The Prognostic Utility of Heart Rate and Blood Pressure Response to Regadenoson Stress.

BACKGROUND: Although heart rate response (HRR) to regadenoson stress has been shown to be a strong predictor of outcome, it has not been investigated in a large all-comers cohort. The prognostic utility of systolic blood pressure response (SBPR) has not been investigated in comparison to HRR. METHODS AND RESULTS: In a retrospective cohort of 10,227 patients undergoing regadenoson stress SPECT myocardial perfusion imaging (MPI), HRR, and SBPR were calculated as 100*(Peak hyperemia value-Baseline value)/Baseline value. During 35±21 months follow-up, 921 (8.8%) deaths were observed. The median HRR was 35% (Interquartile range [IQR], 21% to 51%). The median SBPR was -9% (IQR, -17% to -2%). HRR and SBPR were independently associated with all-cause mortality with adjusted hazard ratio [HR] of 0.980 per 1% increment in HRR (CI, 0.977-0.984) and 0.994 per 1% increment in SBPR (CI, 0.988-0.999). Mortality rates increased with decreasing HRR quartile and SBPR tertile. HRR provided incremental prognostic value for all-cause mortality beyond clinical and imaging parameters (area under the curve [AUC] increase, 0.03; P<0.001) and SBPR data (AUC increase, 0.11; P<0001). SBPR did not provide significant incremental prognostic value beyond clinical and imaging parameters or HRR data. We derived and validated HRR of < 20% as a cutoff that can improve risk stratification beyond clinical and MPI findings. CONCLUSION: Among patients undergoing stress MPI, impaired HRR to regadenoson provided independent and incremental prognostic value for all-cause mortality beyond clinical, imaging, and SBPR data. SBPR positively correlates with HRR, but it does not provide incremental prognostic utility. HRR, but not SBPR, should be routinely reported and considered in assessing patients' overall risk. An abnormal HRR threshold of < 20% can improve risk stratification.

Abnormal heart rate responses to exercise in non-severe COPD: relationship with pulmonary vascular volume and ventilatory efficiency.

BACKGROUND: Despite being a prognostic predictor, cardiac autonomic dysfunction (AD) has not been well investigated in chronic obstructive pulmonary disease (COPD). We aimed to characterise computed tomography (CT), spirometry, and cardiopulmonary exercise test (CPET) features of COPD patients with cardiac AD and the association of AD with CT-derived vascular and CPET-derived ventilatory efficiency metrics. METHODS: This observational cohort study included stable, non-severe COPD patients. They underwent clinical evaluation, spirometry, CPET, and CT. Cardiac AD was determined based on abnormal heart rate responses to exercise, including chronotropic incompetence (CI) or delayed heart rate recovery (HRR) during CPET. RESULTS: We included 49 patients with FEV1 of 1.2-5.0 L (51.1-129.7%), 24 (49%) had CI, and 15 (31%) had delayed HRR. According to multivariate analyses, CI was independently related to reduced vascular volume (VV; VV ≤ median; OR [95% CI], 7.26 [1.56-33.91]) and low ventilatory efficiency (nadir VE/VCO2 ≥ median; OR [95% CI], 10.67 [2.23-51.05]). Similar results were observed for delayed HRR (VV ≤ median; OR [95% CI], 11.46 [2.03-64.89], nadir VE/VCO2 ≥ median; OR [95% CI], 6.36 [1.18-34.42]). CONCLUSIONS: Cardiac AD is associated with impaired pulmonary vascular volume and ventilatory efficiency. This suggests that lung blood perfusion abnormalities may occur in these patients. Further confirmation is required in a large population-based cohort.

Effects of childhood obesity on myocardial performance, autonomic and conduction properties of the heart.

BACKGROUND: Childhood obesity tends to persist into adulthood and associated with increase in developing ischemic and non-ischemic cardiovascular diseases. We aimed to evaluate the effect of obesity on cardiac functions, atrial electromechanical coupling, and heart rate response, which are considered to be predictors of atrial fibrillation and sudden cardiac arrest. METHODS: Study population included 52 obese children and 52 healthy controls. We performed 12-lead electrocardiography, echocardiographic examination, and treadmill exercise testing. Mitral, septal, and tricuspid segments were analysed by tissue Doppler imaging. RESULTS: Myocardial performance index (p = 0.011, p < 0.001, and p = 0.001, respectively) was higher and E'/A' ratio (p = 0.011, p < 0.001, and p < 0.001, respectively) was lower in obese group than controls. Atrial electromechanical coupling was longer in the obese group at all three segments (p < 0.001, p = 0.009, and p = 0.04, respectively). They had significantly longer interatrial (p < 0.001) and intra-atrial (p = 0.003) electromechanical conduction delay. While chronotropic index was similar between two groups, heart rate reserve was lower in obese children than controls (p = 0.043). The 1st- and 2nd-minute heart rate recovery indices of the obese group were lower compared to controls (p < 0.001 and p = 0.03, respectively). Body mass index was positively correlated with intra- and inter-atrial conduction times, whereas it was negatively correlated with heart rate recovery indices. CONCLUSION: We showed a deterioration in the diastolic function, atrial conduction, and heart rate response properties in children with obesity. Given the prognostic importance of these parameters, obese patients are might be at risk for atrial fibrillation and severe dysrhythmias from a young age.

Association of CETP Gene Polymorphisms and Haplotypes with Acute Heart Rate Response to Exercise.

Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity is closely related to individual cardiovascular health. This study aimed to investigate the effect of CETP gene polymorphisms on AHRR. Our analysis examines the association of five single nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene with AHRR in 607 people from the Hungarian population. Individual AHRR in the present study was assessed using the YMCA 3-min step test and was estimated as the difference between resting and post-exercise heart rate, i.e., delta heart rate (ΔHR). To exclude the direct confounding effect of the CETP gene on the lipid profile, adjustments for TG and HDL-C levels, next to conventional risk factors, were applied in the statistical analyses. Among the examined five SNPs, two showed a significant association with lower ΔHR (rs1532624-Cdominant: B = -8.41, p < 0.001; rs708272-Gdominant: B = -8.33, p < 0.001) and reduced the risk of adverse AHRR (rs1532624-Cdominant: OR = 0.44, p = 0.004; rs708272-Gdominant: OR = 0.43, p = 0.003). Among the ten haplotypes, two showed significant association with lower ΔHR (H3-CAGCA: B = -6.81, p = 0.003; H9-CGGCG: B = -14.64, p = 0.015) and lower risk of adverse AHRR (H3-CAGCA: OR = 0.58, p = 0.040; H9-CGGCG: OR = 0.05, p = 0.009) compared to the reference haplotype (H1-AGACG). Our study is the first to report a significant association between CETP gene polymorphisms and AHRR. It also confirms that the association of the CETP gene with cardiovascular risk is mediated by changes in heart rate in response to physical activity, in addition to its effect on lipid profile.

Genetic Background of Acute Heart Rate Response to Exercise.

The acute heart rate response (AHRR) to physical activity, which refers to the change in heart rate during and after exercise, has been associated with cardiovascular and all-cause mortality. Previous studies have shown that AHRR is significantly determined by genetics in addition to environmental and lifestyle factors. The aim of this study was to investigate the genetic background of AHRR by analysing ten single nucleotide polymorphisms (SNPs) associated with leisure-time physical activity (LTPA) in 620 samples from the Hungarian population. The AHRR can be characterised as the difference between post-exercise and resting heart rate, i.e., the delta heart rate (ΔHR) defined by the YMCA 3 min step test, with a lower value indicating better cardiovascular fitness. The association of SNPs with ΔHR was analysed both separately and in combination using an optimised polygenic score (oPGS). The results showed that five SNPs (rs10252228, rs459465, rs6022999, rs8097348, and rs12405556) had at least nominally significant (p < 0.05) individual associations with ΔHR. After optimizing the PGS, a cumulative effect was observed for eight SNPs (rs6022999, rs12405556, rs459465, rs10252228, rs8097348, rs10887741, rs12612420, and rs7023003) that had a strong and statistically significant association with ΔHR (B = -2.51, 95% CI: -3.46--1.76; p = 2.99 × 10-9). Of the four main domains of physical activity, the oPGS showed a significant positive association only with LTPA (B = 84.60; 95%CI: 25.23-143.98; p = 0.005). In conclusion, our results suggest that the SNPs we investigated influence individual leisure-time physical activity, mediated by their effects on the acute heart rate response.

Autonomic dysfunction after mild acute ischemic stroke and six months after: a prospective observational cohort study.

INTRODUCTION: Autonomic dysfunction is prevalent in ischemic stroke patients and associated with a worse clinical outcome. We aimed to evaluate autonomic dysfunction over time and the tolerability of the head-up tilt table test in an acute stroke setting to optimize patient care. PATIENTS AND METHOD: In a prospective observational cohort study, patients were consecutively recruited from an acute stroke unit. The patients underwent heart rate and blood pressure analysis during the Valsalva maneuver, deep breathing, active standing, and head-up tilt table test if active standing was tolerated. In addition, heart rate variability and catecholamines were measured. All tests were performed within seven days after index ischemic stroke and repeated at six months follow-up. RESULTS: The cohort was comprised of 91 acute stroke patients, mean (SD) age 66 (11) years, median (IQR) initial National Institute of Health Stroke Scale 2 (1-4) and modified Ranking Scale 2 (1-3). The head-up tilt table test revealed 7 patients (10%) with orthostatic hypotension. The examination was terminated before it was completed in 15%, but none developed neurological symptoms. In the acute state the prevalence of autonomic dysfunction varied between 10-100% depending on the test. No changes were found in presence and severity of autonomic dysfunction over time. CONCLUSION: In this cohort study of patients with mild stroke, autonomic dysfunction was highly prevalent and persisted six months after index stroke. Head-up tilt table test may be used in patients who tolerate active standing. Autonomic dysfunction should be recognized and handled in the early phase after stroke.

Cardiovascular Benefit of Continuous Positive Airway Pressure in Adults with Coronary Artery Disease and Obstructive Sleep Apnea without Excessive Sleepiness.

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Objectives: Here, in this post hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; nCPAP:ncontrol = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). Measurements and Main Results: The CPAP-related reduction in risk increased progressively with increasing pretreatment ΔHR (interaction hazard ratio [95% confidence interval], 0.49 [0.27 to 0.90] per SD increase in ΔHR; P < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) (P < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

The Sleep Apnea-Specific Pulse-Rate Response Predicts Cardiovascular Morbidity and Mortality.

Rationale: Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with a heightened pulse-rate response to apneas and hypopneas (ΔHR). Methods: We measured the ΔHR in the MESA (Multi-Ethnic Study of Atherosclerosis) (N = 1,395) and the SHHS (Sleep Heart Health Study) (N = 4,575). MESA data were used to determine the functional form of the association between the ΔHR and subclinical cardiovascular biomarkers, whereas primary analyses tested the association of the ΔHR with nonfatal or fatal cardiovascular disease (CVD) and all-cause mortality in longitudinal data from the SHHS. Measurements and Main Results: In the MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium, NT-proBNP [N-terminal prohormone BNP], and Framingham risk score) and the ΔHR; notably, a high ΔHR (upper quartile) was associated with elevated biomarker scores compared with a midrange ΔHR (25th-75th centiles). In the SHHS, individuals with a high ΔHR compared with a midrange ΔHR were at increased risk of nonfatal or fatal CVD and all-cause mortality (nonfatal adjusted hazard ratio [95% confidence interval (CI)], 1.60 [1.28-2.00]; fatal adjusted hazard ratio [95% CI], 1.68 [1.22-2.30]; all-cause adjusted hazard ratio [95% CI], 1.29 [1.07-1.55]). The risk associated with a high ΔHR was particularly high in those with a substantial hypoxic burden (nonfatal, 1.93 [1.36-2.73]; fatal, 3.50 [2.15-5.71]; all-cause, 1.84 [1.40-2.40]) and was exclusively observed in nonsleepy individuals. Conclusions: Individuals with OSA who demonstrate an elevated ΔHR are at increased risk of cardiovascular morbidity and mortality. This study identifies a prognostic biomarker for OSA that appears useful for risk stratification and patient selection for future clinical trials.

Renal Functional Reserve Is Related to the Nondipping Phenotype and to the Exercise Heart Rate Response in Patients with Essential Hypertension and Preserved Renal Function.

BACKGROUND: Renal functional reserve (RFR), defined as the difference between stress and resting glomerular filtration rate (GFR), may constitute a diagnostic tool to identify patients at higher risk of developing acute kidney injury or chronic kidney disease. Blunted RFR has been demonstrated in early stages of hypertension and has been attributed to impaired vascular reactivity due to an overactive sympathetic nervous system (SNS). OBJECTIVE: The purpose of this study was to investigate whether RFR correlates with other phenotypes expressing overactivity of the SNS in patients with essential hypertension and preserved renal function. METHODS: Thirty-six patients with untreated essential hypertension and a GFR >60 mL/min/1.73 m2 were enrolled. The following parameters were measured: RFR, 24-h ambulatory blood pressure (BP) profile, a treadmill stress test, and an echocardiographic examination. Urine and venous samples were obtained at specific time points for the determination of clinical parameters, and both resting and stress GFR were calculated by using endogenous creatinine clearance for the measurement of RFR after an acute oral protein load (1 g/kg). RESULTS: Twenty-one patients had a RFR <30 mL/min/1.73 m2 and 15 had a RFR above this cutoff. A nondipping pattern of 24-h BP was significantly more frequent in patients with low RFR (57.1 vs. 25.0%, p < 0.05 for systolic BP and 52.3 vs. 10.0%, p < 0.02 for diastolic BP). Moreover, patients with lower RFR values showed a blunted heart rate (HR) response to exercise during treadmill test (r = 0.439, p < 0.05). None of the echocardiographic parameters differed between the two groups of patients. CONCLUSIONS: In hypertensive patients with preserved GFR, reduced RFR is related to nondipping BP phenotype as well as to attenuated exercise HR response. Overactivity of the SNS may be a common pathway. Since loss of RFR may represent a risk factor for acute or chronic kidney injury, hypertensive patients with blunted RFR might need a more careful renal follow-up.

Gender-related differences in side-effects and hemodynamic response to regadenoson in patients undergoing SPECT myocardial perfusion imaging.

PURPOSE: To evaluate differences in side-effects and hemodynamic response between men and women undergoing regadenoson-stress SPECT myocardial perfusion imaging (MPI). METHODS: The initial population of the study included 858 consecutive patients who underwent regadenoson-stress MPI at our institution. These patients underwent prospective assessment and classification of regadenoson-induced side-effects in six categories and recording of heart rate (HR) and blood pressure (BP) before and after regadenoson administration. From this initial population, after adjustment with 1:1 propensity matching using gender as the dependent variable and age, BMI, diabetes mellitus, hypertension, smoking, presence of coronary artery disease, LVEF, baseline systolic and diastolic blood pressure (BP) and HR, on-going use of cardio-active medications during test, and abnormal MPI scan as independent variables, a population of 279 pairs of opposite gender was formed and studied. RESULTS: Compared with men, women had a significantly higher rate of any side-effect (71% vs. 58%, p = 0.002), chest pain (23% vs. 12%, p < 0.001), gastrointestinal discomfort (20% vs. 12%, p = 0.01), dizziness (12% vs. 5%, p = 0.002), and headache (20% vs. 13%, p = 0.03) and similar rates of dyspnea and other side-effects. Women demonstrated a higher median HR-response compared with men (41% (- 8, 127) vs. 34% (- 5, 106), p = 0.001) while men demonstrated a lower median systolic BP response (- 3% (- 27, 48) vs. 0% (- 36, 68), p = 0.02) compared with women. CONCLUSIONS: Gender is independently associated with a differential response to regadenoson with regard to overall side-effects and HR-response. These observations have the potential of important management and prognostic implications respectively.

Heart rate reserve is a long-term risk predictor in women undergoing myocardial perfusion imaging.

BACKGROUND: Although women with cardiovascular disease experience relatively worse outcomes as compared to men, substantial knowledge gaps remain regarding the unique female determinants of cardiovascular risk. Heart rate (HR) responses to vasodilator stress mirror autonomic activity and may carry important long-term prognostic information in women. METHODS AND RESULTS: Hemodynamic changes during adenosine stress were recorded in a total of 508 consecutive patients (104 women) undergoing clinically indicated 13N-ammonia Positron-Emission-Tomography (PET) at our institution. Following propensity matching, 202 patients (101 women, mean age 61.3 ± 12.6 years) were analyzed. During a median follow-up of 5.6 years, 97 patients had at least one cardiac event, including 17 cardiac deaths. Heart rate reserve (% HRR) during adenosine infusion was significantly higher in women as compared to men (23.8 ± 19.5 vs 17.3 ± 15.3, p = 0.009). A strong association between 10-year cardiovascular endpoints and a blunted HRR was observed in women, while this association was less pronounced in men. Accordingly, in women, but not in men, reduced HRR was selected as a strong predictor for adverse cardiovascular events in a Cox regression model fully adjusted for imaging findings and traditional risk factors (HR 2.41, 95% CI 1.23-4.75, p = 0.011). Receiver operating characteristics (ROC) curves revealed that a blunted HRR <21% was a powerful predictor for MACE in women with a sensitivity of 77% and a specificity of 68%. CONCLUSION: Blunted HRR to adenosine stress adds incremental prognostic value for long-term cardiovascular outcomes in women beyond that provided by traditional risk factors and imaging findings.

The prognostic value of heart rate response during vasodilator stress myocardial perfusion imaging in patients with end-stage renal disease undergoing renal transplantation.

BACKGROUND: In asymptomatic end-stage renal disease (ESRD) patients undergoing vasodilator stress myocardial perfusion imaging (MPI) prior to renal transplantation (RT), the impact of pre-transplant heart rate response (HRR) to vasodilator stress on post-RT outcomes is unknown. METHODS: We analyzed a retrospective cohort of asymptomatic patients with ESRD who underwent a vasodilator stress SPECT-MPI and subsequently received RT. Blunted HRR was defined as HRR <28% for regadenoson stress and <20% for adenosine stress. The primary endpoint was major adverse cardiac events (MACE), defined as cardiac death or myocardial infarction. Clinical risk was assessed using the sum of risk factors set forth by the AHA/ACCF consensus statement on the assessment of RT candidates. RESULTS: Among 352 subjects, 140 had an abnormal pre-transplant HRR. During a mean follow-up of 3.2 ± 2.0 years, 85 (24%) MACEs were observed. Blunted HRR was associated with increased MACE risk (hazard ratio 1.72; 95% confidence interval 1.12-2.63, P = 0.013), and remained significant after adjustment for gender, sum of AHA/ACCF risk factors, summed stress score, baseline heart rate, and ß-blocker use. HRR was predictive of MACE in patients with normal MPI and irrespective of clinical risk. Blunted HRR was associated with a significant increase in post-operative (30-day) MACE risk (17.9% vs 8.5%; P = 0.009). CONCLUSION: In asymptomatic ESRD patients being evaluated for RT, a blunted pre-transplant HRR was predictive of post-RT MACE. HRR may be a valuable tool in the risk assessment of RT candidates.

Effect of carvedilol on heart rate response to cardiopulmonary exercise up to the anaerobic threshold in patients with subacute myocardial infarction.

Resting heart rate (HR) plus 20 or 30 beats per minute (bpm), i.e., a simplified substitute for HR at the anaerobic threshold (AT), is used as a tool for exercise prescription without cardiopulmonary exercise testing data. While resting HR plus 20 bpm is recommended for patients undergoing beta-blocker therapy, the effects of specific beta blockers on HR response to exercise up to the AT (ΔAT HR) in patients with subacute myocardial infarction (MI) are unclear. This study examined whether carvedilol treatment affects ΔAT HR in subacute MI patients. MI patients were divided into two age- and sex-matched groups [carvedilol (+), n = 66; carvedilol (-), n = 66]. All patients underwent cardiopulmonary exercise testing at 1 month after MI onset. ΔAT HR was calculated by subtracting resting HR from HR at AT. ΔAT HR did not differ significantly between the carvedilol (+) and carvedilol (-) groups (35.64 ± 9.65 vs. 34.67 ± 11.68, P = 0.604). Multiple regression analysis revealed that old age and heart failure after MI were significant predictors of lower ΔAT HR (P = 0.039 and P = 0.013, respectively), but not carvedilol treatment. Our results indicate that carvedilol treatment does not affect ΔAT HR in subacute MI patients. Therefore, exercise prescription based on HR plus 30 bpm may be feasible in this patient population, regardless of carvedilol use, without gas-exchange analysis data.

Impact of integrating heart rate response with perfusion imaging on the prognostic value of regadenoson SPECT myocardial perfusion imaging in patients with end-stage renal disease.

BACKGROUND: We investigated whether integrating heart rate response (HRR) to regadenoson with myocardial perfusion imaging (MPI) analysis can enhance risk prediction in end-stage renal disease (ESRD) patients. METHODS AND RESULTS: We prospectively followed 303 ESRD patients after regadenoson stress MPI for a mean of 35 months. Normal HRR to regadenoson was defined as ≥28% increase from baseline. Normal MPI was defined as a summed stress score ≤3 and left ventricular ejection fraction ≥50%. The study cohort was divided in four groups based on various combinations of normal/abnormal HRR and MPI. There was a step-wise increase in the risk of primary endpoint of all-cause death and the composite secondary endpoint of cardiac death or myocardial infarction; patients with Normal MPI/Normal HRR had the lowest event rates and those with Abnormal MPI/Abnormal HRR had the highest, whereas subjects with Abnormal MPI/Normal HRR and Normal MPI/Abnormal HRR had intermediate event rates. This pattern was maintained after adjusting for important clinical covariates. CONCLUSION: In ESRD patients, integrating HRR to vasodilator stress with MPI interpretation improves risk stratification. Normal HRR/Normal MPI identify truly low-risk group, whereas abnormal MPI or abnormal HRR portrays elevated risk.

The reproducibility and prognostic value of serial measurements of heart rate response to regadenoson during myocardial perfusion imaging.

PURPOSE: The heart rate response (HRR, percentage change from baseline) to regadenoson during myocardial perfusion imaging (MPI) can provide incremental prognostic value in patients with known or suspected coronary artery disease. Our purpose was to evaluate the variability and prognostic value of HRR on serial measurements. METHODS: We studied 648 consecutive patients (61 ± 11 years, 48 % with diabetes) who underwent two regadenoson MPI studies (16 ± 9 months between studies). HRR <30 % was defined as abnormal. All-cause mortality was determined by chart review and verified using the US Social Security Death Master File. RESULTS: HRR was well correlated between the two studies (intraclass correlation coefficient 0.72, 95 % CI 0.67 - 0.76) with no systematic bias (mean difference 0.88 %, p = 0.2) or proportional bias (p = 0.5) by Bland-Altman analysis in all patients and in those with normal MPI on both studies. Of the 308 patients (48 %) with normal baseline HRR (HRR-1), 33 % had developed a blunted HRR on the second MPI study (HRR-2). Older age, male gender, end-stage renal disease, and abnormal baseline left ventricular ejection fraction were independent predictors of a new-onset abnormal HRR. During a mean follow-up of 2.4 ± 1.2 years, 55 patients (8.5 %) died. Patients with a blunted HRR-1 had increased mortality risk irrespective of their HRR-2 (p = 0.9, log-rank test). Among patients with normal HRR-1, a blunted HRR-2 was an independent predictor of all-cause mortality beyond clinical and traditional MPI data (hazard ratio 2.83, 95 % CI 1.14 - 7.03). Finally, patients with a normal HRR-1 and HRR-2 had the lowest event rate, while those with any abnormal HRR had an increased risk of death (hazard ratio 2.5, 95 % CI 1.2 - 5.4). CONCLUSION: There was good correlation in the HRR to regadenoson on serial measurements without systematic or proportional biases. Patients with consistently normal HRR had the best prognosis.

The prognostic value of non-perfusion variables obtained during vasodilator stress myocardial perfusion imaging.

Myocardial perfusion imaging (MPI) is an established diagnostic test that provides useful prognostic data in patients with known or suspected coronary artery disease. In more than half of the patients referred for stress testing, vasodilator stress is used in lieu of exercise. Unlike exercise, vasodilator stress does not provide information on exercise and functional capacity, heart rate recovery, and chronotropy, and ECG changes are less frequent. These non-perfusion data provide important prognostic and patient management information. Further, event rates in patients undergoing vasodilator MPI are higher than in those undergoing exercise MPI and even in those with normal images probably due to higher pretest risk. However, there are a number of non-perfusion variables that are obtained during vasodilator stress testing, which have prognostic relevance but their use has not been well emphasized. The purpose of this review is to summarize the prognostic values of these non-perfusion data obtained during vasodilator MPI.

Prognostic value of heart rate response during regadenoson stress myocardial perfusion imaging in patients with end stage renal disease.

BACKGROUND: Blunted heart rate response (HRR) to vasodilator stress agents is associated with worse outcomes. There are limited data assessing the effect of impaired HRR to regadenoson among patients with end-stage renal disease (ESRD) undergoing stress myocardial perfusion imaging (MPI). METHODS: We prospectively followed patients with ESRD enrolled in the ASSUAGE and ASSUAGE-CKD trials. HRR was defined as 100*(peak stress heart rate-resting heart rate)/resting heart rate. Study cohort was dichotomized to blunted and normal HRR groups according to an established median HRR value <28% or ≥28%, which were propensity-score matched based on 22 clinical and imaging covariates. The Primary endpoint was all-cause death. The secondary cardiac-specific endpoints included: (1) the composite endpoint of cardiac death or myocardial infarction; (2) the composite endpoint of cardiac death, myocardial infarction, or late (>90 days) coronary revascularization. RESULTS: There were 303 patients followed for 35 ± 10 months. In the entire cohort, there was a stepwise increase in the rates of death and all secondary endpoints with worsening HRR (P values ≤.001). Blunted HRR (<28%) was associated with increased risk of death (unadjusted hazard ratio 4.10 [1.98-8.46], P < .001) and all secondary endpoints (P ≤ .001). After multivariate adjustment, HRR remained an independent predictor of mortality and secondary endpoints whether used as continuous or dichotomous variable, and added incremental prognostic value for all-cause death (P = .046). Blunted HRR was associated with increased event rate among patients with normal myocardial perfusion (P = .001) and abnormal perfusion (P = .053). In the propensity-matched cohort of 132 patients (66 in each group), blunted HRR was associated with significant increase in all-cause death (21% vs. 5%, HR 5.09 [1.46-17.7], P=.011), and similarly for the secondary endpoints. CONCLUSION: Blunted HRR (<28%) to regadenoson is a strong and independent predictor of death and cardiovascular events in patients with ESRD and adds incremental prognostic value.

Heart rate response during 6-minute walking testing predicts outcome in operable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Six-minute walk test (6MWT) is routinely performed in chronic thromboembolic pulmonary hypertension (CTEPH) before pulmonary endarterectomy (PEA). However, the clinical relevance of heart rate response (ΔHR) and exercise-induced oxygen desaturation (EID) during 6MWT is remaining unknown. METHODS: Patients undergoing PEA in our center between 03/2013-04/2014 were assessed prospectively with hemodynamic and exercise parameters prior to and 1 year post-PEA. Patients with symptomatic chronic thromboembolic disease (mean pulmonary artery pressure (mPAP) <25 mmHg) and clinical relevant obstructive pulmonary disease were excluded. The following definitions were used: ΔHR = (peak HR - resting HR), percent heart rate reserve (HRR) = (peak HR -rest HR)/(220 - age - rest HR) x 100 and EID = SpO2 ≤88 %. RESULTS: Thirty-seven patients (of 116 patients screened) with mPAP of 43.2 ± 8.7 mmHg, pulmonary vascular resistance (PVR) of 605.5 ± 228.7 dyn*s/cm(5), cardiac index (CI) of 2.4 ± 0.5 l/min/m(2) and a 6MWT-distance of 404.7 ± 148.4 m and a peak VO2 of 12.3 ± 3.4 ml/min/kg prior to PEA were included. Baseline ΔHR during 6MWT was significantly associated with PVR 1 year post-PEA using linear regression analysis (r = 0.43, p = 0.01). Multivariate analysis indicated an association of HRR during 6MWT and residual PH with a hazard ratio of 1.06 (95 % Confidence interval for hazard ratio 0.99-1.14, p = 0.08). EID was observed commonly during 6MWT but no correlations to outcome parameters were found. CONCLUSIONS: This is the first prospective study to describe an association of ΔHR during 6MWT with pulmonary hemodynamics 1 year post-PEA. Our preliminary results indicate that HRR derived from 6MWT is of clinical significance. EID was commonly observed, albeit failed as a significant prognostic factor.

A Comparison of Heart Rate Response between 12 hours Caffeine Abstinence and 24 hours in Adenosine Stress Myocardial Perfusion Imaging.

The aim of this study was to examine whether the heart rate response to adenosine differs after 12 hours [Good control (Good-C)] versus 24 hours [Excellent control (Exc-C)] of caffeine abstinence in adenosine stress thallium-201 (TL) myocardial perfusion imaging (MPI). Patients (n=729) with suspected ischemic heart disease underwent adenosine TL-MPI after 12 (n=226) and 24 (n=503) hours of caffeine abstinence. There was not significant differences between the heart rate of Exc-C and Good-C in 0-2 min after adenosine infusion (0 min 63.7±9.5 versus 63.7±10.0, 1 min 66.4±10.6 versus 65.3±10.5, 2 min 72.3±11.2 versus 70.6±11.4). The heart rate of Exc-C was higher compared to Good-C in 3-6 min after adenosine infusion (3 min 75.6 ±11.7 versus 73.3±11.6 p=0.013, 4 min 79.2±12.9 versus 76.7±12.2 p=0.012, 5 min 79.4±12.6 versus 76.8±12.4 p=0.009, 6 min 79.4±12.5 versus 77.0±12.3 p=0.016). Therefore, the longer caffeine abstinence, namely 24 hours self-restraint, is effective in adenosine TL-MPI.

Effect of acute exercise-induced fatigue on maximal rate of heart rate increase during submaximal cycling.

Different mathematical models were used to evaluate if the maximal rate of heart rate (HR) increase (rHRI) was related to reductions in exercise performance resulting from acute fatigue. Fourteen triathletes completed testing before and after a 2-h run. rHRI was assessed during 5 min of 100-W cycling and a sigmoidal (rHRIsig) and exponential (rHRIexp) model were applied. Exercise performance was assessed using a 5-min cycling time-trial. The run elicited reductions in time-trial performance (1.34 ± 0.19 to 1.25 ± 0.18 kJ · kg(-1), P < 0.001), rHRIsig (2.25 ± 1.0 to 1.14 ± 0.7 beats · min(-1) · s(-1), P < 0.001) and rHRIexp (3.79 ± 2.07 to 1.98 ± 1.05 beats · min(-1) · s(-1), P = 0.001), and increased pre-exercise HR (73.0 ± 8.4 to 90.5 ± 11.4 beats · min(-1), P < 0.001). Pre-post run difference in time-trial performance was related to difference in rHRIsig (r = 0.58, P = 0.04 and r = 0.75, P = 0.003) but not rHRIexp (r = -0.04, P = 0.9 and r = 0.27, P = 0.4) when controlling for differences in pre-exercise and steady-state HR. rHRIsig was reduced following acute exercise-induced fatigue, and correlated with difference in performance.