Over five decades ago, Gorlin et al. [1] introduced the “hyperkinetic heart syndrome”, delineating a new clinical entity marked by an unexplained primary elevation (in contrast to all conceivable secondary causes) in stroke volume (SV), cardiac output (CO), pulse pressure, and left ventricular (LV) ejection rate. This syndrome, observed predominantly in young, mostly asymptomatic individuals, also exhibited mild systolic hypertension, a positive cold pressor test, and heightened oxygen consumption [1–4]. The authors ascribed the “hyperkinetic heart syndrome” to a “defect in central (neurohumoral) regulation of cardiac output”. Later, they concluded that the common denominator in the syndrome appears to be an increased ejection rate by the heart, rather than an increased CO. The characteristics of the ejection rate and the arterial pressure pulse indicate a greatly enhanced vigor of contraction, regardless of minute output [2].

Animal experiments discovered that in vivo, the inbred hypertrophic heart rat exhibits pronounced diastolic dysfunction while maintaining relatively preserved systolic function. Surprisingly, in vitro cardiomyocyte functional studies of Ca²⁺ handling and shortening performance revealed a hypercontractile state underlying the in vivo diastolic dysfunction. Additional notable features include focal and relatively discrete areas of interstitial fibrosis, as well as an in vivo susceptibility to dysrhythmia and sudden death. Preservation of LV ejection fraction (EF) in hypertrophic heart rat is achieved through hypercontractility, compensating for cardiomyocyte deficit and structural slippage at fibrotic foci. This hypercontractility likely stems from a significant increase in the density of the L-type Ca²⁺ channel [5]. Researchers have also found that hyperdynamic contraction and impaired relaxation in young hypertrophic cardiomyopathy (HCM) patients with gene mutations. This hypercontractility and blunted contractile reserve were associated downregulation of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA-2) mRNA, resulting in altered calcium handling [6]. In brief, hyperdynamic contraction of LV usually stems from cardiomyocyte hypercontractility through Ca²⁺ handling.

In recent years, an increasing number of studies proposed a concept of “supra-normal LVEF”, which is, to some extent, analogous to the concept of “hypercontractile phenotype” (HYPER-Phen) [7–9]. To date, there is no uniform definition of HYPER-Phen.

The primary and most widely used approach to evaluate LV systolic function in clinical settings involves estimating the LVEF. This is typically derived from dimensions obtained through various methods, M-mode, 2D, 3D techniques, or cardiac magnetic resonance (CMR). LVEF, a volume ratio to assesses LV “pumping function”, expressed by ventricular ejection SV to preload [end-diastolic volume (EDV)]. Ideally, a contractility index should respond to variations in myocardial contractile status while remaining unaffected by loading conditions [10]. However, LVEF cannot be regarded as a pure indicator of LV systolic function due to its influence from LV contractility, afterload, ventricular-arterial coupling, and LV mechanical efficiency [10, 11]. Studies have demonstrated poor correlation between LVEF and changes in LV contractility when employing LV end-systolic elastance (Ees) as a load-independent measurement of cardiac contractility, particularly in cases of altered afterload [12]. For instance, normal LVEF may persist despite severely impaired LV intrinsic contractility, as observed in conditions such as sepsis, characterized by markedly reduced arterial tone [13]. Moreover, the reliability of changes in LVEF following the administration of vasoconstrictors has been questioned, as they may indicate genuine alterations in LV contractility or alternatively reveal preexisting LV dysfunction once LV afterload is corrected [13, 14]. Chronic mitral regurgitation (MR) establishes an alternative low-resistance pathway for LV ejection, elevating LVEF despite significant LV contractile dysfunction, potentially leading to misinterpretation regarding the necessity and timing of intervention [15]. Present guidelines employ a supranormal LVEF cutoff of 60% as the benchmark for LV systolic function. This threshold indicates the need for surgical intervention in cases of asymptomatic severe MR [16].

Severe aortic stenosis and other conditions with significantly increased afterload might exhibit contrasting effects. Bradycardia could potentially inflate LVEF value due to elevated SV. Conversely, decreased SV at tachycardia or irregular R-R intervals could result in an underestimate of LVEF. Occasionally, LV malperfomance might only become apparent with alterations in loading conditions at post-surgical or interventional correction, resulting in the emergence of overt LV dysfunction and congestive heart failure (HF). Consequently, LVEF primarily serves as an integrated indicator of cardiovascular performance and LV mechanical efficiency rather than a direct measure of LV contractility. Monge García et al. [17] proposed an afterload-adjusted LVEF (adjusted to Ea), which was expressed as EF*EA. After adjusting, it exhibited improved accuracy in estimating Ees and enhanced tracking of LV contractility changes [17]. While more clinical researches are needed to verify its accuracy and application in different kinds of cardiovascular diseases.

The linear slope of the end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work stand out as the most reliable techniques for gauging intrinsic ventricular contractility. These methods exhibit less susceptibility to variations in loading conditions. The ESPVR slope, delineated by alterations in LV pressure relative to volume (or elastance), has been somewhat underutilized in clinical practice [18]. Sophisticated and costly technologies often excel in initial efficacy studies but frequently struggle to transition into widespread use in real-world scenarios, with genuine patients, practitioners, and challenges. Initially termed elastance by Suga et al. [19] in their groundbreaking experimental research, the end systolic pressure (ESP)/end-systolic volume (ESV) ratio, is now more commonly known as “force”, offering a simplified and preferable parameter means of assessing LV contractility [19, 20].

As mentioned earlier, LVEF, even with its intrinsic pros and cons, stands as the predominant metric for evaluating ventricular function among patients with established or suspected heart diseases. An extensive dataset has unveiled a U-shaped correlation between survival and LVEF evaluated via echocardiography in routine clinical settings, demonstrating elevated all-cause mortality rates among patients with LVEF ≥ 65%. These findings shed light on a novel phenotype distinguished by supra-normal LVEF, suggesting an overlooked entity necessitating deeper exploration [9].

HF is traditionally classified into two primary phenotypes based on LVEF: HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF). In both phenotypes, CO diminishes (< 5 L/min), failing to meet metabolic demands. However, some patients display symptoms and signs of systemic or pulmonary congestion despite a high CO (> 8 L/min) or a cardiac index surpassing 4 L/min/m², identified as high output HF [21]. The compensatory responses observed in low-output HF seem tailored to maintain arterial blood pressure [22–24], partly through an increase in systemic vascular resistance (SVR) and expansion of the blood volume. In all high-output HF scenarios where the CO is elevated, as seen in chronic severe anemia [25], chronic obstructive pulmonary disease [26], and large arteriovenous fistula [27, 28], the arterial blood pressure is concurrently jeopardized or diminished due to significant vasodilatation. The neurohormonal reaction witnessed in these high-output situations closely resemble that observed in low-output HF.

Notably, high CO patients often exhibit a hypercontractile state. However, it is essential to clarify that a HYPER-Phen does not equal to high CO states. High CO can mask LV contractile dysfunction in some clinical scenarios [21, 29]. Thus, accurately quantifying LV contractility remains a significant challenge. For instance, in the initial stages of severe MR, LV may exhibit a hypercontractility state (supra-normal LVEF), which then progresses to contractility impairment, potentially eluding detection by traditional LV function assessment methods. de Isla et al. [29] showcased that utilizing longitudinal speckle tracking, interventricular septal strain rate offers precise detection of initial abnormalities in LV contractile function [29].

Furthermore, numerous studies have shown that global longitudinal strain (GLS) is a superior prognostic marker compared to LVEF, and patients with HFpEF have significantly impaired GLS compared with normal controls [30]. However, whether GLS follows a similar U-shaped hazard ratio curve as LVEF or demonstrates a linear relationship remains unknown. Therefore, the definition of HYPER-Phen needed to be identified by a more precise parameter.

Echocardiography, whether at rest or under stress, unmask the hemodynamics of hypercontractility, both of which highlighting different features of this condition.

HYPER-Phen usually demonstrates a supra-normal LVEF. According to the definition, a supra-normal LVEF can be caused either by a relatively high SV (usually occurs in case of a small ESV) or by decreased LV EDV, both of which are characterized by a reduced preload reserve and/or excessive LV afterload [31]. This hyperdynamic state often leads to LV outflow tract obstruction (LVOTO), a dynamic phenomenon defined by intraventricular peak gradient ≥ 25 mmHg identified through Doppler echocardiography. It is deemed hemodynamically significant when gradients reach ≥ 50 mmHg [37]. Typically, LVOTO fluctuates based on loading conditions. Factors such as preload and afterload, the Valsalva maneuver, drug administration, or meals can reveal or worsen intraventricular obstruction in patients without a significant resting intraventricular gradient [38, 39]. LVOTO is a characteristic feature of HCM, although the prevalence of various LVOTO causes remain incompletely explored. In a case series involving 73 patients with an intraventricular pressure gradient ≥ 50 mmHg, associated conditions included HCM (74%), hypertensive hypertrophy (9%), post-cardiac surgery (7%), sigmoid septum (4%), hyperkinetic LV (3%), Takotsubo syndrome (TTS) (1.5%), and subaortic stenosis (1.5%) [40].

A hyperdynamic state typically manifests as augmented circulatory volume and reduced SVR [41–43]. This heightened CO state may correlate with elevated heart rate and pulse pressure [21, 44, 45]. Moreover, increased CO can induce pulmonary hypertension through multiple pathways, including augmented blood flow within the pulmonary circuit [46, 47], increased LV end-diastolic pressure [46], and shear stress on the pulmonary vasculature. Consequently, this may trigger pulmonary vascular remodeling and/or vasoconstriction of pulmonary vessels due to the release of vasoactive compounds by the endothelium [47, 48]. In cases of high-output HF, systemic arterial vasodilation emerges as the primary mechanism driving compensatory CO elevation [21]. A diminished SVR results in decreased afterload and renal perfusion, prompting fluid retention and augmented circulatory volume, both of which contribute to a compensatory rise in CO [21].

To date, there’s no uniform definition of “hypercontractile phenotype”. We should bear in mind that the intrinsic hypercontractility of myocardium, supra-normal LVEF, and/or high SV/CO are all different types of manifestations for HYPER-Phen.

LV pumping function served as the primary cardiac performance to maintain the body’s blood supply. Compared to per-minute LV output (CO, cardiac index), per-beat LV output (SV index) better reflects LV pumping function [49]. However, LVEF has involved into a fundamental aspect of contemporary clinical practice, serving as a robust independent prognostic factor in patients with HF and acute myocardial infarction, guiding therapeutic strategies [50, 51]. The European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE) suggest evaluating LVEF in 2D using a modified Simpson’s method of discs, obtaining LV volumes from apical 4- and 2-chamber views, or alternatively, when accessible and feasible, by 3D images [52]. Even with ideal imaging conditions, LVEF might provide an incomplete or inaccurate assessment of LV function, particularly in instances of significant concentric remodeling, HCM, or diminished cavity size, where substantial systolic dysfunction with decreased SV is present despite a normal or supranormal LVEF. Strain image offers a more accurate reflection of systolic function in these patients with preserved EF due to geometric factors.

Speckle tracking derived strain captures solely the active contraction of myocardial fibers, thus negating the “tethering effect” error, which involves the passive movement of fibrous tissue through adjacent viable myocardium. GLS has demonstrated greater sensitivity as an indicator of LV systolic function compared to LVEF, offering superior prognostic value across various heart diseases characterized by a broad spectrum of myocardial dysfunction [53]. This quantitative approach to assessing regional and global LV function has garnered recognition for its ability to detect LV systolic dysfunction in cardiomyopathies, cardio-oncology, or cases of cardiac remodeling where LVEF remains within normal limits. GLS delivers a more precise evaluation of systolic function in conditions featuring increased LV mass or altered LV geometry, particularly notable in HCM where severely depressed systolic function may coexist with a supranormal LVEF. The ESC (European Society of Cardiology) guidelines for diagnosis and management advocate for myocardial strain imaging in early HCM disease assessment [37]. The ASE/EACVI consensus statement incorporates a relative percentage decrease in GLS of > 15% from baseline as an indicator of cancer therapeutics-related cardiac dysfunction [54].

It’s essential to emphasize that myocardial strain is influenced by loading conditions [18]. Strain rate, representing the rate of deformation, exhibits less reliance on loading. Consequently, there’s been curiosity about employing it as an indicator of contractility. Nonetheless, reproducibility with tissue Doppler methods is constrained by angle dependency, diminished spatial resolution, and decreased signal-to-noise ratio, notwithstanding excellent temporal resolution. Alternative techniques may lack the requisite frame rate to precise quantification of deformation velocity [55]. These constraints have thus far impeded its integration into routine practice.

Data are in progress with the estimation of HYPER-Phen with LV force and stroke work. In theory, the use of force holds potential since it is a relatively pure index of contractility, less affected by afterload or preload changes than EF, and has already been shown to be more efficient than EF in stratifying prognosis in patients with reduced EF [35]. Another potentially beneficial method involves evaluating myocardial function by combining strain analysis with noninvasive estimation of LV pressure using pressure-strain loop analysis. By integrating diverse myocardial work elements like index, efficiency, and constructive and wasted work, a comprehensive evaluation of LV mechanics and energetics can be attained [56].

Indeed, normal systolic function arises from the contraction of myocardial fibers arranged in a right-handed helix within the subendocardium, a left-handed helix in the subepicardium, and a layer of circumferential fibers in between [57]. Simply put, the interaction of these double helical-oriented muscle layers induces longitudinal and circumferential shortening, alone with radial thickening, coupled with a twisting motion along the long axis during systole. Thus, a HYPER-Phen can be characterized either by viewing the LV as a unified entity (e.g., myocardial work, GLS) or as a more intricate assembly spheres (e.g., longitudinal, circumferential, radial strain, or strain rate, etc.).

The hyperfunction of cardiac sarcomeric myosin, whether primary or secondary to increased sympathetic drive, presents a promising therapeutic target. For example, modulating stressed volume, targeting arterial stiffness and/or vascular load would be beneficial. This can be addressed through interventions such as cardiac myosin inhibitors and/or beta-blockers. Currently, therapeutic indications rely on suboptimal indices such as LVOTO in HCM or EF with beta-blockers. The resurgence of interest in the hypercontractile state as an actionable therapeutic target has intensified our focus on noninvasive methods for identifying this condition. As many hypercontractile states are treatable, identifying the underlying cause of hypercontraction is pivotal to determining the suitable remedy, such as identifying the characteristics of reduced preload reserve and/or excessive LV afterload, distinguishing high-CO from normal-to-decreased CO variants, and validating easily accessible parameters like force and SV based on volumetric echocardiography. Today, this is also operator-independent and highly reproducible with artificial intelligence software already on board in commercially available machines.

The development of simple-to-use and prognostically validated indices will facilitate defining their prognostic correlates in various patient subsets. It will also enable assessing the feasibility and value of echocardiography-driven therapeutic interventions. These efforts align with ongoing large-scale multicenter studies utilizing force and other indices derived from volumetric echocardiography across diverse patient subsets, ranging from chronic coronary syndromes and ischemia with non-significant coronary artery disease to HCM and HFpEF.

A common underlying hypothesis in all subprojects of SE2030 is that therapy guided by a more precise characterization of the hypercontractile state can enhance the current indications, efficacy, and safety of treatments based on imperfect biomarkers of LV contractility, such as EF or LVOT gradient. So far, there is no standardized definition for the “hypercontractile phenotype”. So, we will introduce different kinds of diseases in hypercontractile state according to various manifestations, such as the intrinsic hypercontractility of myocardium (increased afterload or decreased preload), supra-normal LVEF, and high SV/CO.

Previous reports have shown the adverse effect of the outcome of an increased, supra-normal resting LV function [8, 34, 36, 91, 92] (Table 3). In particular, Wehner et al. [9] described a nadir of risk for LVEF values of 60% to 65%, with a symmetrical increase in risk for EF values > 70% [hazard ratio (HR) 1.71] and < 40% (HR 1.73) in a sizable cohort exceeding 400,000 individuals with established or suspected coronary artery disease assessed through resting TTE. Similar findings were reported by Stewart et al. [92] in a population of close to half a million patients, with a nadir of risk corresponding to EF values of 65–69% (reference group). However, Kondo et al. [33] found no evidence of worse outcomes in patients with supranormal EF in a merged dataset of 336,999 participants. Force is simpler to measure than EF (ESV instead of EDV and ESV), load-independent as opposed to EF, and a pure index of LV contractility rather than a hybrid index of the form (EDV) and function (ESV) as EF. In head-to-head comparisons with EF, force proved to be more effective in distinguishing normal from diseased patients and in predicting outcomes [92].

Patients with HYPER-Phen identified with increased force were more often women and off beta-blockers, consistent with the findings of van Essen et al. [8] among a cohort of individuals experiencing acute HF with supranormal LVEF. In addition, the level of N-terminal pro-brain natriuretic peptide (NT pro-BNP) was significantly elevated although not as high as other types of HF.

The supernormal LV contractile phenotype is a newly recognized state associated with multiple cardiovascular or systemic diseases and increased adverse outcomes. The HYPER-Phen can be described by various noninvasive parameters. The most commonly used traditional systolic parameter, LVEF, is influenced by both preload and afterload, which leads us to seek more reliable and simple metrics with less dependence on loading conditions, such as force as mentioned above. Hypercontractility occurs in some acute and chronic pathophysiological states, and treating the hypercontractile state hinges on identifying the underlying cause, which usually leads to improvement and even resolution of this unstable hemodynamics.