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Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalised cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.

The diagnosis of heart failure (HF) primarily relies on signs and symptoms that are neither sensitive nor specific. This impedes timely diagnosis and delays effective therapies or interventions, despite the availability of several evidence-based treatments for HF. Through monumental collaborative efforts from representatives of HF societies worldwide, the universal definition of HF was published in 2021, to provide the necessary standardized framework required for clinical management, clinical trials, and research. This review elaborates the key concepts of the new universal definition of HF, highlighting the key merits and potential avenues, which can be nuanced further in future iterations. We also discuss the key implications of the universal definition document from the perspectives of various stakeholders within the healthcare framework, including patients, care providers, system/payers and policymakers.

The diagnosis of heart failure (HF) primarily relies on signs and symptoms that are neither sensitive nor specific. This impedes timely diagnosis and delays effective therapies or interventions, despite the availability of several evidence‐based treatments for HF. Through monumental collaborative efforts from representatives of HF societies worldwide, the universal definition of HF was published in 2021, to provide the necessary standardized framework required for clinical management, clinical trials, and research. This review elaborates the key concepts of the new universal definition of HF, highlighting the key merits and potential avenues, which can be nuanced further in future iterations. We also discuss the key implications of the universal definition document from the perspectives of various stakeholders within the healthcare framework, including patients, care providers, system/payers and policymakers.

Background Speckle tracking echocardiographic global longitudinal strain (GLS) predicts outcome in patients with new onset heart failure. Still, its incremental value on top of left ventricular ejection fraction (LVEF) in patients with nonischemic, nonvalvular dilated cardiomyopathy (DCM) after optimal heart failure treatment remains unknown. Methods and Results Patients with DCM were included at the outpatient clinics of 2 centers in the Netherlands and Italy. The prognostic value of 2‐dimensional speckle tracking echocardiographic global longitudinal strain was evaluated when being on optimal heart failure medication for at least 6 months. Outcome was defined as the combination of sudden or cardiac death, life‐threatening arrhythmias, and heart failure hospitalization. A total of 323 patients with DCM (66% men, age 55±14 years) were included. The mean LVEF was 42%±11% and mean GLS after optimal heart failure treatment was −15%±4%. Twenty percent (64/323) of all patients reached the primary outcome after optimal heart failure treatment (median follow‐up of 6[4–9] years). New York Heart Association class ≥3, LVEF, and GLS remained associated with the outcome in the multivariable‐adjusted model (New York Heart Association class: hazard ratio [HR], 3.43; 95% CI, 1.49–7.90, P =0.004; LVEF: HR, 2.13; 95% CI, 1.11–4.10, P =0.024; GLS: HR, 2.24; 95% CI, 1.18–4.29, P =0.015), whereas left ventricular end‐diastolic diameter index, left atrial volume index, and delta GLS were not. The addition of GLS to New York Heart Association class and LVEF improved the goodness of fit (log likelihood ratio test P Conclusions Within this bicenter study, GLS emerged as an independent and incremental predictor of adverse outcome, which exceeded LVEF in patients with optimally treated DCM. This presses the need to routinely include GLS in the echocardiographic follow‐up of DCM.