Intracardiac multimorbidity: assessing right ventricular function in left-sided heart failure through cardiopulmonary exercise testing

KEYWORDS:

• Ventilatory efficiency
• peak oxygen consumption
• pulmonary hypertension
• expired gas analysis

1. Introduction

Left-sided heart failure (HF) is a complex chronic syndrome that affects multiple physiologic systems and continues to carry a poor prognosis. In addition to primary pathophysiology, a majority of patients with HF suffer from multimorbidity, defined as the presence of two or more chronic medical conditions; hypertension, dyslipidemia and cardiac arrhythmias are common comorbid conditions in the HF population [1]. Multimorbidity worsens prognosis in patients with HF [2] and new paradigms are needed to more effectively treat HF patients with multimorbidity to improve outcomes [3,4]. Ideally comorbid conditions are identified as early as possible with each condition addressed using guideline-based approaches, treating the ‘whole’ patient [5].

2. Intracardiac multimorbidity in left-sided HF

Left-sided HF, as the name implies, originates from one or several conditions causing left ventricular (LV) dysfunction and diminished systemic cardiac output. As LV dysfunction (e.g., restrictive LV filling pattern, decreased stroke volume, etc.) progressively worsens, in addition to the parallel decline in systemic circulation, there is a retrograde increase in pressure in the pulmonary circulation system, which can lead to pulmonary hypertension (PH), a common occurrence in patients with HF [6]. A highly undesirable consequence of PH in left-sided HF is right ventricular (RV) stress, dysfunction and ultimately failure. Pulmonary hypertension that leads to RV failure is a prognostically ominous development in patients with left-sided HF [7]. Unfortunately there is often a delay in the diagnosis of PH in patients with left-sided HF, which contributes to poorer health outcomes as it allows for unchecked progression toward RV dysfunction and failure [8,9]. These conditions (i.e., LV and RV dysfunction) should each be routinely assessed, and treatment should be titrated to align with up-to-date guideline-based strategies. While there are currently limited treatment options for PH in left-sided HF [7], identification of PH should change the approach to treatment, titrating pharmacology to optimize the balance between RV preload and afterload) [10]. Perhaps we can learn from the concept of and desired approach to multimorbidity to improve clinical outcomes in patients with left-sided HF and PH – viewing LV and RV dysfunction as both intricately linked and separate conditions. In this context, we introduce the concept of intracardiac multimorbidity, treating the left and right ventricle as unique entities whose dysfunction should be viewed as separate conditions. The first step in addressing intracardiac multimorbidity is employing effective examinations that can provide insight into LV and RV function as well as pulmonary hemodynamics. Ideally, patients with left-sided HF are regularly monitored for the possibility of elevated PH, before RV dysfunction and ultimately failure manifests.

3. Diminished exercise capacity in left-sided HF

A hallmark characteristic of left-sided HF is a diminished cardiorespiratory fitness (CRF); as HF disease severity progresses CRF declines further. The gold standard assessment of CRF in patients with left-sided HF is cardiopulmonary exercise testing (CPX) [11]. Peak oxygen consumption (VO₂) and the minute ventilation/carbon dioxide production (VE/VCO₂) slope are primary CPX measures that carry strong prognostic value as well as serve as gauges for disease severity and the response to therapy. The clinical precision of CPX, as well as its non-invasive nature and cost-efficacy, warrants consideration as a front-line assessment in patients with left-sided HF; the clinical value of information obtained from CPX justifies this assessment being performed annually in this patient population [12]. Peak VO₂, as defined by the Fick equation, is primarily driven by left-sided cardiac output. As such, the degree of reduction in peak VO₂ seen in left-sided HF is a surrogate for the degree of LV dysfunction. The link between peak VO₂ and LV function is a primary reason for the consistently demonstrated prognostic value this CPET measure holds in the HF population. A peak VO₂ < 10 mlO₂⋅kg⁻¹⋅min⁻¹, well below the age- and sex-predicted normal value across the lifespan, is particularly ominous in patients with left-sided HF. The VE/VCO₂ slope, a primary measure of what has been described as ventilatory efficiency, reflects the matching between ventilation and perfusion during exercise. In the presence of elevated pulmonary pressure in left-sided HF, pulmonary perfusion lags pulmonary ventilation, resulting in an increase in the VE/VCO₂ slope. A normal VE/VCO₂ slope is defined as a value <30; this value is commonly well surpassed in patients with left-sided HF. In fact, a VE/VCO₂ slope ≥45 portends a significant risk for adverse events and mortality in this patient population. The pathophysiologic mechanism most closely associated with a VE/VCO₂ slope substantially elevated beyond the normal threshold, particularly values ≥45, is PH, which may foretell eminent or ongoing RV dysfunction/failure [13,14]. It should be noted that other abnormal CPX responses, such as a low partial pressure of end-tidal CO₂ during exercise and exercise oscillatory ventilation, also are related to PH and may provide additional clinical insight [15].

4. Using CPX to identify intracardiac multimorbidity

In the context of peak VO₂ and the VE/VCO₂ slope as central measures, CPX can provide insight into intracardiac multimorbidity; peak VO₂ provides an indirect assessment of LV function while the VE/VCO₂ slope provides an indirect assessment of RV function. These two CPX measures should be uniquely assessed and drive distinct diagnostic conclusions and clinical decisions moving forward. For example, a left-sided HF patient with a peak VO₂ of 12 mlO₂⋅kg⁻¹⋅min⁻¹ and a VE/VCO₂ slope of 29 would indicate LV dysfunction without PH and concomitant RV dysfunction. This patient should be prescribed an individually tailored exercise program, similar to those recommended for PAH [16] and have his/her pharmacologic regimen reviewed to ensure optimal evidence-based therapy is being prescribed to minimize stress placed upon the left ventricle [17,18]. Conversely, a left-sided HF patient with a peak VO₂ of 12 mlO₂⋅kg⁻¹⋅min⁻¹ and a VE/VCO₂ slope of 49 is a markedly different clinical presentation. While LV dysfunction and reduced cardiac output to systemic circulation is clear, there is also a strong indication that PH is present, and the right ventricle is under concomitant excess stress. In such a patient, further assessment of pulmonary hemodynamics and RV function would be warranted (e.g., echocardiography and right-sided catheterization), and, if PH is confirmed, all efforts should be made to reduce pulmonary pressure with the goal of reducing excessive RV afterload [10].

In current practice, clinicians often view CPX from a singular point of view, with all measures reflecting the primary pathophysiology of left-sided HF (i.e., LV dysfunction) and thus a singular condition. This results in an incomplete interpretation of CPX data with less than optimal clinical value. If an intracardiac multimorbidity paradigm was adopted and considered in the context of CPX, clinicians would more appropriately assess the unique responses of peak VO₂ and the VE/VCO₂ slope in the left-sided HF population; the former assessing LV function and the latter representing RV function. A reconceptualization of how the left and right side of the heart are viewed, as interwoven yet independent systems, and when compromised, as independent conditions, may help improve clinical interpretation of CPX and clinical decision-making processes thereafter. Figure 1 illustrates this reconceptualization, depicting the right and left sides of the heart as separate entities with the two primary CPX measures in left-sided HF distinctly reflecting function of these separate entities. Moreover, the Ventilatory and Weber Class Systems [11] are also included in Figure 1, placed near the side of the heart they assess. Clinicians responsible for assessing CPX findings and providing a final report to the referring cardiologist should consider the paradigm in Figure 1, commenting on the VE/VCO₂ slope in the context of pulmonary hemodynamics and its implications for RV afterload, dysfunction and failure.

Figure 1. Gear and circuit mechanism illustrating unique roles of the right and left ventricle in the response to exercise.

Legend: O₂, oxygen; VE/VCO₂, minute ventilation/carbon dioxide production; VO₂, oxygen consumption.

5. Conclusion

Left-sided HF, initiated by LV dysfunction, precipitates a cascade of pathophysiologic events that worsen outcome. Pulmonary hypertension is part of this cascade, raising RV afterload and potentially leading to concomitant right-sided HF. In a sense, this scenario may be viewed as intracardiac multimorbidity, two linked but distinct conditions that results in a substantially poorer prognosis and clinical trajectory. All efforts should be made to assess for increased pulmonary pressure and excess RV stress. While several assessments are available and frequently utilized (e.g., echocardiography and right heart catheterization), CPX is the gold-standard exercise assessment as well as a standard of care in patients with left-sided HF. Presently, there is recognition of the value of assessing multiple key CPX variables that reflect unique aspects of exercise physiology particularly relevant to patients with left-sided HF. In the context of detecting intracardiac multimorbidity as described herein, CPX can play an important role in comprehensively evaluating CRF, including the detection of elevated pulmonary pressure and excess RV stress.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Review disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.