Mechanisms of Sinoatrial Node Dysfunction in Heart Failure with Preserved Ejection Fraction

Background: The ability to increase heart rate (HR) during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiologic HR response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. Methods: Dahl salt-sensitive rats fed with a high-salt diet and C57Bl6 mice fed with high fat and an inhibitor of constitutive nitric oxide synthase (L-NAME, 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction (HFrEF). Rats and mice fed with a normal diet or having a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiological studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. Results: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired β-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in HFrEF rats. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca 2+ clock" (spontaneous Ca 2+ release events). The physiological impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. Conclusions: Thus, chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.

Chronotropic Incompetence in Non-Hospitalized Patients with Post-COVID-19 Syndrome

Patients recovering from COVID-19 commonly report persistence of dyspnea, exertional fatigue, and difficulties in carrying out their daily activities. However, the nature of these symptoms is still unknown. The purpose of the study was to identify limiting causes of cardiopulmonary origin for the performance of physical exercise in post-COVID-19 condition that could explain the symptomatic persistence of dyspnea or fatigue-related symptoms. Thirty-two non-hospitalized patients with post-COVID-19 condition (i.e., still presenting a chronic symptomatic phase lasting >90 days since debut of symptoms that lasted for at least 2 months and cannot be explained by an alternative diagnosis) completed a clinical examination including echocardiography, submaximal and maximal cardiorespiratory fitness tests (Ekblom-Bak and Bruce’s protocols), and a battery of validated questionnaires about fatigue and exercise intolerance. Four participants (12.5%) reported an abnormal cardiac response to exercise during the submaximal test, which aroused suspicion of the presence of chronotropic incompetence. All of them were confirmed with a positive diagnosis maximal exercise test after cardiology screening, even with a comprehensive clinical examination, resting ECG, and echocardiogram, without other findings. No statistical differences were found in any physiological variables or questionnaire values, between patients with positive and negative diagnoses. Chronotropic incompetence and other autonomic disorders may appear in patients with mild forms of COVID-19 presentation and may persist in the long term, being responsible for exercise intolerance after resolution of acute infection. Clinicians should be aware that chronotropic incompetence and other autonomic disorders may be a complication of COVID-19 and should consider appropriate diagnostic and therapeutic interventions in these patients, especially when early exercise-related fatigability is reported.

Functional capacity and gender-related differences in Fabry disease

Background Fabry disease (FD) is a rare x-linked lysosomal storage disease characterized by accumulation of glicosphingolipids in several organs, including the heart. Cardiac involvement manifests as left ventricular (LV) hypertrophy, often complicated by myocardial fibrosis. The impact of disease on functional capacity is not well defined, as well as the potential gender-related differences. Aim To evaluate the functional capacity in a cohort of FD patients with different degree of cardiac involvement. Methods Seventy-two patients were prospectively enrolled from March 2015 to December 2019. Patients underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) with cycle ergometer. In addition to standard CPET parameters, Chronotropic Index (CI) was calculated as (HR max − HR rest) / (HR max predicted − HR rest), adjusting with HR max predicted calculated as 119 + (HR rest/2) − (age/2) in case of beta-blockers treatment. Results CMR showed left ventricle (LV) hypertrophy (LV mass greater than normal reference value) in 36.1% of patients, LGE and reduced T1 values were detected in 30.6% and 59.7% of subjects respectively. Twenty-eight patients were males (39%), the median age was 40 (28–54) [median (25th–75th)] years and only 11 (15%) subjects were on beta-blockers. All subjects performed a maximal test [RQ max = 1.21 (1.14–1.26)] using a ramp protocol of 15 (15–20) Watt. The absolute peakVO2 was 18.2 (15.75–24.08) mL/min/kg, whilst the percentage of predicted peakVO2 was 67.7 (57.3–76.6)%. The chronotropic response of the overall population was characterized by reduced peak heart rate (HRmax) [80.3 (73.8–87.6)% of predicted], and diminished chronotropic index (CI) [0.67 (0.55–0.77) normal value: 0.80], but preserved heart rate reserve (HRR) [21 (12–28) bpm]. Ventilatory efficiency was preserved [VE/VCO2 = 25.70 (23.18–28.00)]. At gender analysis, men showed higher absolute peakVO2 [men vs females: 19.95 (17.20–28.28) vs 17.80 (15.50–21.28) mL/min/kg, p=0.02] but lower percentage of predicted [64.24 (52.58–70.61) vs 70.75 (59.05–78.02)%, p<0.001] than females. No differences between genders were observed in chronotropic response [HRmax = 138 (108–154) vs 142 (135–153) bpm, p=0.38; HRR = 22 (13–36) vs 20 (11–26), p=0.097; CI: 0.67 (0.51–0.76) vs 0.67 (0.58–0.79), p=0.33], whilst females showed a lower peak O2 pulse (VO2/HR) than males [men vs females: 12.08 (10.04–13.64) vs 7.76 (6.88–9.22), p<0.001], possibly related to gender differences in LV dimensions and stroke volume. Conclusions This large cohort of FD patients with different degree of cardiac involvement showed a significantly impaired functional capacity, mainly characterized by relevant chronotropic incompetence (independent from the use of beta-blockers), consistent with systemic autonomic dysfunction. The degree of chronotropic incompetence was similar between the genders, but females showed higher predicted peakVO2 despite a lower peak O2 pulse. FUNDunding Acknowledgement Type of funding sources: None.

Prognostic value of heart rate reserve in patients with suspected coronary artery disease undergoing stress myocardial perfusion imaging

Background Chronotropic incompetence is common in patients with cardiovascular disease and is associated with increased risk of adverse events. We assessed the incremental prognostic value of heart rate reserve (HRR) over stress myocardial perfusion single-photon emission computed tomography (MPS) findings in patients with suspected coronary artery disease (CAD). Methods We studied 866 patients with suspected CAD undergoing exercise stress-MPS as part of their diagnostic program. The primary study endpoint was all-cause mortality. All patients were followed for at least 5 years. HRR was calculated as the difference between peak exercise and resting HR, divided by the difference of age-predicted maximal and resting HR and expressed as percentage. Results During 7 years follow-up, 61 deaths occurred, with a 7% cumulative event rate. Patients experiencing death were older (P < .001), and had a higher prevalence of male gender (P < .001) and diabetes (P < .05). Patients with event also had lower values of HRR (65% ± 27% vs 73% ± 18%, P < .0001) and higher prevalence of stress-induced myocardial ischemia (25% vs 8%, P < .0001). Male gender, HRR and stress-induced ischemia were independent predictors of all-cause mortality (all P < .01). HRR improved the prognostic power of a model including clinical data and MPS findings, increasing the global χ2 from 66 to 82 (P < .005). Conclusions Chronotropic incompetence has independent and incremental prognostic value in predicting all-cause mortality in patients with suspected CAD undergoing exercise stress-MPS. Hence, the evaluation of HRR may further improve patients’ risk stratification.

Hemodynamic Heterogeneity of Reduced Cardiac Reserve Unmasked by Volumetric Exercise Echocardiography

Background: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. Purpose: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. Methods: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients (age 59.8 ± 11.4 years; ejection fraction = 63 ± 8%) referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values ≤2.0). Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. Results: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve (odds ratio [OR]: 5.610; 95% confidence intervals [CI]: 4.025 to 7.821), chronotropic incompetence (OR: 3.923, 95% CI: 2.915 to 5.279), and abnormal LVCR (OR: 1.579; 95% CI: 1.105 to 2.259) were independently associated with lowest tertile of cardiac index reserve at peak stress. Conclusions: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.

Prognostic value of heart rate reserve in patients with suspected coronary artery disease undergoing stress myocardial perfusion imaging

Funding Acknowledgements Type of funding sources: None. Background. The prognostic value of stress myocardial perfusion single-photon emission computed tomography (MPS) has been widely demonstrated. Also, chronotropic incompetence, evaluated by heart rate reserve (HRR) is associated with increased risk of adverse events. Yet, the incremental prognostic value of HRR over stress MPS data has not been fully investigated. Purpose. To assess the incremental prognostic value of HRR over stress MPS finding in patients with suspected coronary artery disease (CAD) undergoing exercise stress MPS. Methods. The study population consisted of 866 consecutive patients with suspected CAD undergoing exercise stress-MPS at University of Naples Federico II, between May 2002 and January 2014 as part of their diagnostic program. The primary study endpoint was all-cause mortality. All patients were followed for at least 60 months. HRR was calculated as the difference between peak exercise and resting HR, divided by the difference of age-predicted maximal and resting HR and expressed as percent. The summed difference score (SDS) was considered an index of ischemic burden. Patients were considered to have mild ischemia with a SDS of 2 to 6, and moderate-severe ischemia with a SDS ≥6. During follow-up, the occurrence of all-cause of deaths was noted and considered as event. Follow-up was censored at 84 months. Results. During follow-up, 61 deaths occurred, with a 7% cumulative event rate. Patients experiencing death were older (56.2 ± 10.7 years vs. 66.4 ± 8.6 years), with a higher prevalence of male gender (56% vs. 87 %, P &lt; 0.05) and diabetes mellitus (23% vs. 36%, P &lt; 0.05). At stress-MPS, patients with event had lower mean values of HRR (53.2 ± 21.3% vs. 61.5 ± 16.4%, P &lt; 0.0001) and higher prevalence of moderate-severe ischemia (24% vs. 8%, P &lt; 0.0001). The best trade-off between sensitivity and specificity for identifying chronotropic incompetence was a HRR &lt;67% with an area under the receiver operating characteristic curve of 0.62. The event free survival was lower in patients with HRR &lt;67% compared to those with HRR ≥67% (log-rank 9.75, P &lt; 0.005). Accordingly, the annualized event rate was 0.006 in patients with HRR &lt;67% and 0.014 in those with HRR ≥67% (P &lt; 0.001). At Cox regression analysis, univariable predictors of all-cause mortality were age, male gender, diabetes mellitus, HRR and moderate-severe ischemia (all P &lt; 0.05). At multivariable analysis age, male gender, HRR and moderate-severe ischemia were independent predictors of all-cause mortality (all P &lt; 0.05). HRR improved the prognostic power of a model including clinical data and MPS findings for the prediction of all-cause mortality, increasing the global chi-square from 76.16 to 82.68 (P &lt; 0.005). Conclusion. Chronotropic incompetence assessed by HRR evaluation, has independent and incremental prognostic value in predicting all cause of death in patients with suspected CAD undergoing exercise stress-MPS.