures versus cardiac transplantation will likely be determined by biomolecular studies. At present, these new surgical procedures are promising therapies and potential alternatives to cardiac transplantation. Controlled studies to determine the clinical and survival benefit compared with medical therapy will ultimately be required, after the surgical techniques and patient selection criteria are refined. Randomized, prospective controlled studies assessing LVAD therapy and cardiomyoplasty are in progress.

Prevention of ventricular remodeling after myocardial infarction and in congestive heart failure

Myocardial infarction is associated with remodeling of infarcted and noninfarcted myocardium over weeks to months, resulting in progressive ventricular dilation, hypertrophy, and dysfunction. Major determinants of infarct remodeling are infarct size and transmurality, the efficacy of infarct healing, and magnitude of mechanical deformation forces such as the degree of ventricular loading and the magnitude of ventricular wall stress. These factors also influence remodeling of noninfarcted myocardium. In addition, two other factors that play major roles in the remodeling of non-infarcted myocardium are the patency of the non-infarct-related coronary artery and the integrity of the supporting collagen matrix. Prevention of remodeling involves efforts to decrease infarct size and transmurality, to reduce ventricular loading and wall stress, to promote healing, to preserve the supporting collagen matrix, and to restore patency of the infarct and non-infarct-related coronary arteries. Outcome depends critically on the timing and duration of therapy, and attention to the pathophysiologic stage of the remodeling process. Thrombolytic therapy is of proven value and should be available to all. Maximum benefit from ventricular un-loading therapy is achieved when it is begun very early, spans the infarct-healing process, and extends beyond. Early un-loading therapy should avoid hypotension and the paradoxical J-curve effect. Several large clinical trials favor the long-term use of angiotensin-converting enzyme (ACE) inhibitors to prevent progressive ventricular remodeling, to improve function, to prevent congestive heart failure, and to improve survival. Optimal strategies targeted at restoring ventricular funetion in viable but stunned or hibernating myocardium and preserving collagen matrix are lacking and need to be developed.

Effective Management of Congestive Cardiomyopathy

Until recently, congestive cardiomyopathy has had a poor prognosis on standard treatment because of severe congestive failure, arrhythmias, and embolism from endocardial thrombi in both ventricles. This pluricausal disorder differs from other heart disease because of disproportionately small hypertrophy in relation to ventricular dilation, with ultimate severe impairment of systolic function. Absence of hypertrophy adequate to compensate dilation exaggerates ventricular wall stress beyond that seen in other disorders. Newer treatments seeming to promise unprecedented improvement include unloading therapy with vasodilators, nonglycoside inotropic therapy, beta-adrenoceptor blockade (experimental only), combinations of these agents with or without digitalis and diuretics, and intra-aortic balloon pumping for critical failure. New surgical approaches include mitral annuloplasty, coronary bypass (for ischemic cardiomyopathy), and, for appropriate recipients, cardiac transplantation.

Hemodynamic effects of concomitant nitroglycerin ointment and nifedipine treatment in acute myocardial infarction.

Nitroglycerin ointment and nifedipine were used concurrently for vasodilator therapy in 10 patients with acute myocardial infarction. Nitroglycerin ointment 20 mg (4 cm) induced a significant reduction in pulmonary capillary wedge pressure from 14.1 +/- 1.8 (mean +/- standard error of the mean) to 12.4 +/- 1.2 mmHg (p less than 0.05) 30 min after application, while cardiac output, mean blood pressure, and systemic vascular resistance did not show a significant change. When nifedipine 10 mg was added orally, mean blood pressure significantly decreased from 99.0 +/- 6.3 to 82.8 +/- 5.9 mmHg (p less than 0.005) and systemic vascular resistance from 25.7 +/- 1.5 to 19.2 +/- 1.6 units (p less than 0.001) 30 min after; on the other hand, cardiac index significantly increased from 2.28 +/- 0.12 to 2.57 +/- 0.14 l/min/m2 (p less than 0.001). From these results, it was concluded that combined use of these two drugs was a useful and safe form of unloading therapy.

About unloading and dietary therapy in general therapeutic terms

A controversy is being held with the author of the article "Experience in the use of therapeutic fasting in hypothalamic disorders, published as a discussion in No. 4 of" Kazan Medical Journal "for 1980. At the same time, on the basis of his own observations, an idea is given about the mechanism of the positive effect of therapeutic fasting, which the author intends to define as a method of unloading diet therapy.

Noninvasive assessment of load reduction in patients with asymptomatic aortic regurgitation

Afterload reduction in chronic asymptomatic aortic regurgitation might retard left ventricular enlargement and hypertrophy and, consequently, delay the onset of myocardial dysfunction and the need for surgical intervention. Since afterload is best expressed as wall stress, the effect of nitroglycerin on wall stress was determined in 10 normal subjects and in eight asymptomatic subjects with aortic regurgitation and normal left ventricular and circulatory function. Peak and end-systolic wall stress were estimated using a noninvasive echocardiographic technique. At rest, despite significantly larger left ventricular dimensions in the subjects with aortic regurgitation, peak systolic wall stress in this group (134 ± 29 × 10 3 dynes/cm 2) was similar to that in normal subects (134 ± 26 × 10 3 dynes/cm 2). In contrast, end-systolic wall stress was higher in aortic regurgitation (84 ± 12 versus 59 ± 15 × 10 3 dynes/cm 2) (P < 0.01). Following the administration of nitroglycerin, the subjects with aortic regurgitation had larger reductions in left ventricular end-diastolic (3.5 mm) and end-systolic (3.1 mm) dimensions than did the normal subjects (0.6 and 1.1 mm, respectively), despite similar changes in blood pressure. This resulted in normalization of end-systolic wall stress and in reduction of peak systolic wall stress below normal in aortic regurgitation. We conclude that (1) nitroglycerin offers a simple and effective means of acutely reducing afterload in asymptomatic aortic regurgitation; (2) left ventricular dimensional changes after the administration of nitroglycerin are larger in subjects with aortic regurgitation than in normal subjects. Consequently, unloading therapy may be effective in protecting the left ventricle in this disorder.

The renin-angiotensin-aldosterone system and catecholamines in chronic congestive heart failure. Effect of angiotensin I converting enzyme inhibitor SQ 14225 (Captopril).

In order to elucidate the role of the renin-angiotensin-aldosterone system and catecholamines in the pathophysiology of chronic congestive heart failure (CHF), a study was made of the relationship between these humoral factors and the hemodynamic parameters. In 36 patients with various degrees of CHF, urinary norepinephrine (U-NE) was significantly increased in Class III-IV (NYHA) patients with a positive correlation to total systemic vascular resistance (SVR) (p < 0.05) as well as to peripheral venous pressure (VP) (p < 0.05). Plasma renin activity (PRA) was increased in Class IV patients and tended to be positively correlated with SVR. Plasma aldosterone levels (PA) correlated well with PRA (p < 0.01). In six Class III-IV patients, the acute effect of oral angiotensin I converting enzyme inhibitor SQ 14225 (captopril) on mean arterial pressure (MAP), VP, PRA, PA and plasma catecholamines was examined. PRA was consistently increased (306%) and PA decreased (37%) following captopril administration, indicating that captopril effectively inhibited angiotensin 11 formation. MAP fell (17%), especially in two patients with mitral stenosis. The heart rate tended to decrease (7%). VP also fell (27%) with symptomatic improvement. The decline in VP correlated with the decrease in plasma norepinephrine concentrations (P-NE) (p < 0.01). In patients with mitral stenosis, urine volume decreased as blood pressure fell. In two patients with CHF refractory to conventional treatment, captopril induced increased urinary sodium excretion and body weight reduction despite only a slight fall in MAP and was useful as chronic unloading therapy. These results suggest that norepinephrine plays a role in elevating SVR as well as VP, and the renin-angiotensin system also appears to contribute to the rise in SVR in CHF when the circulatory impairment is more severe. Captopril seems to dilate arterioles by reducing angiotensin 11 levels and also to reduce VP by decreasing P-NE. It is a useful therapeutic measure in selected patients with severe CHF.