Most patients survive acute myocardial infarction (MI). Yet this encouraging development has certain drawbacks: heart failure (HF) prevalence is increasing and patients affected tend to have more comorbidities worsening economic strain on healthcare systems and impeding effective medical management. The heart’s pathological changes in structure and/or function, termed myocardial remodelling, significantly impact on patient outcomes. Risk factors like diabetes, chronic obstructive pulmonary disease, female sex, and others distinctly shape disease progression on the ‘road to HF’. Despite the availability of HF drugs that interact with general pathways involved in myocardial remodelling, targeted drugs remain absent, and patient risk stratification is poor. Hence, in this review, we highlight the pathophysiological basis, current diagnostic methods and available treatments for cardiac remodelling following MI. We further aim to provide a roadmap for developing improved risk stratification and novel medical and interventional therapies.

Background: Transient pulmonary congestion during exercise is emerging as an important determinant of reduced exercise capacity in heart failure with preserved ejection fraction (HFpEF). We sought to determine whether an abnormal cardiac energetic state underpins this process. Methods: We recruited patients across the spectrum of diastolic dysfunction and HFpEF (controls, n=11; type 2 diabetes, n=9; HFpEF, n=14; and severe diastolic dysfunction attributable to cardiac amyloidosis, n=9). Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to ATP ratio. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging and echocardiography and lung water using magnetic resonance proton density mapping. Studies were performed at rest and during submaximal exercise using a magnetic resonance imaging ergometer. Results: Paralleling the stepwise decline in diastolic function across the groups (E/e′ ratio; P <0.001) was an increase in NT-proBNP (N-terminal pro-brain natriuretic peptide; P <0.001) and a reduction in phosphocreatine/ATP ratio (control, 2.15 [2.09, 2.29]; type 2 diabetes, 1.71 [1.61, 1.91]; HFpEF, 1.66 [1.44, 1.89]; cardiac amyloidosis, 1.30 [1.16, 1.53]; P <0.001). During 20-W exercise, lower left ventricular diastolic filling rates (r=0.58; P <0.001), lower left ventricular diastolic reserve (r=0.55; P <0.001), left atrial dilatation (r=–0.52; P <0.001), lower right ventricular contractile reserve (right ventricular ejection fraction change, r=0.57; P <0.001), and right atrial dilation (r=–0.71; P <0.001) were all linked to lower phosphocreatine/ATP ratio. Along with these changes, pulmonary proton density mapping revealed transient pulmonary congestion in patients with HFpEF (+4.4% [0.5, 6.4]; P =0.002) and cardiac amyloidosis (+6.4% [3.3, 10.0]; P =0.004), which was not seen in healthy controls (–0.1% [–1.9, 2.1]; P =0.89) or type 2 diabetes without HFpEF (+0.8% [–1.7, 1.9]; P =0.82). The development of exercise-induced pulmonary congestion was associated with lower phosphocreatine/ATP ratio (r=–0.43; P =0.004). Conclusions: A gradient of myocardial energetic deficit exists across the spectrum of HFpEF. Even at low workload, this energetic deficit is related to markedly abnormal exercise responses in all 4 cardiac chambers, which is associated with detectable pulmonary congestion. The findings support an energetic basis for transient pulmonary congestion in HFpEF.

Background: Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition. Methods: We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction <55% (SevAS-reduced ejection fraction, n=15), healthy volunteers with nonhypertrophied hearts with normal systolic function (normal healthy volunteer, n=30), and patients with nonhypertrophied, non–pressure-loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (non–pressure-loaded heart biopsy, n=7). All underwent cardiac magnetic resonance imaging and 31 P magnetic resonance spectroscopy for myocardial energetics. LV biopsies (AS and non–pressure-loaded heart biopsy) were analyzed for CK total activity, CK isoforms, citrate synthase activity, and total creatine. Mitochondria-sarcomere diffusion distances were calculated by using serial block-face scanning electron microscopy. Results: In the absence of failure, CK flux was lower in the presence of AS (by 32%, P =0.04), driven primarily by reduction in phosphocreatine/ATP (by 17%, P <0.001), with CK k f unchanged ( P =0.46). Although lowest in the SevAS-reduced ejection fraction group, CK flux was not different from the SevAS-preserved ejection fraction group ( P >0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower ( P <0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity ( r =0.86, P =0.003). Conclusions: Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.

Changes in the kinetics of the creatine kinase (CK) shuttle are sensitive markers of cardiac energetics but are typically measured at rest and in the prone position. This study aims to measure CK kinetics during pharmacological stress at 3 T, with measurement in the supine position. A shorter “stressed saturation transfer” (StreST) extension to the triple repetition time saturation transfer (TRiST) method is proposed. We assess scanning in a supine position and validate the MR measurement against biopsy assay of CK activity. We report normal ranges of stress CK forward rate (k f CK ) for healthy volunteers and obese patients. TRiST measures k f CK in 40 min at 3 T. StreST extends the previously developed TRiST to also make a further k f CK measurement during <20 min of dobutamine stress. We test our TRiST implementation in skeletal muscle and myocardium in both prone and supine positions. We evaluate StreST in the myocardium of six healthy volunteers and 34 obese subjects. We validated MR‐measured k f CK against biopsy assays of CK activity. TRiST k f CK values matched literature values in skeletal muscle (k f CK = 0.25 ± 0.03 s −1 vs 0.27 ± 0.03 s −1 ) and myocardium when measured in the prone position (0.32 ± 0.15 s −1 ), but a significant difference was found for TRiST k f CK measured supine (0.24 ± 0.12 s −1 ). This difference was because of different respiratory‐ and cardiac‐motion‐induced B 0 changes in the two positions. Using supine TRiST, cardiac k f CK values for normal‐weight subjects were 0.15 ± 0.09 s −1 at rest and 0.17 ± 0.15 s −1 during stress. For obese subjects, k f CK was 0.16 ± 0.07 s −1 at rest and 0.17 ± 0.10 s −1 during stress. Rest myocardial k f CK and CK activity from LV biopsies of the same subjects correlated ( R = 0.43, p = 0.03). We present an independent implementation of TRiST on the Siemens platform using a commercially available coil. Our extended StreST protocol enables cardiac k f CK to be measured during dobutamine‐induced stress in the supine position.

Aims Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). Methods and resultsThe EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatineto-adenosine triphosphate ratio, as measured by 31 Phosphorus-MRS. Conclusions EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

No abstract

A rare consequence of dog bites is the infection with Capnocytophaga canimorsus, and only a few cases have been documented. We describe a 41-year-old, formerly healthy woman who died from septic shock and multiorgan failure. It is the first case of a young individual without obvious immunosuppression.