Nitrate induced vasoplegia depletes cardiac energy reserves: a model for acute cardiomyopathy in septic shock?
Authors: Watson W , Green P.G , Burrage M.K , Chamley R.R , Lewis A.J , Neubauer S , Rider O.J 
Published: November 2020

Abstract

Introduction
The healthy heart is at its most efficient when contractile filaments are stretched with preload. To produce the same cardiac output, oxygen requirement rises are proportionally greater with increased inotropy or heart rate than with increased preload. We hypothesized that in vasoplegia, loss of preload (owing to dilation of capacitance veins) and compensatory rises in heart rate and contractility would compromise the efficiency of the heart. We speculated that this may be one factor impairing cardiac function in conditions of distributive shock such as sepsis and looked to model the effects. We used cardiac magnetic resonance imaging to capture changes in cardiac volumes and contractility and magnetic resonance spectroscopy to investigate changes in ATP metabolism within the myocardium in healthy volunteers given GTN as a vasodilator.

Methods
We recruited 7 healthy volunteers (mean age 40 years, range 28–62 years; mean BMI 21.9, range 18.5–24.5) and measured their baseline cardiac volumes and function, PCr/ATP ratio and Creatine Kinase first order rate constant (CKkf), using cardiac magnetic resonance imaging and magnetic resonance spectroscopy and saturation transfer at 3 Tesla. At the same visit, they received a glyceryl trinitrate (GTN) infusion to induce vasoplegia and the measurements were repeated. We targeted GTN infusion rate to a fall in mean arterial pressure of 15mmHg.

Results
The GTN infusion brought about a fall in mean arterial pressure (from a baseline of 79±7mmHg to 64±7 mmHg, p&lt;0.0001) and a fall in LV end diastolic volume (169±57 ml vs 148±58 ml, p=0.003) indicating a reduction in preload. As expected, there was a compensatory rise in heart rate (61±7 bpm vs 69±10bpm, p=0.0005) and ejection fraction (62±3% vs 67±3%, p=0.001), however cardiac output remained unchanged (6.72±1.49 L/min vs 6.68±1.48 L/min, p=0.87). Cardiac work (calculated as stroke volume x MAP x heart rate) fell (477±123 vs 424±119 L.mmHg/min, p=0.03).
There was a fall in PCr/ATP ratio on GTN (2.18±0.25 vs 1.91±0.2, p 0.03) while CKkf more than doubled (0.14±0.06 s-1 vs 0.23±0.08 s-1, p=0.02) and creatine kinase flux also showed a significant increase (1.65±0.78 μmol/g/s vs 2.28±0.71 μmol/g/s, p=0.05).

Conclusions
What is novel here is that we show a fall in PCr/ATP ratio: as ATP concentrations in the cell are strictly maintained, this suggests phosphocreatine pool depletion occurs when preload is lost and cardiac output is maintained by an increase in inotropy and chronotropy. The rise in CKkf and CK flux confirm the increased energy demand.
Progressive energetic depletion during high demand may give rise to contractile dysfunction over time as the heart is unable to keep up with increased requirements for ATP, and progressively becomes more starved of energy. This could be a mechanism of cardiac dysfunction in septic shock and other vasoplegic states.
Figure 1

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): British Heart Foundation