Peter L. M. Kerkhof

Left ventricular volume regulation in heart failure with preserved ejection fraction

Ejection Fraction (EF) has attained the recognition as indicator of global ventricular performance. Remarkably, precise historical origins promoting the apparent importance of EF are scant. During early utilization EF has been declared a gold standard for the evaluation of the heart as a pump. In contrast, during the last two decades, clinicians have developed a measure of doubt in the universal applicability of EF. This reluctance lead to the introduction of a new and prevalent syndrome in which heart failure (HF) is diagnosed as having a preserved EF (pEF). We examine the existing criticism regarding EF, and describe a novel avenue to characterize ventricular function within the unifying framework of cardiac input–output volume regulation. This approach relates end‐systolic volume (ESV) to end‐diastolic volume (EDV), and derives for a subgroup matching pEF criteria a distinct pattern in the ESV–EDV domain. In patients with pEF (n = 34), a clear difference (P < 0.0004) in the slope of the regression line for ESV versus EDV was demonstrated compared to control patients with EF < 50% (n = 29). These findings are confirmed by analysis of data presented in two independent publications. The volume regulation approach proposed employs primary end‐point determinants (such as ESV and EDV) rather than derived quantities (e.g., the ratio EF or its differential parameter, that is, stroke volume) and confirms a distinct advantage over the classical Starling curve. Application of the ESV‐EDV‐construct provides the basis and clarifies why some patients present as HFpEF, while others have reduced EF.

Exploring Guidelines for Classification of Major Heart Failure Subtypes by Using Machine Learning

Background Heart failure (HF) manifests as at least two subtypes. The current paradigm distinguishes the two by using both the metric ejection fraction (EF) and a constraint for end-diastolic volume. About half of all HF patients exhibit preserved EF. In contrast, the classical type of HF shows a reduced EF. Common practice sets the cut-off point often at or near EF = 50%, thus defining a linear divider. However, a rationale for this safe choice is lacking, while the assumption regarding applicability of strict linearity has not been justified. Additionally, some studies opt for eliminating patients from consideration for HF if 40 < EF < 50% (gray zone). Thus, there is a need for documented classification guidelines, solving gray zone ambiguity and formulating crisp delineation of transitions between phenotypes. Methods Machine learning (ML) models are applied to classify HF subtypes within the ventricular volume domain, rather than by the single use of EF. Various ML models, both unsupervised and supervised, are employed to establish a foundation for classification. Data regarding 48 HF patients are employed as training set for subsequent classification of Monte Carlo–generated surrogate HF patients (n = 403). Next, we map consequences when EF cut-off differs from 50% (as proposed for women) and analyze HF candidates not covered by current rules. Results The training set yields best results for the Support Vector Machine method (test error 4.06%), covers the gray zone, and other clinically relevant HF candidates. End-systolic volume (ESV) emerges as a logical discriminator rather than EF as in the prevailing paradigm. Conclusions Selected ML models offer promise for classifying HF patients (including the gray zone), when driven by ventricular volume data. ML analysis indicates that ESV has a role in the development of guidelines to parse HF subtypes. The documented curvilinear relationship between EF and ESV suggests that the assumption concerning a linear EF divider may not be of general utility over the complete clinically relevant range.

Quantifying ventricular fibrillation: in silico research and clinical implications

Cardiovascular disease remains the leading cause of death in otherwise healthy humans. In particular, most cases of sudden cardiac death occur as a result of failure of the mechanical function of the heart which is triggered by a turbulent pattern of electrical excitation of the heart e.g., ventricular fibrillation (VF). Although the exact mechanisms of VF remain unknown, increasing evidence indicates that it is organized by multiple reentrant sources (wavelets).

Ejection fraction as related to basic components in the left and right ventricular volume domains

BACKGROUND Ejection fraction (EF) is commonly applied as a clinically relevant metric to assess ventricular function. The numerical value of EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). Remarkably, the relative impact of the two constitutive components on EF received little attention. METHODS Three patient groups not using beta-blockers were analyzed for a robust investigation into the relative contribution of ESV and EDV when assessing EF: cardiac patients (N=155) with left ventricular (LV) data obtained by biplane ventriculography, near-normals (N=276) by gated SPECT investigation, and an MRI-based post Fallot repair study including right ventricular (RV) data (N=124), besides LV. We compared various routes to evaluate EF via linear and several types of nonlinear regression with ESV as independent variable. Advanced statistics was applied to evaluate sex-specific differences. RESULTS In all cases ESV emerges as the dominant component of EF, with less (P<0.0001) impact of EDV. The relationship for EF versus ESV is nonlinear (P<0.0001), and similar for both sexes. A linear approach may be inadequate and generate erroneous statistical outcomes when comparing subgroups of patients. CONCLUSIONS Values for EF primarily depend on ESV, both for LV and RV. This relationship is essentially nonlinear, and similar for both sexes. A logarithmic approximation is convenient and often acceptable. However, application of linear regression for EF vs ESV may lead to incorrect conclusions, particularly when comparing males and females.

Left ventricular volume analysis as a basic tool to describe cardiac function

The heart is often regarded as a compression pump. Therefore, determination of pressure and volume is essential for cardiac function analysis. Traditionally, ventricular performance was described in terms of the Starling curve, i.e., output related to input. This view is based on two variables (namely, stroke volume and end-diastolic volume), often studied in the isolated (i.e., denervated) heart, and has dominated the interpretation of cardiac mechanics over the last century. The ratio of the prevailing coordinates within that paradigm is termed ejection fraction (EF), which is the popular metric routinely used in the clinic. Here we present an insightful alternative approach while describing volume regulation by relating end-systolic volume (ESV) to end-diastolic volume. This route obviates the undesired use of metrics derived from differences or ratios, as employed in previous models. We illustrate basic principles concerning ventricular volume regulation by data obtained from intact animal experiments and collected in healthy humans. Special attention is given to sex-specific differences. The method can be applied to the dynamics of a single heart and to an ensemble of individuals. Group analysis allows for stratification regarding sex, age, medication, and additional clinically relevant covariates. A straightforward procedure derives the relationship between EF and ESV and describes myocardial oxygen consumption in terms of ESV. This representation enhances insight and reduces the impact of the metric EF, in favor of the end-systolic elastance concept advanced 4 decades ago.

Hemodynamic determinants and ventriculo-arterial coupling are sex-associated in heart failure patients

End-systolic volume (ESV) and end-diastolic volume (EDV) are key parameters in the analysis of left ventricular (LV) function, and the study of cardiac remodeling. The volume regulation graph (VRG) relates these fundamental determinants, and permits convenient stratification for clinically relevant covariates. This contribution analyzes sex-associated differences in hemodynamic parameters for 197 heart failure (HF) patients, evaluated by biplane ventriculography, in combination with arterial pressure. We calculated LV parameters such as stroke volume (SV), cardiac output (CO), ESV, EDV, ejection fraction (EF), end-systolic elastance (Emax), besides arterial parameters: effective arterial elastance (Ea), elastance ratio (the coupling index k), peripheral resistance (Rs), pulse pressure (PP), and arterial compliance (C), all normalized for body surface area when appropriate. Average values for heart rate, SV, CO, Ea, C, Rs are similar between the sexes, as are the VRG regression lines. However, ESV and EDV are significantly (P<;0.034 and P<;0.016, respectively) smaller in women (N=67), whereas EF, Emax, mean arterial pressure, PP, and k are higher (P<;0.008 or less). We conclude that the various sex-associated differences observed in these HF patients are striking, and thus require due attention when evaluating the clinical status of HF patients. Formulation of distinct cut-off values for male and female patients with HF seems warranted, when considering specific HF phenotypes.

On tubes, strings, and resonance in the arterial system-what makes the beat go on?

In conclusion, Wang et al. propose a challenging concept of energy transfer which is inherently consistent with the basic constitutive relations of fluid flow in elastic tubes. However, some of the basic parameters which underlie the natural frequency of the arterial system and current matching concepts need further investigation and in vivo experimental validation. Furthermore, the present fundamental discussion offers a convincing example of how investigations in the field of classical hemodynamics continue to form a scientific challenge, in addition to controversies related to newer fields such as molecular biology.

Arterial Flow, Pulse Pressure and Pulse Wave Velocity in Men and Women at Various Ages

The increase in pulse pressure (PP) that occurs with advancing age is predominantly due to reduced arterial distensibility leading to decreased aortic compliance, particularly in the elderly, in whom high blood pressure mainly manifests as isolated systolic hypertension. Since age-related changes in stroke volume are minimal compared with changes in PP, PP is often considered a surrogate measure of arterial stiffness. However, since PP is determined by both cardiac and arterial function, a more precise and reliable means of assessment of arterial stiffness is arterial pulse wave velocity (PWV), a parameter that is only dependent on arterial properties. Arterial stiffness as measured by PWV has been found to be a powerful pressure-related indicator for cardiovascular morbidity and mortality. We analyzed PP and PWV in men and women of various age groups in healthy volunteers as well as cardiac patients with different types of diseases. The findings identified several striking sex-specific differences which demand consideration in guidelines for diagnostic procedures, for epidemiological analysis, and in evaluation of therapeutic interventions.

Women and Men in the History of Western Cardiology: Some Notes on Their Position as Patients, Role as Investigational Study Subjects, and Impact as Professionals

Nowadays, it is generally appreciated that studies in the medical field should not only include sex-related aspects but also consider age. In the past, taking the era of Hippocrates as a starting point for the Western medical sciences, such aspects were less urgent and barely relevant. However, considering such details during daily life became increasingly important as the traditional roles of men and women in society and household converged. In the Western world, this fundamental transition process started recently and is advancing at an accelerated pace. Research about the role of women has also evolved, starting from plain history about the lives of women to a description of the relation between men and women, resulting in the gender concept. The present survey highlights a historical selection of observations referring to the impact of men and women on the medical sciences, as patient, study object, and professional. Whenever relevant, focus will be on the field of cardiovascular investigations as documented in the Western world. Rather than being exhaustive, we focus on a few remarkable icons, including Trota of Salerno, Hildegard von Bingen, and Miguel Serveto.

Cardiovascular Implications of Diabetes, Metabolic Syndrome, Thyroid Disease, and Cardio-Oncology in Women

Cardiovascular disease may be associated with several comorbidities, including diabetes mellitus, thyroid disorders, and the metabolic syndrome, which are predominantly observed in women and often starting at particular ages. In addition, common treatment options for carcinomas frequently seen in women may induce serious cardiotoxic effects. We review the scope of the problem, the pathophysiologic mechanisms involved, as well as the resulting abnormalities regarding cardiac structure and function as observed by using imaging techniques.