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Hypertension and Arrhythmias

Hypertension and Arrhythmias. Introduction. Hypertension is one of the earliest recorded medical conditions (2.600BC) Consequences of hypertension will soon be the leading global cause of death The risk of death increases with increasing SBP

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Hypertension and Arrhythmias

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  1. Hypertension and Arrhythmias

  2. Introduction • Hypertension is one of the earliest recorded medical conditions (2.600BC) • Consequences of hypertension will soon be the leading global cause of death • The risk of death increases with increasing SBP • On one hand is a risk factor for the development of coronary artery disease, and on the other hand for the incidence of ventricular arrhythmias or even cardiac death.

  3. Hypertension and Arrhythmias Pathophysiology Arrhythmias Prediction of Risk Treatment

  4. Mechanisms regulating mean arterial blood pressure

  5. LVH: Causative Factors Hemodynamic load VolumePressure Genetic/ environmental factors Age Gender Race Other illness Trophic factors Angiotensin II Aldosterone Catecholamines Insulin

  6. Arterial hypertension Left ventricular hypertrophy ↑Fibrosis ↑Media hypertrophy ↑Wall stress ↑Sympathetic tone ↓Coronary flow Stretching of myocytes ↑Heart rate reserve ↑Catecholamines Ischemia Increased automaticity Triggered activity Conduction – and depolarization disorders Re-entry Ventricular tachycardia Sudden cardiac death

  7. Arrhythmogenic Mechanisms in Hypertension Duration of the action potential is increased The plateau phase of the action potential is more labile than non-LVH Disorders of the cytosolic calcium concentrations The normal regional differences of action potential duration are reversed Reentry seems to be directly linked with fibrosis Link of LV wall stress and arrhythmias The HRV is decreased Electrolyte imbalance such as disorders of calcium and potassium channels

  8. Experimental Evidence for Beneficial Effects of Potassium Mcdonald JE et al. J Am Coll Cardiol 2004;43: 155

  9. Coronary Hemodynamic Characteristics Group 1 Hypertensive With LVH Group 2 Hypertensive Without LVH Group 3 Normotensive No.of patients CBF at baseline(ml/min) Coronary flow reserve to adenosine Coronary vascular resistance (mm Hg min/ml) CBF change induced by acetylcholine (min/ml) % change of CBF induced by Acetylcholine (%) % change of CAD induced by Acetylcholine (%) n=13 81.1 ±9.9*† 2.3 ±0.2*† 1.7 ±0.3*‡ 99.3 ±29.0 1.5 ±20.5† -31.6 ±9.5 n=30 56.5 ±6.2 2.7 ±0.1 2.7 ±0.3 78.1 ±11.5 46.9 ±20.2 -11.3 ±5.4 n=68 48.1 ±3.2 2.8 ±0.1 2.9 ±0.2 69.8 ±6.8 56.1 ±13.1 -12.3 ±4.2 Values are mean ± SE. CAD = coronary artery diameter; CBF = coronary blood flow; LVH = left ventricular hypertrophy. *p < 0.05 versus group 2; †p < 0.01; ‡<0.05 versus group 3. Hamasaki S. et al. J Am Coll Cardiol 2000. Attenuated Coronary Flow Reserve and Vascular Remodeling in Patients With Hypertension and Left Ventricular Hypertrophy

  10. 3.2 3.1 3 2.9 CFR CORONARY FLOW RESERVE CHANGES FOLLOWING CLONIDINE INFUSION Heart Rate, Mean Blood Pressure and CFR Changes After Clonidine Infusion Baseline Post Clonidine 120 * 100 * 80 60 40 20 0 HR MBP Voudris V, Manolis AJ et al Am J Hypertens 2003 * p < . 01

  11. Hemodynamic and Humoral Correlates in Essential HTN: Relationship Between Patterns of LVH and Myocardial Ischemia ETT (-) ETT(+), Th(+), CA(-) Holter: (+), HRV: (+), LPs: (+) NE: p:NS Manolis AJ et al. Hypertension. 1997

  12. Sympathetic Response to Ventricular Extrasystolic Beats in Hypertension and HF MSNA responses to spontaneous PVCs are similar in controls and EH but markedly impaired in CHF, presumably because of the baroreflex alteration Grassi G et al. Hypertension 2002; 39:886

  13. Renin-Angiotensin Aldosterone System Non-ACE pathways(eg, chymase) • Vasoconstriction • Cell growth • Na/H2O retention • Sympathetic activation Angiotensinogen AT1 Angiotensin I Renin Angiotensin II ACE AT2 Aldosterone • Vasodilation • Antiproliferation(kinins) Cough,angioedema Benefits? Inactivefragments Bradykinin

  14. Hypertension and Arrhythmias Pathophysiology Arrhythmias Prediction of Risk Treatment 19th Annual Scientific Meeting of the American Society of Hypertension

  15. Ventricular ectopy in patients with normal left ventricular (LV) mass and left ventricular hypertrophy

  16. Percentage of Patients with Supraventricular and Ventricular Arrhythmias in Hypertensives with or without LVH Novo S. et al. Am J Hypertens 1997;10:843

  17. Coefficients of Correlation (R) Between SBP, DBP, HR and Supraventricular and Ventricular Arrhythmias in two Groups of Hypertensives with or without LVH Novo S. et al. Am J hypertens 1997;10:843

  18. Associations of Systolic and Diastolic Blood Pressure with Prevalence of Atrial Fibrillation Ciaroni S et al. Am J Cardiol 2004;94:2566

  19. Factors Associated With Ischemic Stroke Multivariate Analysis SPAF I-III Trial Hart R.G. et al. Stroke. 1999; 30: 1223-1229

  20. Predictive parameters for the onset of AF Age Diurnal and nocturnal BP Max duration of the depression of P wave in the ECG LVMI Left atrial dimension Velocity of the A wave Minimum P wave velocity

  21. Hypertension and Arrhythmias Pathophysiology Arrhythmias Prediction of Risk Treatment

  22. Electrocardiographic and Signal-Averaged Data Gatzoulis KA et al. Am J Hypertens 2000; 13: 340

  23. Signal-Averaged ECG Parameters and Ventricular Repolarization Facchini M et al. J Hypertens 2000; 18: 763

  24. Relative risk of non- invasive parameters concerning cardiac mortality and sudden cardiac death (univariate analysis). The only significant parameter in the multivariate analysis was Lown-class IVB Galinier M et al. Eur Heart J 1997;18:1484

  25. Hypertension and Arrhythmias Pathophysiology Arrhythmias Prediction of Risk Treatment

  26. ALLHAT Biochemical Results * p<.05 compared to chlorthalidone † Ann Intern Med. 1999;130:461-470

  27. Drug Treatment and Potassium SHEP Trial:7.2% of subjects taking diuretic developed hypokalemia and they lost the cardioprotective effect of BP reduction MRFIT Trial: patients who received higher doses of diuretics had increased risk of SCD, especially those with ECG LVH, and for 1 mmol/l reduction of serum potassium, ventricular arrhythmias increased by 28%. MRC Trial: ventricular ectopy was unaffected by thiazide therapy after 2 months, but was increased after 2 years and was related to hypokalemia. Gatzoulis K. et al. Am J Hypertension 2000.

  28. Clinical Evidence for Beneficial Effects of Potassium and Recommended Targets for Serum Potassium Concentration in Cardiovascular Disorders Mcdonald JE et al. J Am Coll Cardiol 2004;43: 155

  29. Symptomatic Treatment of Cardiac Arrhythmias • HTN and/or LVH suffering Supraventricular arrhythmias and AF First line: class Ic (propaphenone, Flecainide, except low EF) Avoid: class III (amiodarone, sotalol )and class Ia (quinidine, disopyramide) and Drugs increasing QT interval Sotalol: 5-8% torsades de-points tachydardia (Hohnloser et al. N Engl J Med 1994) Propafenone effective in terminating SVT and AF in 84% (Reimold SC et a. Am J Cardiol 1998) If class Ic agents are not effective: amiodarone (Podril PJ. Ann Intern Med 1995) • If Pharmacologic therapy has failed Modulation of AV-node or ablation of AV-node and pacemaker permanent atrial pacing radiofrequence ablation

  30. Calcium channel-blockers ACE inhibitors Clonidine Regression of Hypertrophy Beta-blockers Diuretics Reduction of ventricular premature beats Normalization of ventricular electrophysiology behaviour in animal model Improvement of QT-dispersion Reduction of sudden cardiac death?

  31. Ca- antagonist ACE- inhibitors Diuretics -blockers ARBs 0 -2 -4 -6% -6 LV mass Reduction (%) -8% -8 -10% -11% -10 -13% -12 -14 80 randomized controlled trials; 4,113 patients -16 Meta-analysis of randomized, controlled trials of LV hypertrophy regression in essential hypertension Schmieder RE et al. Am J Med 2003; 115:41-6.

  32. Comparison of Spirapril Isradipine and their Combination in HTN Patients with LVH:Effects on LVH Regression and Arrhythmogenic Propensity % SBP (mmHg) -11.6+8* -11.4+7* -18+10* % DBP (mmHg) -15+18* -14+6* -20+6* % LVMI (g/M2) -7.9+4+ -9.6+8* -7.8+10+ % NE (ng/ml) 31+72 -7.8+70 44+96 % PRA (ng/ml/hr) 186+213 192+267 115+113 % AVP (pg/ml) 236+259 411+772+ 120+336 ISR SPIR ISR+SPIR *p<0.001, +p<0.05 Manolis AJ et al. Am J Hypertens 1998

  33. 67% # # 54% 70 0 CBF CVR CR PCA TIC LVMI * 12% * 22% # 33% * 54% -70 Repair of Coronary Arterioles After Treatment with Perindopril in Hypertensive Heart Disease % Morphological and Haemodynamic changes before and after treatment. * p < 0,04 # p < 0.001 PCA: Periarteriolar collagen area TIC: Total Interstitial Collagen Hypertension 2000

  34. Occurrence of Atrial Fibrillation According to Antihypertension Treatment: IR per 1,000 Person-Years of Atrial Fibrillation – Related Hospitalization, Adjusted Incidence Ratio, and 95% CI Incidence rate of AF-related hospitalizations L’Allier PL et al. J Am Coll Cardiol 2004

  35. ACE-Inhibition in HTN Patients is Associated with a Reduction in the Occurrence of Atrial Fibrillation Kaplan-Meir curves for the time to first occurrence of AF L’Allier PL et al. J Am Coll Cardiol 2004

  36. Cornell Product Sokolow-Lyon 0 -2 -4 -6 -8 Change from baseline (%) -10 P<0.0001 -12 -14 Losartan -16 Atenolol P<0.0001 -18 LIFE Study Change in Cornell Voltage Duration Product and Sokolow-Lyon

  37. Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 LIFE Study Primary Composite Endpoint 16 Intention-to-treat 14 Adjusted risk reduction 13·0%, P=0·021 Unadjusted risk reduction 14·6%, P=0·009 12 10 Atenolol Proportion of patients with first event (%) 8 Losartan 6 4 2 Study Month 0 6 12 18 24 30 36 42 48 54 60 66

  38. Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study 10 Adjusted HR (95% CI) 0 -10 -20 -30 -40 # p<0.05 -50 # -60 Non Coronary CV Death CV Death CHD Death Sudden Death Non SD Lindholm LH, et al: Lancet 2003 #: p< 0.03

  39. Reduction in Risk of Stroke in Patients with AF 25 Fatal and nonfatal stroke Atenolol 20 Losartan 15 Proportion of patients with first event (%) 10 5 Adjusted risk reduction 49%, p = 0.018 0 0 48 6 30 36 42 54 12 18 24 60 66 Time (months)

  40. Cardiac remodeling/enlargement Hemodynamic factors (central and peripheral blood pressure) Emboli formation Vascular remodeling Embolic occlusion Plaque fragments Atherosclerotic plaques Ischemic stroke Plaque rupture Endothelial dysfunction Thrombotic occlusion Circulating factors (glucose, insulin, RBCs, PAI, TXA2, uric acid) Thrombus formation Prothrombotic state Hemorrhagic stroke Vascular hemorrhage Ischemic Stroke“Mosaic of Interacting Factors” .

  41. How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Reduced ECG–LVH Cardiac remodeling/enlargement Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Vascular remodeling Endothelial dysfunction Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Prothrombotic state Please refer to notes page for reference citations.

  42. Conclusions • Patients with HTN suffer from an increased risk of arrhythmias. • The arrhythmogenic causes of arrhythmias in HTN concern triggered activity with early and delayed after- depolarizations and re-entry. • The mechanisms are associated with ischemia, myocardial fibrosis, increased wall stress and acute changes of BP. • The predictive accuracy of non-invasive parameters is not high enough • A regression of LVH leads to a reduction of ventricular ectopic activity, sudden death and improves CV morbidity and mortality

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