The Pathogenesis of Acute Pulmonary Edema Associated with Hypertension

Gandhi, Sanjay; Powers, John C.; Nomeir, Abdel-Mohsen; Fowle, Karen M.; Kitzman, Dalane W.; Rankin, Kevin M.; Little, William C.

doi:10.1056/nejm200101043440103

Cited by 641 publications

(273 citation statements)

References 16 publications

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“…However, to provide additional information on the potential beneficial effects of serelaxin in these groups of patients, echocardiograms are obtained during the index hospitalization in RELAX‐AHF‐2. The timing of the echocardiograms was not specified, since a prior study suggested that left ventricular function does not change significantly in these types of AHF patients33 and it would be undesirable to have the echocardiogram interfere with randomization and initiation of study drug.…”

Section: Discussionmentioning

confidence: 99%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

109

103

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Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

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Section: Discussionmentioning

confidence: 99%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

109

103

View full text Add to dashboard Cite

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“…The mechanism of sudden apical tenting remains therefore to be elucidated. None of the patients presented with marked hypertension during the acute episodes [18]. Systematic triggering of MR by methylergonovine injection, chest pain and ST segment depression in patient 3 during the regurgitation, rapid reversibility with nitroglycerine and methylergonovine-induced perfusion defect on scintigraphy during the regurgitation phase favor its ischemic origin.…”

Section: Discussionmentioning

confidence: 99%

Eclipsed Mitral Regurgitation: A New Form of Functional Mitral Regurgitation for an Unusual Cause of Heart Failure with Normal Ejection Fraction

et al. 2007

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Background: Transient functional mitral regurgitation (MR) has never been reported as a cause of heart failure (HF) with normal ejection fraction (EF) in the absence of epicardial coronary artery stenosis. Results: Performance of echocardiography in patients with acute HF before initiation of HF medical treatment allowed identification of three patients with normal EF but transient massive functional MR during the HF episode. In all patients, massive MR occurred as a consequence of sudden extreme apical tenting of both leaflets with total lack of coaptation, despite normal EF and absence of detectable left ventricular (LV) remodeling, and despite absence of significant stenosis on coronary arteries. In all patients MR was triggered by methylergonovine injection and was reversible either spontaneously or after nitroglycerine administration, leaving patients with normal echocardiogram between HF episodes. In two patients, long-term administration of calcium channel blockers prevented recurrences of MR and HF, whereas in one, mitral valve was eventually replaced. Conclusion: Sudden reversible apical tenting of mitral leaflets with subsequent torrential MR and acute HF can occur despite normal EF, absence of pre-existing LV remodeling and absence of coronary artery stenosis. This atypical type of functional MR is an unusual mechanism of HF in patients with normal LVEF.

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“…Many patients with HFpEF have concomitant systolic dysfunction abnormalities, particularly in the long axis [4,21,28,41], which may limit their tolerated systolic pressures. Beyond the profound structural changes underlying diastolic dysfunction and volume loading, limited tolerance to systolic pressures may provide additional mechanistic information on hypertensive pulmonary edema [15,17].…”

Section: Discussionmentioning

confidence: 99%

Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease

et al. 2012

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In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP iso ) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP iso (r = -0.96), and directly related to changes in the time constant of relaxation s (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP iso (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterloadinduced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P \ 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading.

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The Pathogenesis of Acute Pulmonary Edema Associated with Hypertension

Abstract: In patients with hypertensive pulmonary edema, a normal ejection fraction after treatment suggests that the edema was due to the exacerbation of diastolic dysfunction by hypertension--not to transient systolic dysfunction or mitral regurgitation.

Cited by 641 publications

References 16 publications

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Eclipsed Mitral Regurgitation: A New Form of Functional Mitral Regurgitation for an Unusual Cause of Heart Failure with Normal Ejection Fraction

Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease

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