Supplementary Material for: Haemodynamic gain index is associated with risk of sudden cardiac death and improves risk prediction: a cohort study

Introduction: Haemodynamic gain index (HGI) is a novel haemodynamic parameter which can be obtained from cardiopulmonary exercise testing (CPX), but its association with sudden cardiac death (SCD) is not known. We aimed to assess the association of HGI with SCD risk in a long-term prospective cohort study. Methods: Haemodynamic gain index was calculated using heart rate and systolic blood pressure (SBP) measured in 1897 men aged 42-61 years during CPX from rest to peak exercise, using the formula: [(Heart rate max x SBPmax) - (Heart rate rest x SBPrest)]/(Heart rate rest x SBPrest). Cardiorespiratory fitness (CRF) was measured using respiratory gas exchange analysis. Multivariable adjusted hazard ratios (HRs) (95% confidence intervals, CIs) were analyzed for SCD. Results: During a median follow-up of 28.7 years, 205 SCDs occurred. The risk of SCD decreased gradually with increasing HGI (p-value for non-linearity=.63). A unit (bpm/mmHg) higher HGI was associated with a decreased risk of SCD (HR 0.84; 95% CI 0.71–0.99), which was attenuated following adjustment for CRF. Cardiorespiratory fitness was inversely associated with SCD, which remained after further adjustment for HGI: (HR 0.85; 95% CI 0.77–0.94) per each unit higher CRF. Addition of HGI to a SCD risk prediction model containing established risk factors improved risk discrimination (C-index change=0.0096; p=.017) and reclassification (NRI=39.40%, p=.001). The corresponding values for CRF were (C-index change=0.0178; p=.007) and (NRI=43.79%, p=.001). Conclusion: Higher HGI during CPX is associated with a lower SCD risk, consistent with a dose-response relationship, but dependent on CRF levels. Though HGI significantly improves the prediction and classification of SCD beyond common cardiovascular risk factors, CRF remains a stronger risk indicator and predictor of SCD compared to HGI

Supplementary Material for: Haemodynamic gain index is associated with risk of sudden cardiac death and improves risk prediction: a cohort study

Introduction: Haemodynamic gain index (HGI) is a novel haemodynamic parameter which can be obtained from cardiopulmonary exercise testing (CPX), but its association with sudden cardiac death (SCD) is not known. We aimed to assess the association of HGI with SCD risk in a long-term prospective cohort study. Methods: Haemodynamic gain index was calculated using heart rate and systolic blood pressure (SBP) measured in 1897 men aged 42-61 years during CPX from rest to peak exercise, using the formula: [(Heart rate max x SBPmax) - (Heart rate rest x SBPrest)]/(Heart rate rest x SBPrest). Cardiorespiratory fitness (CRF) was measured using respiratory gas exchange analysis. Multivariable adjusted hazard ratios (HRs) (95% confidence intervals, CIs) were analyzed for SCD. Results: During a median follow-up of 28.7 years, 205 SCDs occurred. The risk of SCD decreased gradually with increasing HGI (p-value for non-linearity=.63). A unit (bpm/mmHg) higher HGI was associated with a decreased risk of SCD (HR 0.84; 95% CI 0.71–0.99), which was attenuated following adjustment for CRF. Cardiorespiratory fitness was inversely associated with SCD, which remained after further adjustment for HGI: (HR 0.85; 95% CI 0.77–0.94) per each unit higher CRF. Addition of HGI to a SCD risk prediction model containing established risk factors improved risk discrimination (C-index change=0.0096; p=.017) and reclassification (NRI=39.40%, p=.001). The corresponding values for CRF were (C-index change=0.0178; p=.007) and (NRI=43.79%, p=.001). Conclusion: Higher HGI during CPX is associated with a lower SCD risk, consistent with a dose-response relationship, but dependent on CRF levels. Though HGI significantly improves the prediction and classification of SCD beyond common cardiovascular risk factors, CRF remains a stronger risk indicator and predictor of SCD compared to HGI

Supplementary Material for: Patent Foramen Ovale, Ischemic Stroke and Migraine: Systematic Review and Stratified Meta-Analysis of Association Studies

<b><i>Background:</i></b> Observational data have reported associations between patent foramen ovale (PFO), cryptogenic stroke and migraine. However, randomized trials of PFO closure do not demonstrate a clear benefit either because the underlying association is weaker than previously suggested or because the trials were underpowered. In order to resolve the apparent discrepancy between observational data and randomized trials, we investigated associations between (1) migraine and ischemic stroke, (2) PFO and ischemic stroke, and (3) PFO and migraine. <b><i>Methods:</i></b> Eligibility criteria were consistent; including all studies with specifically defined exposures and outcomes unrestricted by language. We focused on studies at lowest risk of bias by stratifying analyses based on methodological design and quantified associations using fixed-effects meta-analysis models. <b><i>Results:</i></b> We included 37 studies of 7,686 identified. Compared to reports in the literature as a whole, studies with population-based comparators showed weaker associations between migraine with aura and cryptogenic ischemic stroke in younger women (OR 1.4; 95% CI 0.9–2.0; 1 study), PFO and ischemic stroke (HR 1.6; 95 CI 1.0–2.5; 2 studies; OR 1.3; 95% CI 0.9–1.9; 3 studies), or PFO and migraine (OR 1.0; 95% CI 0.6–1.6; 1 study). It was not possible to look for interactions or effect modifiers. These results are limited by sources of bias within individual studies. <b><i>Conclusions:</i></b> The overall pairwise associations between PFO, cryptogenic ischemic stroke and migraine do not strongly suggest a causal role for PFO. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect