Dataset Information

Identification of physiologic treatment targets with favourable haemodynamic consequences in heart failure with preserved ejection fraction.

ABSTRACT:

Aims

Heart failure with preserved ejection fraction (HFpEF) is characterized by complex pathophysiology including an impaired diastolic reserve. We recently showed that milrinone favourably modifies filling pressures at rest and during exertion in HFpEF patients; however, the responsible mechanism is uncertain. The objective of this study was to develop a clearer understanding of the acutely modifiable physiologic parameters that may be targeted in HFpEF.

Methods and results

We conducted computer modelling simulations based on invasive haemodynamic assessments, by right heart catheterization, in HFpEF patients at baseline and in response to milrinone. Our aim was to develop a detailed understanding of the physiologic mechanisms, which accounted for the observed actions. The resultant circulatory model of HFpEF encompassed the left ventricular (LV) end-systolic and end-diastolic pressure-volume relations, together with stressed blood volume, heart rate, and arterial mechanics. To support the modelled action of milrinone, we conducted complementary LV conductance catheter and echocardiography studies in sheep to evaluate LV end-systolic and end-diastolic pressure-volume relations. In HFpEF patients, the acute haemodynamic effects of intravenous milrinone (n = 10) administration compared with placebo (n = 10) included significant reductions in right atrial pressure (7 ± 1 to 3 ± 1 mmHg, P < 0.001) and pulmonary capillary wedge pressure (13 ± 1 to 8 ± 1 mmHg, P < 0.001), while cardiac index increased (2.77 ± 0.19 to 3.15 ± 0.14 L/min/m² , P < 0.05), and mean arterial pressure remained unchanged (95 ± 2 to 93 ± 3 mmHg, P = not significant). Computer simulations showed that these haemodynamic effects were explained by a concomitant 31% reduction in stressed blood volume together with 44% increase in LV end-systolic elastance (LV E_es ). Individually, changes in these parameters were not sufficient to explain the haemodynamic effects of milrinone. In vivo studies conducted in sheep (n = 5) showed that milrinone reduced LV filling pressure (8.0 ± 0.8 to 2.7 ± 0.6 mmHg, P < 0.01) and increased LV E_es (0.96 ± 0.07 to 2.07 ± 0.49, P < 0.05), while no significant effect on LV stiffness was observed (0.038 ± 0.003 to 0.034 ± 0.008, P = not significant).

Conclusions

These data demonstrate that stressed blood volume in HFpEF represents a relevant physiologic target in HFpEF; however, concomitant modulation of other cardiovascular parameters including LV contractility may be required to achieve desirable haemodynamic effects.

SUBMITTER: Kaye DM

PROVIDER: S-EPMC7754909 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Identification of physiologic treatment targets with favourable haemodynamic consequences in heart failure with preserved ejection fraction.

Kaye David M DM Byrne Melissa M Mariani Justin J Nanayakkara Shane S Burkhoff Daniel D

ESC heart failure 20200909 6

<h4>Aims</h4>Heart failure with preserved ejection fraction (HFpEF) is characterized by complex pathophysiology including an impaired diastolic reserve. We recently showed that milrinone favourably modifies filling pressures at rest and during exertion in HFpEF patients; however, the responsible mechanism is uncertain. The objective of this study was to develop a clearer understanding of the acutely modifiable physiologic parameters that may be targeted in HFpEF.<h4>Methods and results</h4>We co ...[more]

PMID: 32902205

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Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

Project description:Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Dataset Information

Identification of physiologic treatment targets with favourable haemodynamic consequences in heart failure with preserved ejection fraction.

Aims

Methods and results

Conclusions

Publications

Identification of physiologic treatment targets with favourable haemodynamic consequences in heart failure with preserved ejection fraction.

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