Maurizio D. Guazzi

Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction A Target of Phosphodiesterase-5 Inhibition in a 1-Year Study

Background— The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Methods and Results— Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (−42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (−54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, −71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, −15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, −13.0±1.9%; isovolumic relaxation time, −14.0±1.7%; septal mitral annulus velocity, −76.4±9.2%). Results were similar at 12 months. Conclusions— The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. Clinical Trial Registration— URL: . Unique identifier: [NCT01156636][1]. # Clinical Perspective {#article-title-45} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01156636&atom=%2Fcirculationaha%2F124%2F2%2F164.atomBackground— The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Methods and Results— Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (−42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (−54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, −71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, −15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, −13.0±1.9%; isovolumic relaxation time, −14.0±1.7%; septal mitral annulus velocity, −76.4±9.2%). Results were similar at 12 months. Conclusions— The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156636.

Treatment of hypertension with nifedipine, a calcium antagonistic agent.

Hemodynamic monitoring after a single dose (10 mg) of nifedipine in 27 primary hypertensive subjects (diastolic pressure ≥ 110 mm Hg) documented that this calcium antagonistic agent exerts a potent arteriolar vasodilating action, which results in prompt (−21% of control at 30 minutes) persistent (−16% of control at 120 minutes) fall in mean arterial pressure associated with a rise in cardiac output pulse rate. The same patients received oral treatment for 3 weeks. Hourly pressure readings showed that 1) the antihypertensive response to each dose lasts 8–12 hours; 2) nifedipine every 6 hours significantly reduced blood pressure throughout the 24 hours, without postural hypotension. Side effects were short-lasting (headache in five patients, palpitation without arrhythmias in eight patients, burning sensation in the face legs in five patients sporadic extrasystoles in five patients) tended disappear with continued treatment. Development of drug resistance, sodium retention, plasma volume expansion, renin release or angina pectoris were not observed during the study. Although these findings seem to differentiate nifedipine from other vasodilators currently used in the treatment of hypertension, broader experience more prolonged trials with nifedipine as an antihypertensive agent will be needed before conclusions can be drawn on these particular aspects.

Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: Failure of furosemide to provide the same result

OBJECTIVES This study was designed to investigate whether a subclinical accumulation of fluid in the lung interstitium associated with moderate congestive heart failure interferes with the patients functional capacity, and whether furosemide treatment can promote reabsorption of the excessive fluid. BACKGROUND In patients with moderate congestive heart failure, pulmonary overhydration may be detected by chest roentgenography even if therapy is optimized to keep the urinary output normal and to prevent weight gain and dependent edema formation. Removal of the overhydration may help define its significance. METHODS Patients, whose regimens of digoxin, oral furosemide, and angiotensin-converting enzyme (ACE) inhibitor therapy were kept constant, were randomly allocated to receive ultrafiltration (8 cases) or an intravenous bolus of supplemental furosemide (mean dose: 248 mg; 8 cases). The amount of body fluid removed with each method approximated 1600 mL. Functional performance was assessed with cardiopulmonary exercise tests. RESULTS Soon after fluid withdrawal by either method, the filling pressures of the two ventricles and body weight were reduced and plasma renin activity, norepinephrine, and aldosterone were augmented. After furosemide administration, hormone levels remained elevated for the next 4 days, and during this period, patients had positive water metabolism, recovery of the elevated ventricular filling pressures, and re-occurrence of lung congestion with no improvement in functional capacity. After ultrafiltration, levels of renin, norepinephrine, and aldosterone fell to below control values within the first 48 hours and water metabolism was equilibrated at a new set point (less fluid intake and diuresis without weight gain). The favorable circulatory and ventilatory adjustments consequent to the reabsorption of lung water improved the functional capacity of these patients. That may also have restored the lungs ability to clear norepinephrine, thus restraining its facilitation of renin release. The improvement continued 3 months after the procedure. CONCLUSIONS In patients with congestive heart failure the set point of fluid balance is altered in spite of oral furosemide therapy; supplemental intravenous furosemide does not shift the set point, at least not when combined with ACE inhibition. Excessive, although asymptomatic, lung water limits the functional capacity of the patient.

Nifedipine, a new antihypertensive with rapid action.

Oral (17 cases) or sublingual (9 cases) administration of nifedipine (10 mg), a new coronary dilator, induced a prompt and large pressure reduction in patients with severe primary hypertension. Pressure started to fall within 20 and 5 min after oral and sublingual administration, respectively, and reached the lowest levels in the next 10 min. Maximal mean arterial pressure reduction averaged 36 mm Hg; 120 min after the drug, mean arterial pressure was diminished by 19.5% of control. The hypotension was mediated through diminished peripheral resistance associated with rise of cardiac output and pulse rate. Nifedipine was also administered sublingually in 3 cases with hypertensive encephalopathy and acute left ventricular failure with average systemic and pulmonary arterial pressures from 307/164 and 91/55 mm Hg, respectively, which fell to 237/115 and 68/35 mm Hg 15 min after 10 mg of the drug, and were further reduced to 176189 and to 47/19 mm Hg by an additional 10 mg.

Upward shift of the lower range of coronary flow autoregulation in hypertensive patients with hypertrophy of the left ventricle.

BackgroundAt any given perfusion pressure, coronary reserve is expressed by the difference between autoregulated and maximally vasodilated flow. In hypertension the raised coronary resistance reduces the steepness of the pressure-flow relationship at maximal vasodilatation. In the presence of cardiac hypertrophy the line of autoregulated flow becomes higher. For these reasons coronary reserve is reduced and the point at which baseline flow approaches the maximal achievable flow might be shifted to a higher perfusion pressure. Thus, any reduction below this elevated and critical value of pressure would lower the coronary flow. Methods and ResultsThe investigated patients were normotensive (controls, nine) and hypertensive with normal (group I, seven) or augmented LV mass index because of concentric LV hypertrophy (group II, eight). All had effort-induced angina and angiographically normal left epicardial branches. Flow in the great cardiac vein was measured by thermodilution in the baseline and during stepwise (5 mm Hg every 5 minutes) decrease of the coronary perfusion pressure with a titrated nitroprusside i.v. infusion; perfusion pressures of 60 mm Hg in the controls and 70 mm Hg in the hypertensives were taken as end points. Baseline flow averaged 102 ml/min in normotensives, 104 ml/min in hypertensive group I and 148 ml/min in hypertensive group II. At the end points flow was similar to baseline in the controls and group I. In group II coronary flow started to decline and myocardial 02 extraction started to slightly but significantly rise at perfusion pressures of 90-80 mm Hg; at the end point flow was reduced by 26% (p<0.01 from baseline). The perfusion patterns did not seem to be related to the changes in tension-time index and heart rate. ConclusionsThe association of high blood pressure (reduced ability of the coronary arterioles to dilate) and hypertrophy of the myocardium (augmented baseline coronary flow) may shift the point of exhaustion of coronary reserve to a higher perfusion pressure and make the myocardium vulnerable to treatment-induced relative hypertension. (Circulation 1991;83:845–853)

Clinical use of a calcium antagonistic agent (nifedipine) in acute pulmonary edema

Nifedipine induces vascular smooth muscle relaxation through a calcium antagonistic action. The possibility of clinical use of the drug as a ventricular unloading agent has been explored in this study. In patients with hypertensive (seven cases), primary (seven cases) or rheumatic (aortic insufficiency five cases, mitral regurgitation five cases) cardiac disease, nifedipine, administered in a single sublingual dose (10 mg), relieved acute pulmonary edema. Circulatory variations from control were the following: decrease of systemic and pulmonary arterial pressures, and of vascular resistances, of pulmonary wedge pressure, of left ventricular diastolic and systolic dimensions (echocardiography); increase of cardiac and stroke index, of left ventricular mean rate of circumferential fiber shortening, of left and right mean pre-ejection delta P/delta t and mean rate of ejection; improvement of forward output in primary and rheumatic disease. Nifedipine benefits acute congestive heart failure by sustained fall of both preload and afterload and, possibly, by an enhanced contractility. It seems to have an appropriate indication in cases in which left ventricular afterload reduction is desirable.

PDE5 Inhibition With Sildenafil Improves Left Ventricular Diastolic Function, Cardiac Geometry, and Clinical Status in Patients With Stable Systolic Heart FailureClinical Perspective

Background—In heart failure (HF), a defective nitric oxide signaling is involved in left ventricular (LV) diastolic abnormalities and remodeling. PDE5 inhibition, by blocking degradation of nitric oxide second-messenger cyclic guanosine monophosphate, might be beneficial. In a cohort of systolic HF patients, we tested the effects of PDE5 inhibition (sildenafil) on LV ejection fraction, diastolic function, cardiac geometry, and clinical status. Methods and Results—Forty-five HF patients (New York Heart Association class II-III) were randomly assigned to placebo or sildenafil (50 mg three times per day) for 1 year, with assessment (6 months and 1 year) of LV ejection fraction, diastolic function, geometry, cardiopulmonary exercise performance, and quality of life. In the sildenafil group only, at 6 months and 1 year, LV ejection fraction, early diastolic tissue Doppler velocities (E′) at the mitral lateral (from 4.62 to 5.20 and 5.19 m/s) and septal (from 4.71 to 5.23 and 5.24 m/s) annuli significantly increased, whereas the ratio of early transmitral (E) to E′ lateral decreased (from 13.1 to 9.8 to 9.4) (P<0.01). Changes were accompanied by a reverse remodeling of left atrial volume index (from 32.0 to 29.0 and 29.1 mL/m2; P<0.01) and LV mass index (from 148.0 to 130.0 and 128.0 g/m2; P<0.01). Furthermore, sildenafil improved exercise performance (peak VO2), ventilation efficiency (ventilation to CO2 production slope), and quality of life (P<0.01). Minor adverse effects were noted: flushing in 4 and headache in 2 treated patients. Conclusions—Findings confirm that in HF, sildenafil improves functional capacity and clinical status and provide the first human evidence that LV diastolic function and cardiac geometry are additional targets of benefits related to chronic PDE5 inhibition. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00975494.

Hemofiltration as short-term treatment for refractory congestive heart failure

Hemofiltration has been suggested as a new therapeutic tool in refractory heart failure. In this study, 11 patients with primary or ischemic heart disease in New York Heart Association class IV, in whom there was no response to medical treatment, were subjected to hemofiltration. The pathophysiologic adjustments promoted by subtraction of plasma water were investigated, and guidelines for an appropriate use of this procedure in heart failure are provided. Fluid was removed from plasma at a rate of 500 ml/hour until either normalization of the right atrial pressure (which was increased in all cases) was achieved or the hematocrit exceeded 50 percent. According to these criteria, the duration of treatment ranged from four to six hours and the total amount of fluid removed was 2,000 to 3,000 ml. In each case, hemofiltration promoted relief of dyspnea and of clinical and radiographic evidence of lung congestion and pleural effusion, and substantially reduced the dependent edema and abdominal girth. These effects were paralleled by progressive decrease of the right (-70 percent) and left (-45 percent) ventricular filling pressures and of the pulmonary arterial pressure and arteriolar resistance, without significant variations in heart rate, aortic pressure, cardiac index, and systemic vascular resistance. Changes in the right atrial and wedge pulmonary pressures are interpreted as reflecting a combined effect of a decrease in pressure on the outside of the heart due to fluid reabsorption (from lung interstitial spaces and pericardial, pleural and abdominal cavities) and of intravascular volume subtraction. The arterial partial pressure of oxygen was raised, the partial pressure of carbon dioxide and pH were unchanged, and urinary output was substantially enhanced by the procedure. The study indicates that: hemofiltration may be a short-term treatment for refractory cardiac insufficiency with overhydration; a filtration rate of 500 ml/hour is effective and safe; and the central venous pressure may be a reliable guide to volume subtraction.

Isolated ultrafiltration in moderate congestive heart failure.

OBJECTIVES The aim of this study was to evaluate whether ultrafiltration is beneficial in patients with moderate congestive heart failure. BACKGROUND Ultrafiltration is beneficial in patients with severe congestive heart failure. METHODS We studied 36 patients in New York Heart Association functional classes II and III in stable clinical condition. Eighteen patients (group A) were randomly selected and underwent a single session of ultrafiltration (venovenous bypass, mean [+/- SEM] ultrafiltrate 1,880 +/- 174 ml, approximately 600 ml/h) and 18 (group B) served as control subjects. RESULTS Two patients in group A and three in group B did not complete the 6-month follow-up study. In group A, soon after ultrafiltration there were significant reductions in right atrial pressure (from 8 +/- 1 to 3.4 +/- 0.7 mm Hg, pulmonary wedge pressure (from 18 +/- 2.5 to 10 +/- 1.9 mm Hg) and cardiac index (from 2.8 +/- 0.2 to 2.3 +/- 0.2 liters/min). During the follow-up period, lung function improved, extravascular lung water (X-ray score) decreased and peak oxygen consumption (ml/min per kg) increased significantly from 15.5 +/- 1 (day -1) to 17.6 +/- 0.9 (day 4), to 17.8 +/- 0.9 (day 30), to 18.9 +/- 1 (day 90) and to 19.1 +/- 1 (day 180). Oxygen consumption at anaerobic threshold (ml/min per kg) also increased significantly from 11.6 +/- 0.8 (day -1) to 13 +/- 0.7 (day 4), to 13.7 +/- 0.5 (day 30), to 15.5 +/- 0.8 (day 90) and to 15.2 +/- 0.8 (day 180). These changes were associated with increased ventilation, tidal volume and dead space/tidal volume ratio at peak exercise. The improvement in exercise performance was associated with a decrease in norepinephrine at rest, a downward shift of norepinephrine kinetics at submaximal exercise and an increase in norepinephrine during orthostatic tilt. None of these changes were recorded in group B. CONCLUSIONS In patients with moderate congestive heart failure, ultrafiltration reduces the severity of the syndrome.

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.