Treatment of Cardiovascular Dysfunction With PDE5-Inhibitors – Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP

IntroductionCardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies have proposed vasodilation and afterload reduction through arteriole smooth muscle cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators.Materials and MethodsHuman phosphodiesterase-enzymes and inverted erythrocytes were utilized to evaluate how vasodilators sildenafil and vardenafil affected cellular efflux and enzymatic breakdown of cAMP and cGMP, at 37°C, 34°C, 32°C, 28°C, 24°C, and 20°C. The ability of both drugs to reach their cytosolic site of action was assessed at the same temperatures. IC50- and Ki-values were calculated from dose–response curves at all temperatures, to evaluate temperature-dependent effects of both drugs.ResultsBoth drugs were able to reach the intracellular space at all hypothermic temperatures, with no reduction compared to normothermia. Sildenafil IC50 and Ki-values increased during hypothermia for enzymatic breakdown of both cAMP (IC50: 122 ± 18.9 μM at 37°C vs. 269 ± 14.7 μM at 20°C, p < 0.05) and cGMP (IC50: 0.009 ± 0.000 μM at 37°C vs. 0.024 ± 0.004 μM at 32°C, p < 0.05), while no significant changes were detected for vardenafil. Neither of the drugs showed significant hypothermia-induced changes in IC50 and Ki–values for inhibition of cellular cAMP and cGMP efflux.ConclusionSildenafil and particularly vardenafil were ableto inhibit elimination of cGMP down to 20°C. As the cellular effects of these drugs can cause afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia. As in normothermia, both drugs showed higher selectivity for inhibition of cGMP-elimination than cAMP-elimination at low core temperatures, indicating that risk for cardiotoxic side effects is not increased by hypothermia.

Aberrated supraventricular tachycardia associated with neonatal fever and COVID-19 infection

A 9-day-old girl presented during the 2020 SARS-CoV-2 pandemic in wide-complex tachycardia with acute, symptomatic COVID-19 infection. Because the potential cardiac complications of COVID-19 were unknown at the time of her presentation, we chose to avoid the potential risks of haemodynamic collapse associated with afterload reduction from adenosine. Instead, a transoesophageal pacing catheter was placed. Supraventricular tachycardia (SVT) with an aberrated QRS morphology was diagnosed and the catheter was used to pace-terminate tachycardia. This presentation illustrates that the haemodynamic consequences of a concurrent infection with largely unknown neonatal sequelae present a potentially high-risk situation for pharmacologic conversion. Oesophageal cannulation can be used to diagnose and terminate infantile SVT.

Physiological Impact of Afterload Reduction on Cardiac Mechanics and Coronary Hemodynamics Following Isosorbide Dinitrate Administration in Ischemic Heart Disease

Understanding the cardiac-coronary interaction is fundamental to developing treatment strategies for ischemic heart disease. We sought to examine the impact of afterload reduction following isosorbide dinitrate (ISDN) administration on LV properties and coronary hemodynamics to further our understanding of the cardiac-coronary interaction. Novel methodology enabled real-time simultaneous acquisition and analysis of coronary and LV hemodynamics in vivo using coronary pressure-flow wires (used to derive coronary wave energies) and LV pressure-volume loop assessment. ISDN administration resulted in afterload reduction, reduced myocardial demand, and increased mechanical efficiency (all P<0.01). Correlations were demonstrated between the forward compression wave (FCW) and arterial elastance (r=0.6) following ISDN. In the presence of minimal microvascular resistance, coronary blood flow velocity exhibited an inverse relationship with LV elastance. In summary this study demonstrated a reduction in myocardial demand with ISDN, an inverse relationship between coronary blood flow velocity and LV contraction-relaxation and a direct correlation between FCW and arterial elastance. Graphical abstract The pressure volume-loop and corresponding parameters b The pressure volume loop before (solid line) and after (broken line) Isosorbide dintrate

Impact of transcatheter aortic valve implantation on mechanical dispersion

ObjectivesThe physiological determinants of left ventricular (LV) mechanical dispersion (MD) are not fully explored. We aimed to investigate the impact of afterload reduction and changes in ventricular conduction on LV MD after transcatheter aortic valve implantation (TAVI).MethodsPatients with severe aortic stenosis (AS) were examined in a prospective, repeated measures observational cohort study before and after an uncomplicated transfemoral TAVI in a single tertiary centre. LV MD was assessed by speckle tracking echocardiography. Valvulo-arterial impedance (ZVA) was used as a measure of global afterload.ResultsWe included 140 consecutive patients (83±8 years old, 49% women, logistic EuroSCORE 16±10) with severe AS (valve area 0.7±0.2 cm2, mean transvalvular gradient 54±18 mm Hg) and a relatively preserved LV ejection fraction (52%±11%). After TAVI, we observed favourable changes in transvalvular gradients and ZVA in all patients. Compared with baseline, postprocedural MD was significantly lower in 108 patients with unchanged ventricular conduction (55±17 ms vs 51±17 ms, p=0.02) and higher in 28 patients with TAVI-induced left bundle branch block (51±13 ms vs 62±19 ms, p≤0.001). During 22±9 months observation, 22 patients died. Postprocedural MD was associated with mortality in a univariate Cox regression model (HR=1.24 (1.01–1.52), p<0.04, per 10 ms increase).ConclusionsIsolated afterload reduction was associated with reduction of MD, while concomitant impairment of ventricular conduction resulted in a more pronounced MD after TAVI, indicating that loading conditions and conduction should be considered when evaluating MD. A pronounced postprocedural LV MD was associated with mortality.