Recent highlights from the International Journal of Cardiology Heart & Vasculature: cardiometabolic disease

Cardiometabolic disease is not a single entity but a constellation of cardiovascular and metabolism-related features and disorders that interact mutually and with involvement of multiple cellular and organ systems. We here highlight papers published recently in the International Journal of Cardiology Heart and Vasculature which advance the understanding of cardiometabolic disease development and progression, delineate diagnostic and prognostic paramaters, and provide perspectives for improved patient treatment.

1. Cardiometabolic disease and cardiovascular prognosis

Diabetes and obesity are key drivers of multiple cardiovascular diseases. The rising prevalence of childhood overweight, obesity and diabetes has strong impact on health systems, given the projected lifetime cardiometabolic burden. Although to a large extent a conseqence of exposome and lifestyle, cardiometabolic disease is also attributed substantially to an underlying genetic basis. A Mendelian Randomisation study by Li et al. [1] supports the concept that an elevated body mass index (BMI) early in life leads to greater risk of heart failure (HF) and ischemic stroke, and that this is largely driven by maintenance of overweight and obesity into adult life.

Adult obesity also adversely affects compensatory responses to cardiac hemodynamic stress in patients with established HF, as elegantly demonstrated by Okuyama et al. [2]. The authors took up the observation that plasma B-type natriuretic peptide (BNP) levels are often disproportionately low in relation to HF severity in obese individuals, and explored the consequences for compensatory BNP elevation during acute coronary syndromes (ACS). Plasma BNP and left ventricular ejection faction (LVEF), as a measure of HF severity, were significantly and negatively correlated in both non-obese (BMI < 25 kg/m²) and obese (BMI ≥ 25 kg/m²) HF patients undergoing emergency catheterisation. However, in the obese group, the regression line was notably less steep and the BNP/LVEF ratio much lower than in the non-obese group. This suggests that with overweight and obesity, not only is baseline BNP low in relation to LVEF, also the extent of BNP elevation in response to ACS-evoked cardiac hemodynamic stress is blunted. The authors argue that the low BNP levels in obese HF patients and the blunted rise during ACS (i) may lead to underestimation of disease severity and (ii) indicate a loss of adaptive mechanisms to uphold myocardial metabolism. Pharmacological support of biologically active natriuretic peptide levels during ACS may provide therapeutic benefit and improve outcome particularly in this patient population.

2. Cardiometabolic disease and outcome after intervention

Diabetes, hypertension, hypercholesterolaemia and smoking encompass the so-called Standard Modifiable cardiovascular Risk Factors (SMuRFs), with strong causal links to coronary artery disease (CAD) [3]. Particularly unstable CAD is associated with a high rate of adverse outcomes [4,5]. The study by Kobo et al. [6] showed that with an increasing number of SMuRFs, there is an incremental rise in adverse 1-year clincial outcome after percutaneous coronary intervention (PCI). This is predominantly attributable to target lesion failure, myocardial infarction (MI) and cardiac death. Although about 1 in 6 patient undergoing PCI in the study had no SMuRF at all, these select patients generally had more uncomplicated forms of CAD, while over 50 % had multiple SMuRFs and accordingly more complex disease phenotypes and worse composite outcome. The implication is that although a small subset of patients with few or no concomitant SMuRFs have a relatively favourable prognosus, the majority of patients have a less than favourable risk profile and require more decisive and careful therapuetic management and monitoring.

In the context of complex multi-vessel CAD with underlying diabetes, Jaiswal et al. [7] assessed which of PCI or coronary artery bypass graft (CABG) is the better option for long-term survival and cardiovascular outcomes. Their meta-analysis of 27 studies encompassed 37,091 individuals with diabetes and multi-vessel CAD. Just over half underwent PCI, the others CABG. In both groups, participants were aged around 64 years, were predominantly male and had hypertension as the most common comorbidity. Overall, outcome was better after CABG than PCI in terms of all-cause mortality, cardiac death, major adverse cardiovascular events (MACE), and strikingly a 3-fold lower risk of repeat revascularization, irrespective of follow-up duration or study design. However, in patients undergoing CABG, there was a higher incidence of cerebrovascular events. One likely cause is embolisation of atheromatous material as a result of aorta cannulation during surgery. The dedicated editorial by Ostrominski et al. [8] commended the study and discussed its value in light of available evidence and guideline recommendations. Limitations and remaining gaps in knowledge were critically addressed.

In another study, Stefil et al. [9] performed a meta-analysis to identify the optimal vessel conduit for CABG in diabetic and/or obese patients. The authors included 19 studies with diabetic and 3 studies with obese individuals undergoing either single or bilateral thoracic artery (SITA, BITA) grafting. The key finding was a long-term mortality benefit with BITA over SITA in diabetic patients. The same trend, but more modest, was also noted in the obese cohorts. However the better survival came at the expense of more peri-operative sternal wound infections in both diabetic and obese subjects. Sternal wound infections remains a critical barrier for widespread BITA grafting, as highlighted in the accompanying editorial by El-Andari et al. [10]. However, the editorial authors note that the increased infection rate in BITA recipients is a known and accepted limitation that needs to be pragmatically weighed with the mortality benefit now evident from the meta-analysis, especially since strategies to minimise infections in highly prone individuals are available. Essentially this analysis verifies the long-term survival benefit of BITA in diabetic patients, while in obese groups the effect is less clear, perhaps due to underlying differences in cardiometabolic features, while the editorial discusses this finding comprehensively in relation to clincial evidence on conduit type and recipient characteristics.

In a similar manner, two studies examined how obesity impacts on outcome and safety of pulmonary vein isolation (PVI) procedures in patients with AF. Upon AF diagnosis, the ABC pathway strategy [11] should be implemented for best possible patient management, and part of approach is the consideration of rate or rhythm control. Jungen et al. [12] reported that one-year AF recurrence rates and safety were comparable for both pulsed field ablation (PFA) and cryoballoon ablation (CBA) in obese patients, although contrast dye volume and total radiation exposure were somewhat greater in the CBA group. Perhaps on this note it is worth considering another study published in this journal at the same time, which could identify an alarming rate of early AF recurrence during the blanking period in patients fitted with wearable ECG-patch after ablation [13]. The impact of obesity was not addressed in that study, but this could perhaps be pursued in future investigations. The study by Boehmer et al. [14] specifically assessed if obesity affects outcome after CBA in patients with AF. The prospective, single-center non-inferiority study followed nearly 1000 patients, of which around 25 % were obese, for a median of 15 months. The primary efficacy endpoint (recurrence of AF, atrial flutter or atrial tachycardia after a 90-day blanking period) occurred in 31 % of obese and 35 % of non-obese patients, the safety endpoints (death, stroke or procedure-associated complications) were also comparable between the two groups. Diabetes was not found to affect outcome in subroup analysis. This well-designed study therefore supports early rhythm control by CBA regardless of obesity or diabetic status. The accompanying editorial by Gawalko et al. [15] carefully interprets these findings in the light of current evidence and identifies critical issues requiring further consideration and clarification.

The rather challenging clinical scenario of diabetes plus MI in absence of obstructive CAD was highlighted by Kreimer et al. [16]. This study assessed 373 troponin-positive patients with no evidence of coronary artery obstruction, of which just under one in 5 were diabetic. In-hospital MACE and mortality were not significantly more frequent in diabetic vs. non-diabetic patients with MI, but over a median follow-up of 6.2  years, diabetic patients had significantly higher rates of MACE (52 % vs. 31 %) and all-cause mortality (42 % vs. 20 %). The data unveiled that the impact of diabetes on outcomes in troponin-positive patients with non-obstructive coronary arteries intensified over time. The major determinant here was non-cardiac death, with stroke and cardiac arrest showing no difference between the groups. The clinical characteristics of the enrolled subjects showed that the diabetic participants were less often smokers but much more frequently obese (BMI > 30 in 57 % versus 24 % of individuals) and more likely to have kidney disease (26 vs 12 %) or AF (26 % vs 13 %). Accordingly, the diabetic groups was more than twice as likely to be admitted and/or discharged with anticoagulants, aspirin, diuretics, calcium channel blockers, angiotensin system blockers or antiarrhythmics. How much of the net clinical outcome was due to the presence of diabetes and/or associated SMuRFs, or to possible adverse drug effects [17,18] like for example major bleeding on antithrombotics for stroke prevention is unfortunately not clear from the data presented.

3. Strategies for improved detection and diagnosis of cardiometabolic and cardiovascular diseases

In certain patients experiencing chest pain or dyspnea, there is no evidence for obstructive CAD. A frequent culprit cause for the symptoms is undetected coronary microvascular dysfunction (CMD). Invasive assessment of CMD is generally performed only in a select population [19], so how wiedespread CMD truly is in patients with non-obstructive CAD is not really known. Bhaniwad et al. [20] investigated the prevalence and types of PET-detected CMD in symptomatic patients without hemodynamically significant obstructive CAD. Over half were verified to display impaired myocardial flow consistent with CMD, and of these, two-thirds could be designated as classical CMD cases, characterised primarily by reduced coronary flow reserve during evoked stress. Diabetes, obesity and metabolic syndrome were more frequent in this group. The remaining third of cases could be attributed to endogen-type CMD, which manifests as reduced coronary flow at rest with increased metabolic demand. In this group, there was a higher prevalence of arterial hypertension and (morbid) obesity. With incremental severity of metabolic syndrome, a progressive decline in myocardial flow reserve was noted, primarily due to reduced hyperemic myocardial blood flow was noted. The authors conclude with an emphatic recommendation for standardized reporting of CMD subtypes to better implement and tailor medical treatment for these patients.

Since diabetes is a progressive, often silent disease, cumulative organ injury may go undetected until cardiovascular complications manifest. Early identification of imminent and developing cardiovascular risk is therefore critical for improved diagnosis, medical care and outcome in patients, but this requires a widespread standardisation of optimal detection methods. Gašparini et al. [21] report on the use of two techniques to identify early peripheral artery disease (PAD) in diabetic patients. The authors screened 91 type 2 diabetic individuals for asymptomatic PAD by conventional ankle-brachial index (ABI), which captures reduced arterial lumen diameter caused by atherosclerosis. Additonally, the same patients were assessed by carotid-femoral pulse wave velocity (PWV), the gold-standard non-invasive means to detect arterial stiffness and indirectly arteriosclerosis. Data on how the two measures interact is conflicting, and there is no real insight into the comparative longitudinal developments of the two forms of risk assessment. The study here now strikingly shows that while low ABI was determined in around 5 % of patients, an abnormally high PWV was measured in 45 % of subjects. Lower ABI was generally found in those with albuminuria or previous cardiovascular events, whereas higher PWV correlated with advanced age and longer diabetes duration. The authors discuss quite comprehensively how their findings fit into current knowledge, identify important gaps of knowledge, and propose that for timely diagnosis of silent PAD in diabetic patients, cardiovascular risk assessment should ideally combine both ABI and carotid-femoral PWV.

Obesity, like diabetes, is a well-established risk factor for multiple cardiovascular end-points and diseases, including AF, which have a prominent inflammatory component [22,23]. The temporal and mechanistic nature of the obesity-AF interaction, however, is still imprecisely defined, and so the diagnostic benefit of screening obese, especially severely obese, patients for early AF development remains unclear. To shed light on this, Chin et al. [24] performed a cross-sectional study of 192 obese individuals (BMI ≥ 35, aged 35–65) and 50 non-obese controls, all without known cardiac disease. Left atrial (LA) volume, reservoir strain index and premature atrial contractions (PAC) were determined, and heart rhythm was monitored by Holter or implantable loop recorder. Although no single case of AF was identified during the study period, the obese group showed an independent association between LA enlargement and PAC frequency, a known precursor of AF. A modest association was also noted between impaired LA function and PACs in the obese subjects. In the controls, no association between LA cardiomyopathy markers and PAC were detected. The authors propose that although the overall diagnostic yield of AF screening was too low in this population, further investigations could evaluate if LA cardiomyopathy might be incorporated in screening strategies for timely detection of early AF development particularly in obese patients [25,26].

4. Epicardial fat evaluation to diagnose and characterise cardiometabolic disease

The report by Seki et al. [27] neatly demonstrates that the prognostic value of simple anthropometric indices such as age, BMI, blood pressure and serum creatinine and albumin can be improved by incorporating CT-based assessment of adiposity. In their east Asian cohort of 196 patients with HF with preserved ejection fraction (HFpEF), obesity was rare, occurring in only 5 %. The vast majority of subjects had on average a normal BMI of around 22 kg/m². In this lean cohort, the primary endpoint composite of all-cause mortality or HF hospitalization was primarily determined by height-indexed visceral and subcutaneous adipose tissue (VAT, SAT) volumes. Fat volumes were overall low in this study, in association with malnutrition and underweight, which is quite far removed from the cardiometabolic disease problems faced in Western countries, where overnutrition and overweight determine prognosis. Yet the CT-based adipose tissue characterisation reported here yields insights into the causal interaction between ectopic fat depots like epicardial adipose tissue (EAT) and AF [28] and supports the concept of EAT characterisation as an adjunct diagnostic and prognostic measure.

The mechanistic relationship of EAT and AF is manifold and understanding is still evolving [28]. To assess how EAT may predispose specifically to new-onset post-operative AF (POAF), Li et al. [29] retrospectively analysed 143 patinets undergoing aortic valve replacement for incidence of POAF in relation to EAT features. Holster monitoring over 7 days post-op identified 55 patinets who developed POAF, equating to an incidence of 40 % that is typical for POAF after cardiac surgery. The POAF-prone individuals were more frequently male and older, and were found to exhibit higher pre-surgery CT-detected EAT density and volumes. The baseline clinical characteristics suggest that POAF susceptibility also goes in hand with drinking behaviour and smoking, but – surprisingly − not the presence of either diabetes or elevated BMI. Also curious was the finding that in this cohort, EAT density correlated strongly with indices of cardiac structural changes (LV end-diastolic and end-systolic volumes, NT-proBNP, troponin T), but only weakly with age. Specifically, higher EAT density was seen in younger individuals, while the POAF-prone group was generally order, with age being an independent risk factor for POAF. When the authors assessed the patients based on median low or high EAT densities, they verified higher EAD density in those subjects of younger age but also more evidence of cardiac structural remodeling. In this regard, the present study supports the incorporation of specifically LA remodeling and cardiomyopathy in AF risk assessment, as proposed by Chin et al. [24]. The exact implications for the diagnostic and prognostic value of pre-surgery EAT determination as part of a POAF prediction panel requires further clarification. Perhaps with a greater number of cases, the prognostic biomarker value of non-invasive and relatively cost-effective CT-based EAT assessment could be verified.

Fukuta et al. [30] explored the association of EAT with cardiac structure and function and exercise capacity in patients with HFpEF. Exercise intolerance is a major factor limiting quality of life in HFpEF, where peak VO₂ is often inadequate to support physical activities required for everyday life. This may frequently be aggravated by anemia [31,32]. Obesity is correlated with exercise capacity [33,34] and visceral and ecoptopic fat depots, including EAT, are linked to altered myocardial functional parameters and thereby indirectly with exercise tolerance. Fukuta et al. [30] provided a meta-analysis of five echocardiography studies (n = 825) and six studies (n = 562) using magnetic resonance imaging (MRI). A potential association of increased EAT with altered cardiac structure and function and a negative correlation with peak VO₂ could be inferred from the overall meta-analysis study populations. However, the authors acknowledged the inherent bias and lack of causal proof in the cross-sectional study designs, which were moreover small in number and sample size, meaning that more investigations are necessary. The accompanying editorial by Lobeek et al. [35] critically discuss the novelty and insight gained form the meta-analysis and comprehensively review possible causal and temporal interactions between obesity, EAT and myocardial changes leading to exercise intolerance. Finally the authors of both the original study and the editorial provide outlooks for study designs to provide deeper insight in this regard.

The inflammatory nature of EAT has also been increasingly associated with atherosclerosis and underlying CMD [36,37], but the cardiovascular biomarker value of EAT remains unclear. Khan et al. [38] assessed the relationship between EAT volume, coronary plaque vulnerability, and demand MI. The authors examined EAT volume by non-contrast cardiac CT in 125 patients with chest pain and non-obstructive CAD. Coronary plaque volume and vulnerability were assessed by coronary CT angiography (CCTA), and dobutamine stress echocardiography was applied to determine demand MI. The patient subgroup with the highest tertile of EAT volume was more frequently male and burdened by cardiometabolic risk factors, inflammation and plaque vulnerability, However there was no difference between the groups with incremental EAT grading in terms of age, coronary calcium score, total and non-calcified plaque volume or the presence of demand MI. The biomarker validity of EAT for detection of CMD in non-obstructive CAD therefore continues to remain unresolved, and proteomic biomarkers might be a more promising avenue in this regard [39].

5. Novel antidiabetic drugs and cardiovascular outcome beyond glycemic control

The newest oral antidiabetic strategy, the sodium glucose cotransporter 2 inhibitors (SGLT2i) exert clear cardiovascular benefits independent of their canonical glucose-lowering actions. These agents are seen as game-changers in the treatment of HF and are now recommended in patients with reduced, preserved and mid-range ejection fractions (HFrEF, HFpEF, HFmrEF). A growing field of study is dedicated the wider applicability of SGLT2i in certain patients populations that were underrepresented in the major clinical trials so far. Relative underrepresentation of specific patient profiles such as sex in randomised clinical trials (RCT) limits the generalisability of the study outcomes, meaning that guideline-directed therapy may not always align ideally with individual patients needs [40].

Gupta et al. [41] carefully examined the representation of women and racial minorities RCT of SGLT2i in HF. In total, 43 trials with 27,703 participants were analysed. This revealed that overall female involvement was around 36 %, ranging between 10 and 56 % across all 43 studies. The lower proportions of female subjects were reported in studies addressing HFrEF, while studies examining HFpEF alone or combined HFpEF/HFrEF, the proportion of females was 40–44 %. Whether this indicates enrolment bias or a greater susceptibility of woment to develop HFpEF rather than HFrEF, requires clarification. The authors point out that more females were included in the more recent studies and in studies performed in the US. Only 4 studies, less than 10 % oft he 43 trial analysed, enrolled at least 50 % or more women. This may be taken to indicate that while equality in RCT enrolment is improving, there is a still room for improvement. Inclusion of racial minorities also diverged amongst the trial, and notably was reported only in 25 of the 41 studies, which were mainly pharmaceutical-industry funded. Where race was reported, white caucasian made up the vast majority (73 %) of the included subjects, with around 15 % Asian and 6 % afroamerican populations. The authors identify possible reasons and discuss the likely implications of the relative underrepresentation of female sex and racial minorities in RCT on HF, and propose a culturally sensitive and supportive trial recruitment strategy. Perhaps provocatively, the authors also identify a certain sex- and race-disparity at multiple levels of clincial trial design and management, especially regarding the phenotype of lead investigators and authors, and discuss possible reasons for this bias.

How patient eligibility is defined may also limit the wider application of new drugs like the SGLT2i. The EMPEROR-Preserved trial clearly highlighted the therapeutic value of SGLT2i in patinets with HFpEF, but with very strictly defined inclusion criteria. Gómez-Mesa et al. [42] sought to assess the proportion of real-life patients that actually meet the inclusion criteria of ERMPEROR-Preserved. The authors recruited 799 patients with diagnosed HFpEF through the Colombian Heart Failure Registry (RECOLFACA). Since NT-proBNP measurements were available for only 118 of the enrolled subjects, eligibility analyses were performed separately for these and for the other 681 individuals for whom NT-proBNP was not known at the time of registry enrolment. The analysis revealed that regardless of whether or not NT-proBNP levels were considered, between 70 and 80 % of patients with HFpEF in the RECOLFACA cohort would be eligibile for empagliflozin according to EMPEROR-Preserved criteria. However, the RECOLFACA cohort diverged slightly from the EMPEROR-Preserved cohort, with a lower incidence of concomitant arterial hypertension, AF or type 2 diabetes, but overall lower LVEF values and – where available – greater serum NT-proBNP. This suggests that the RECOLFACA cohort had less overall SMuRF burden but perhaps a worse HF profile. Essentially, for the 118 subjects with known NT-proBNP, these rather low levels below the cut-off threshold were the major reason for SGLT2i ineligibility. The authors suggest that perhaps the central position of NT-proBNP in determining SGLT2i eligibility should be reconsidered, since individuals whose BNP levels fall short of the threshold might still benefit. When NT-proBNP levels were disregarded for eligibility assessment, the proportion of those considered eligible increased from 74 to 81 %. Therefore, a substantial number of patients who could benefit from SGLT2i might have been withheld this treatment, and eligibility assessment could be more individualised. This will also apply to patients with HFrEF, who still carry a very high residual risk deposit apparently low NT-proBNP levels [43]. Of course this needs to be done in consideration of local healthcare resource availability and allocations.

El-Saied et al. [44] explored the benefits of adding SGLT2i on top of guideline-directed standard therapy in patients with diabetes and HFmrEF. The prospective non-randomised study enrolled 70 type 2 diabetic individuals with stable HFmrEF, of which half received either empagliflozin or dapagliflozin. The additonal use of SGLT2i led to favorable clinical outcomes compared to standard therapy alone. At 6 months follow-up, the SGLT2i users showed improved symptoms, less need for rehospitalisation, and significant improvements in LA volume, function and strain parameters. Furthermore, there was a further improvement of LV diastolic and longitudinal functions and no decline of estimated glomerular filtration rate (eGFR), indicating protection from the progressive loss of kideny function noted in the control group.

Polypharmacy is an increasingly recognized treatment problem with the ageing of the general population [45]. Although inappropriate polypharmacy should generally be avoided in patients with HF, also underuse of best available options is a problem associated with poor long-term prognosis [46,47]. Given the distinct cardioprotective profiles of SGLT2i and the angiotensin receptor/neprilysin inhibitor (ARNi) combination of sacubitril/valsartan, an additive therapeutic value is likely. The benefits in terms of cardiac remodeling and function of adding SGLT2i on top of an ARNi, were now compared to ARNi treatment alone. Correlae et al. [48] enrolled 100 consecutive patients with HFrEF/HFmrEF, who were grouped as receiving neither ARNi nor SGLT2i (control) or ARNi alone or both ARNi plus SGLT2i. The main finding of the study was greater improvement in biventricular reverse remodeling and function with the combination compared to ARNi alone or control at 3 months follow-up. The authors critically discuss the limitations and implications of their study. One point not really commented on, however, was the distribution of cardiometabolic disease in the three groups. Baseline BMI was listed only in a small supplementary table of the published report and only for the whole population (mean BMI 29 ± 5 kg/m²) not on a per-group basis. Given the strong links between obesity, weight loss and cardiac function, incorporating these data in the analysis might have unveiled deeper insights relevant for HF treatment in obesity-driven cardiometabolic disease. Diabetes (type 2 only presumably, since type 1 was an exclusion criterion of the study) was present in 96 % of controls, in 82 % of those on ARNi alone, and in only 57 % of patients receiving both ARNi and SGLT2i. It seems a bit counter-intuitive that the group with the lowest incidence of diabetes was allocated the SGLT2i. It must be assumed that this group received other forms of antidiabetic treatment; however, these were not mentioned in the patient characteristics. Again an important omission given the pleiotropic properties of metformin but particularly of the newer glucose-lowering glucagon-like peptide-1 receptor agonists (GLP-1 RA).

With regard to GLP-1 RA, however, some concerns have arisen in terms of their arrhythmogenic potential, but the data on this remains limited to small trials with only a low number of clinical events. To examine in a greater number of subjects if the benefits of GLP-1 RA in cardiometabolic disease need to be weighed against possible adverse cardiac actions, Al-Sadawi et al. [49] performed a meta-analysis of 44 RCT to assess how the currently marketed glutides perform in terms of mortality, atrial arrhythmias, and the combined incidence of ventricular arrhythmias and sudden cardiac death. The analysis included the HARMONY, AWARD, DURATION, LEAD and PIONEER series of studies, plus other prominent large-scale RCT. The net finding of this analysis in 78,702 patients (41,800 on GLP-1 RA versus 36,902 controls), was that use of GLP-1 RA reduced all-cause and cardiovascular mortality, importantly without increasing risk of atrial or ventricular arrythmias. The comparative control groups were either on placebo, insulin glargine, sitagliptine, metformin, glimepiride or empagliflozine. Not clear from this pooled analysis though is if all glutides perfomed the same or if some provided better benefit or risk than others, and how they fared overall in a direct head-to-head comparison with SGLT-2i for example. The follow-up periods were also quite variable, ranging from 52 to 208 weeks, which may have influenced outcome events. Also not clear from the present analysis is if weight loss, co-medication or other factors contributed to the cardiovascular profiles over the study periods. The take-home message, however, that the GLP-1RA appear not to promote cardiac arrhythmias, is per se reassuring.

6. Primary and secondary prevention in cardiometabolic patients

Cardiometabolic disease features obesity and/or diabetes, additional SMuRFs and other non-modifiable risk factors. These are all well-characterised drivers of various cardiovascular diseases with an underlying inflammatory and oxidative stress phenotype. Therefore preventative interventions to reduce overall cardiometabolic and cardiocascular burden are increasingly emerging.

There are observational and animal studies suggesting that fish oils enriched in polyunsaturated fatty acid might provide a cardiovascular survival benefit. Not so clear is the evidence regarding the ability of fish oils to reduce ventricular arrhythmias in patients with ICDs or to influence mortality due to ICD-shocks. Kohansal et al. [50] analysed the 4 available randomised, double-blind, placebo-controlled trials on this topic, 2 studies each from Europe and the US. There was no net survival benefit or evidence for antiarrhythmic actions in the overall cohort of 1714 patients with ICD (mainly male, aged over 60). The authors critically discuss the findings and limitations of their analysis but essentially conclude that there was no evidence to support the benefits of polyunsaturated fatty acid supplementation at least in wearers of ICD.

Negative data were also reported by Hill et al. [51] who investigated if statins could improve hospitalisation and mortality associated with AF or HF in overweight and obese patients. Despite the well-known pleiotropic anti-inflammatory and anti-oxidative actions of statins in various cardiovascular settings, the authors here found no evidence to support the use of statins for secondary prevention at least in overweight or obese patients with AF. This single-center retrospective cohort study included 2503 adults with diagnosed AF, of which just over half were on baseline statin therapy. Mortality was lower with increasing BMI, but was consistently worse − albeit non-significantly − in obese patients taking statins compared to obese individuals not being on statins. This rather unexpected finding remained even evident after adjustment for demographics and cardiovascular comorbidities. The risk of cardiovascular events associated with either AF or HF did not differ based on BMI/statin interactions. Overall this study does not support global statin use for secondary prevention of adverse outcomes based on overweight/obesity status alone. Instead, the authors propose that more defined studies of subpopulations with more specific outcome measures such as AF symptoms and burden could unveil a statin benefit in certain patient phenotypes.

Monayer et al. [52] also examined the candidate therapeutic benefits of statins, but in the context of acute decompensated HF (ADHF), for which data remain inconclusive. This retrospective observational study grouped 5978 patients with ADHF according to statin therapy status at admission and discharge. The authors noted that 74 % of the total patient cohort had an indication for statin therapy, but only around half of these were actually on statins at admission. At discharge, this number had increased from 38 % to 56 %, but this reflects under-use of guideline-directed medical therapy. A critical finding was that statin use or initiation during admission was independently associated with improved 5-year survival. Acute mortality within 30 days was also lower (3 % vs. 7.5 %) but notably so over the 12 months after admission (20 % vs 33 %). Subgroup analysis identified particularly younger, predominantly male patients and those with prior ischemic heart disease or diabetes as preferentially being discharged on statins. Curiously is the prescribing pattern between admittance and discharge. The baseline characteristics of the enrolled study participants show that of 3533 patients discharged on statins, 2163 (61 %) had already been on these drugs when admitted. Of the 2445 patients discharged without statins, 119 (5 %) had actually been prescribed these at admittance, raising the question why it was decided to withhold the prescription. Closer examination of the comorbidities and comedications revealed that the group discharged on statins were also more likely to have been receiving beta blockers, an ACE inhibitor or angiotensin receptor blocker, and antiplatelets (although it was not specified if this was aspirin and/or other platelet inhibitors) prior to admittance. These baseline medications were presumably continued after discharge, and may also have contributed to the lower all-cause mortality rates. This issue is critically addressed by the authors, as is the wider statin prescription to all patients with HF but without an independent statin indication.

Exercise probably remains the best approach to limit cardiometabolic and cardiovascular disease outcomes. The meta-analysis by Malandish et al. [53] emphasised the benefits of physical training particularly in overweight and obese patients HF. Data from 3693 individuals across 46 intervention studies verify an overall improvement in systemic inflammatory burden (plasma tumor necrosis factor-α, interleukins-6 and -1β, high sensitivity C-reactive protein). The authors could identify some differences in the degree to which individual inflammation markers were lowered, this being varying with exercise intensity, duration and type as well as with patient age and type of HF.

The clear benefits of exercise and improved health behaviour may not, however, apply for the autonomic dysregulation frequently encountered in cardiometabolic disease. The parasympathetic nervous system (PNS) is critically involved in the regulation of cardiac function and and peripheral resistance, and lower PNS activity likely worsens cardiovascular outcome. Plott et al. [54] provided an elegant and insightful review of the complex cardiovascular brain circuit and its causal role in cardiovascular stress and disease. The authors neatly outline the normal and disturbed neurocardiac axis in health and disease, and discuss the clincial implications for disease detection, therapy and outcome. A clinical study by Roovers et al. [55] assessed how an eHealth-based behavious intervention specifically impacts on heart rate variability, a surrogate index of PNS activity. Although some modest changes were noted, overall an improved health behaviour did not lead to improved autonomic function. The authors detail critically the possible causes for this negative finding, such as the dependence on participant self-reporting, possible confounding comediations, and the limitations of the detection modalities. However, the concept warrants deeper study, to delineate the interplay between health behavior and autonomic regulation in cardiometabiolic disease.

This selection of highlighted studies encompasses the wide field of cardiometabolic disease and its sequelae, providing insights into disease detection, diagnosis and management. What becomes clear is that the data is often still conflicting and in many ways surprising, but that every study in its own way paves the way for future work to fill the remaining gaps in knowledge.

Sources of funding

Supported by the Deutsche Forschungsgemeinschft (FE 1365/4-1 to A.F.; Research Training Group 2989, project 517043330 to D.D.), National Institutes of Health grants (R01HL136389, R01HL163277, R01HL160992, R01HL165704, R01HL164838, and R01HL176651 to D.D.) and the European Union (large-scale integrative project MAESTRIA, No. 965286, to D.D.).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.