Hypertension and ArrhythmiasHypertension and Arrhythmias

IntroductionIntroduction

Hypertension is one of the earliest recorded medical conditions Hypertension is one of the earliest recorded medical conditions

(2.600BC)(2.600BC)

Consequences of hypertension will soon be the leading global Consequences of hypertension will soon be the leading global

cause of deathcause of death

The risk of death increases with increasing SBPThe risk of death increases with increasing SBP

On one hand is a risk factor for the development of coronary On one hand is a risk factor for the development of coronary

artery artery disease, and on the other hand for the incidence of disease, and on the other hand for the incidence of

ventricular arrhythmias or even cardiac death. ventricular arrhythmias or even cardiac death.

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Hypertension and ArrhythmiasHypertension and Arrhythmias

Mechanisms regulating mean arterial blood pressure Mechanisms regulating mean arterial blood pressure

LVH: Causative FactorsLVH: Causative Factors

Genetic/environmental

factors

AgeGender

RaceOther illness

Genetic/environmental

factors

AgeGender

RaceOther illness

Hemodynamic load

Volume Pressure

Hemodynamic load

Volume PressureTrophic factors

Angiotensin IIAldosterone

CatecholaminesInsulin

Trophic factors

Angiotensin IIAldosterone

CatecholaminesInsulin

Arterial hypertensionArterial hypertension

Left ventricular hypertrophyLeft ventricular hypertrophy

↑Fibrosis↑Fibrosis

↓Coronary flow↓Coronary flow

↑ Media hypertrophy

↑ Media hypertrophy

↑ Wall stress↑ Wall stress

IschemiaIschemia

reservereserve

Conduction – and depolarization disorders

Conduction – and depolarization disorders

Re-entryRe-entry

Stretching of myocytes

Stretching of myocytes

Increased automaticityTriggered activity

Increased automaticityTriggered activity

Ventricular tachycardiaVentricular tachycardia

Sudden cardiac deathSudden cardiac death

↑ Catecholamines↑ Catecholamines

↑ Heart rate↑ Heart rate

↑ Sympathetic tone

↑ Sympathetic tone

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

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

Arrhythmogenic Mechanisms in Hypertension Arrhythmogenic Mechanisms in Hypertension

Experimental Evidence for Beneficial Effects of Potassium

Experimental Evidence for Beneficial Effects of Potassium

Mcdonald JE et al. J Am Coll Cardiol 2004;43: 155 Mcdonald JE et al. J Am Coll Cardiol 2004;43: 155

CardiacCardiacAnti - arrhythmicAnti - arrhythmic ↓↓ Action potential durationAction potential duration

↓↓ Electrical in homogeneityElectrical in homogeneity↓↓ Risk of digoxin toxicityRisk of digoxin toxicity

Diastolic functionDiastolic function Hypokalemia worsens diastolic functionHypokalemia worsens diastolic function

VascularVascular

VasomotorVasomotor Endothelial-dependent vasodilatorEndothelial-dependent vasodilatorVSMCVSMCThrombosisThrombosisAtherosclerosisAtherosclerosis

↓↓ VSMC proliferationVSMC proliferation↓↓ Thrombus formation and platelet activationThrombus formation and platelet activation↓↓ Neointimal proliferationNeointimal proliferation↓↓ Atherosclerotic lesion formationAtherosclerotic lesion formation↓↓ Free radical generationFree radical generation

VSMC = vascular smooth muscle cell.VSMC = vascular smooth muscle cell.

Attenuated Coronary Flow Reserve and Vascular Remodeling in Patients With Hypertension and Left Ventricular Hypertrophy

Attenuated Coronary Flow Reserve and Vascular Remodeling in Patients With Hypertension and Left Ventricular Hypertrophy

Coronary Hemodynamic CharacteristicsCoronary Hemodynamic Characteristics

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

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

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=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=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=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

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 (%)

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 (%)

Group 3

Normotensive

Group 3

Normotensive

Group 2Hypertensive

Without LVH

Group 2Hypertensive

Without LVH

Group 1Hypertensive

With LVH

Group 1Hypertensive

With LVH

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.

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.

Heart Rate, Mean Blood Pressure and CFR Changes After Clonidine Infusion

Heart Rate, Mean Blood Pressure and CFR Changes After Clonidine Infusion

00

2020

4040

6060

8080

100100

120120

HRHR MBPMBP

BaselineBaseline Post ClonidinePost Clonidine

2.92.9

33

3.13.1

3.23.2

CFRCFR

*

* p < . 01* p < . 01

*

CORONARY FLOW RESERVE CHANGES

FOLLOWING CLONIDINE INFUSION

CORONARY FLOW RESERVE CHANGES

FOLLOWING CLONIDINE INFUSION

Voudris V, Manolis AJ et al Am J Hypertens 2003Voudris V, Manolis AJ et al Am J Hypertens 2003

Hemodynamic and Humoral Correlates in Essential HTN:

Relationship Between Patterns of LVH and Myocardial Ischemia

Hemodynamic and Humoral Correlates in Essential HTN:

Relationship Between Patterns of LVH and Myocardial Ischemia

Manolis AJ et al. Hypertension. 1997Manolis AJ et al. Hypertension. 1997

ETT (-)ETT (-) ETT(+), Th(+), CA(-)ETT(+), Th(+), CA(-)

Holter: (+), Holter: (+), HRV: (+), LPs: (+)HRV: (+), LPs: (+)NE: p:NSNE: p:NS

Sympathetic Response to Ventricular Extrasystolic Beats in Hypertension and HF

Sympathetic Response to Ventricular Extrasystolic Beats in Hypertension and HF

MSNA responses to spontaneous PVCs are similar in controls and EH but MSNA responses to spontaneous PVCs are similar in controls and EH but markedly impaired in CHF, presumably because of the baroreflex alteration markedly impaired in CHF, presumably because of the baroreflex alteration

Grassi G et al. Hypertension 2002; 39:886Grassi G et al. Hypertension 2002; 39:886

Renin-Angiotensin Aldosterone SystemRenin-Angiotensin Aldosterone System

AngiotensinogenAngiotensinogen

Non-ACE pathways(eg, chymase)

Non-ACE pathways(eg, chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

Renin Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

ACE

Cough,angioedema

Benefits?

Cough,angioedema

Benefits? Bradykinin Bradykinin

InactivefragmentsInactive

fragments

Vasodilation Antiproliferation

(kinins)

Vasodilation Antiproliferation

(kinins)

AldosteroneAldosterone AT2

AT1

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

1919thth Annual Scientific Meeting of the American Society of Hypertension Annual Scientific Meeting of the American Society of Hypertension

Hypertension and ArrhythmiasHypertension and Arrhythmias

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

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

Novo S. et al. Am J Hypertens 1997;10:843Novo S. et al. Am J Hypertens 1997;10:843

Percentage of Patients with Supraventricular and Ventricular Arrhythmias in Hypertensives with or without LVH

Percentage of Patients with Supraventricular and Ventricular Arrhythmias in Hypertensives with or without LVH

Novo S. et al. Am J hypertens 1997;10:843Novo S. et al. Am J hypertens 1997;10:843

Coefficients of Correlation (R) Between SBP, DBP, HR and Supraventricular and Ventricular Arrhythmias in two

Groups of Hypertensives with or without LVH

Coefficients of Correlation (R) Between SBP, DBP, HR and Supraventricular and Ventricular Arrhythmias in two

Groups of Hypertensives with or without LVH

With LVHWith LVH Without LVHWithout LVH

PSVBPSVB PVBPVB PSVBPSVB PVBPVB

ASBPASBP 0.340.34 0.83*0.83* 0.88*0.88* 0.380.38

ADBPADBP 0.390.39 0.74*0.74* 0.49*0.49* 0.310.31

AHRAHR 0.55*0.55* 0.87*0.87* 0.76*0.76* 0.360.36

* p<.01* p<.01

Associations of Systolic and Diastolic Blood Pressure with Prevalence of Atrial FibrillationAssociations of Systolic and Diastolic Blood Pressure with Prevalence of Atrial Fibrillation

Ciaroni S et al. Am J Cardiol 2004;94:2566Ciaroni S et al. Am J Cardiol 2004;94:2566

OR (95% CI)OR (95% CI)

VariablesVariables Systolic BPSystolic BP

(per 10mm Hg)(per 10mm Hg)

Diastolic BP Diastolic BP

(per 10mm Hg)(per 10mm Hg)

Pulse Pressure Pulse Pressure

(per 9 mm Hg)(per 9 mm Hg)

UnadjustedUnadjusted 1.46*1.46* 1.071.07 1.52*1.52*

AdjustmentAdjustment

Age (5 yrs)Age (5 yrs) 1.25*1.25* 1.051.05 1.23*1.23*

Age and gender (men)Age and gender (men) 1.21*1.21* 1.041.04 1.19*1.19*

Age, gender and BMI (>28kg/mAge, gender and BMI (>28kg/m22)) 1.16*1.16* 1.021.02 1.18*1.18*

Age, gender, BMI and systolic BPAge, gender, BMI and systolic BP -- 1.011.01 1.171.17

Age, gender, BMI and pulse pressureAge, gender, BMI and pulse pressure 1.15*1.15* 0.910.91 --

*p < 0.001*p < 0.001

Factors Associated With Ischemic Stroke Multivariate Analysis SPAF I-III Trial

Factors Associated With Ischemic Stroke Multivariate Analysis SPAF I-III Trial

Hart R.G. et al. Stroke. 1999; 30: 1223-1229 Hart R.G. et al. Stroke. 1999; 30: 1223-1229

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

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

Predictive parameters for the onset of AFPredictive parameters for the onset of AF

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Hypertension and ArrhythmiasHypertension and Arrhythmias

Electrocardiographic and Signal-Averaged DataElectrocardiographic and Signal-Averaged Data

Gatzoulis KA et al. Am J Hypertens 2000; 13: 340Gatzoulis KA et al. Am J Hypertens 2000; 13: 340

No LVHNo LVH LVHLVH PP

Mean HR (bpm)Mean HR (bpm) 77.6 77.6 ++ 26 26 68.8 68.8 ++ 9 9 NSNS

Max HR (bpm)Max HR (bpm) 121.6 121.6 ++ 29 29 123 123 ++ 25 25 NSNS

Min HR (bpm)Min HR (bpm) 51.4 51.4 ++ 13 13 52 52 ++ 10 10 NSNS

PVC/hPVC/h 6.8 6.8 ++ 21 21 6 6 ++ 19 19 NSNS

Multiform PVC (%)Multiform PVC (%) 7.4%7.4% 7.8%7.8% NSNS

R-on-T (%)R-on-T (%) 0%0% 1%1% NSNS

VVcoupcoup/24 h/24 h 0.2 0.2 ++ 1 1 0.04 – 0.20.04 – 0.2 NSNS

VTVTrunsruns/24 h/24 h 00 00 NSNS

FQRS (mc)FQRS (mc) 94 + 2094 + 20 98 + 1198 + 11 NSNS

LAS (ms)LAS (ms) 28.5 + 1028.5 + 10 29.3 + 1029.3 + 10 NSNS

RMS (RMS (μμV)V) 47 + 4447 + 44 46 + 3446 + 34 NSNS

(+) LPs (%)(+) LPs (%) 35.4%35.4% 33.3%33.3% NSNS

Signal-Averaged ECG Parameters and Ventricular RepolarizationSignal-Averaged ECG Parameters and Ventricular Repolarization

Facchini M et al. J Hypertens 2000; 18: 763Facchini M et al. J Hypertens 2000; 18: 763

HH HAHA CC CACA PP

QRSd (ms)QRSd (ms) 98 98 ++ 13 13 96 96 ++ 18 18 97 97 ++ 7 7 97 97 ++ 11 11 NSNS

RMS 40 (RMS 40 (μμV)V) 44 44 ++ 29 29 49 49 ++ 31 31 48 48 ++ 27 27 45 45 ++ 23 23 NSNS

LAS (ms)LAS (ms) 29 29 ++ 8 8 25 25 ++ 7 7 27 27 ++ 9 9 27 27 ++ 9 9 NSNS

LP (%)LP (%) 5%5% 3% 3% 0%0% 2%2% NSNS

QTcQTc 422 422 ++ 25 25 427 427 ++ 27 27 382 382 ++ 20 20 401 401 ++ 28 28 <.0001<.0001

QT > 440msQT > 440ms 4/19 (21%)4/19 (21%) 9/30 (30%)9/30 (30%) 0/28 (0%)0/28 (0%) 3/61 (5%)3/61 (5%) <.001<.001

QTdQTd 33 33 ++ 14 14 41 41 ++ 24 24 31 31 ++ 12 12 47 47 ++ 21 21 <.05<.05

QTd > 65msQTd > 65ms 0/19 (0%)0/19 (0%) 6/30 (20%)6/30 (20%) 0/28 (%)0/28 (%) 7/61 (11%)7/61 (11%) <.05<.05

H: HTN no arrhythmia, HA: HTN with arrhythmia, C: no HTN no arrhythmia, CA: no HTN with arrhythmiaH: HTN no arrhythmia, HA: HTN with arrhythmia, C: no HTN no arrhythmia, CA: no HTN with arrhythmia

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

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;18:1484Galinier M et al. Eur Heart J 1997;18:1484

MortalityMortality Sudden cardiac deathSudden cardiac death

ParameterParameter PP RRRR PP RRRR

Age > 65 yearsAge > 65 years 0.0010.001 5.315.31 0.0020.002 12.112.1

Lown IvbLown Ivb 0.00240.0024 4.374.37 0.00040.0004 17.117.1

QTd> 80 msQTd> 80 ms 0.00020.0002 5.875.87 0.010.01 4.84.8

LVEF < 65%LVEF < 65% 0.430.43 1.821.82 0.320.32 1.71.7

VLPVLP 0.530.53 1.521.52 0.970.97 1.041.04

LVH (echo)LVH (echo) 0.0020.002 4.974.97 0.340.34 1.931.93

VLP: Ventricular Late Potentials; QTd: QT-dispersionVLP: Ventricular Late Potentials; QTd: QT-dispersion

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Pathophysiology

Arrhythmias

Prediction of Risk

Treatment

Hypertension and ArrhythmiasHypertension and Arrhythmias

Biochemical Results

Chlorthalidone Amlodipine Lisinopril

Serum cholesterol- mg/dL

Baseline 216.1 (43.8) 216.5 (44.1) 215.6 (42.4)

4 Years 197.2 (42.1) 195.6 (41.0)* 195.0 (40.6)*

Serum potassium – mmol/L

Baseline 4.3 (0.7) 4.3 (0.7) 4.4 (0.7)*

4 Years 4.1 (0.7) 4.4 (0.7)* 4.5 (0.7)*

Estimated GFR† – mL/min/1.73m2

Baseline 77.6 (19.7) 78.0 (19.7) 77.7 (19.9)

4 Years 70.0 (19.7) 75.1 (20.7)* 70.7 (20.1)*

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

ALLHAT

Gatzoulis K. et al. Am J Hypertension 2000.Gatzoulis K. et al. Am J Hypertension 2000.

Drug Treatment and PotassiumDrug Treatment and Potassium

SHEP Trial:SHEP Trial: 7.2% of subjects taking diuretic developed 7.2% of subjects taking diuretic developed

hypokalemia and they lost the cardioprotective effect of BP hypokalemia and they lost the cardioprotective effect of BP reductionreduction

MRFIT Trial:MRFIT Trial: patients who received higher doses of diuretics had patients who received higher doses of diuretics had increased risk of SCD, especially those with ECG LVH, and increased risk of SCD, especially those with ECG LVH, and for 1 mmol/l reduction of serum potassium, ventricular for 1 mmol/l reduction of serum potassium, ventricular arrhythmias increased by 28%.arrhythmias increased by 28%.

MRC Trial:MRC Trial: ventricular ectopy was unaffected by thiazide therapy ventricular ectopy was unaffected by thiazide therapy after 2 months, but was increased after 2 years and was after 2 months, but was increased after 2 years and was related to hypokalemia. related to hypokalemia.

SHEP Trial:SHEP Trial: 7.2% of subjects taking diuretic developed 7.2% of subjects taking diuretic developed

hypokalemia and they lost the cardioprotective effect of BP hypokalemia and they lost the cardioprotective effect of BP reductionreduction

MRFIT Trial:MRFIT Trial: patients who received higher doses of diuretics had patients who received higher doses of diuretics had increased risk of SCD, especially those with ECG LVH, and increased risk of SCD, especially those with ECG LVH, and for 1 mmol/l reduction of serum potassium, ventricular for 1 mmol/l reduction of serum potassium, ventricular arrhythmias increased by 28%.arrhythmias increased by 28%.

MRC Trial:MRC Trial: ventricular ectopy was unaffected by thiazide therapy ventricular ectopy was unaffected by thiazide therapy after 2 months, but was increased after 2 years and was after 2 months, but was increased after 2 years and was related to hypokalemia. related to hypokalemia.

Clinical Evidence for Beneficial Effects of Potassium and Recommended Targets for Serum Potassium Concentration

in Cardiovascular Disorders

Clinical Evidence for Beneficial Effects of Potassium and Recommended Targets for Serum Potassium Concentration

in Cardiovascular Disorders

DisorderDisorder RecommendedRecommended

LevelLevel

EvidenceEvidence

HypertensionHypertension 3.5 – 5.0 mmol/l3.5 – 5.0 mmol/l High KHigh K++ diet diet ↓↓ BP BP

Hypokalemia ↑ ventricular arrhythmiaHypokalemia ↑ ventricular arrhythmia

StrokeStroke UnknownUnknown High KHigh K++ diet diet ↓↓ risk of stroke risk of stroke

Acute MIAcute MI 4.5 – 5.5 mmol/l4.5 – 5.5 mmol/l Hypokalemia ↑ ventricular arrhythmiaHypokalemia ↑ ventricular arrhythmia

Heart failureHeart failure 4.5 – 5.5% mmol/l4.5 – 5.5% mmol/l Hypokalemia ↑ ventricular arrhythmiaHypokalemia ↑ ventricular arrhythmia

Increasing serum KIncreasing serum K++ ↓↓ ventricular ventricular arrhythmia and arrhythmia and ↓↓ QT QT QT QTdd

Serum KSerum K++ level is inversely related to level is inversely related to prognosisprognosis

BP = Blood pressure; MI = myocardial infractionBP = Blood pressure; MI = myocardial infraction

Mcdonald JE et al. J Am Coll Cardiol 2004;43: 155 Mcdonald JE et al. J Am Coll Cardiol 2004;43: 155

Symptomatic Treatment of Cardiac ArrhythmiasSymptomatic Treatment of Cardiac Arrhythmias

HTN and/or LVH suffering Supraventricular arrhythmias and AFHTN and/or LVH suffering Supraventricular arrhythmias and AF

First line:First line: class Ic (propaphenone, Flecainide, except low EF) class Ic (propaphenone, Flecainide, except low EF)

Avoid:Avoid: class III (amiodarone, sotalol )and class Ia (quinidine, class III (amiodarone, sotalol )and class Ia (quinidine, disopyramide) and Drugs increasing QT interval disopyramide) and Drugs increasing QT interval

Sotalol: 5-8% torsades de-points tachydardia Sotalol: 5-8% torsades de-points tachydardia

(Hohnloser et al. N Engl J Med 1994)(Hohnloser et al. N Engl J Med 1994)

Propafenone effective in terminating SVT and AF in 84%Propafenone effective in terminating SVT and AF in 84%(Reimold SC et a. Am J Cardiol 1998)(Reimold SC et a. Am J Cardiol 1998)

If class Ic agents are not effective: amiodarone If class Ic agents are not effective: amiodarone (Podril PJ. Ann Intern Med 1995)(Podril PJ. Ann Intern Med 1995)

If Pharmacologic therapy has failedIf Pharmacologic therapy has failed

Modulation of AV-node or ablation of AV-node and pacemakerModulation of AV-node or ablation of AV-node and pacemaker

permanent atrial pacingpermanent atrial pacing

radiofrequence ablationradiofrequence ablation

HTN and/or LVH suffering Supraventricular arrhythmias and AFHTN and/or LVH suffering Supraventricular arrhythmias and AF

First line:First line: class Ic (propaphenone, Flecainide, except low EF) class Ic (propaphenone, Flecainide, except low EF)

Avoid:Avoid: class III (amiodarone, sotalol )and class Ia (quinidine, class III (amiodarone, sotalol )and class Ia (quinidine, disopyramide) and Drugs increasing QT interval disopyramide) and Drugs increasing QT interval

Sotalol: 5-8% torsades de-points tachydardia Sotalol: 5-8% torsades de-points tachydardia

(Hohnloser et al. N Engl J Med 1994)(Hohnloser et al. N Engl J Med 1994)

Propafenone effective in terminating SVT and AF in 84%Propafenone effective in terminating SVT and AF in 84%(Reimold SC et a. Am J Cardiol 1998)(Reimold SC et a. Am J Cardiol 1998)

If class Ic agents are not effective: amiodarone If class Ic agents are not effective: amiodarone (Podril PJ. Ann Intern Med 1995)(Podril PJ. Ann Intern Med 1995)

If Pharmacologic therapy has failedIf Pharmacologic therapy has failed

Modulation of AV-node or ablation of AV-node and pacemakerModulation of AV-node or ablation of AV-node and pacemaker

permanent atrial pacingpermanent atrial pacing

radiofrequence ablationradiofrequence ablation

ACE inhibitorsACE inhibitors ClonidineClonidine

DiureticsDiuretics

Calcium channel-blockers

Calcium channel-blockers

Beta-blockersBeta-blockers

Improvement of QT-dispersionImprovement of QT-dispersion

Reduction of ventricular premature beats

Reduction of ventricular premature beats

Normalization of ventricular

electrophysiology behaviour in animal model

Normalization of ventricular

electrophysiology behaviour in animal model

Regression of Hypertrophy

Regression of Hypertrophy

Reduction of sudden cardiac death?Reduction of sudden cardiac death?

Meta-analysis of randomized, controlled trials of LV hypertrophy regression in essential hypertension

Meta-analysis of randomized, controlled trials of LV hypertrophy regression in essential hypertension

Schmieder RE et al. Am J Med 2003; 115:41-6.Schmieder RE et al. Am J Med 2003; 115:41-6.

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00DiureticsDiuretics -blockers-blockers

Ca-antagonist

Ca-antagonist

ACE-inhibitors

ACE-inhibitors ARBsARBs

-8%

-6%

-11%-10%

-13%

LV

mas

sR

edu

ctio

n (

%)

LV

mas

sR

edu

ctio

n (

%)

80 randomized controlled trials;4,113 patients80 randomized controlled trials;4,113 patients

ISRISR

SPIRSPIR

ISR+SPIRISR+SPIR

ISRISR

SPIRSPIR

ISR+SPIRISR+SPIR

% SBP% SBP

(mmHg)(mmHg)

-11.6-11.6++8*8*

-11.4-11.4++7*7*

-18-18++10*10*

% SBP% SBP

(mmHg)(mmHg)

-11.6-11.6++8*8*

-11.4-11.4++7*7*

-18-18++10*10*

% DBP% DBP

(mmHg)(mmHg)

-15-15++18*18*

-14-14++6*6*

-20-20++6*6*

% DBP% DBP

(mmHg)(mmHg)

-15-15++18*18*

-14-14++6*6*

-20-20++6*6*

% LVMI% LVMI

(g/M2)(g/M2)

-7.9-7.9++44++

-9.6-9.6++8*8*

-7.8+10-7.8+10++

% LVMI% LVMI

(g/M2)(g/M2)

-7.9-7.9++44++

-9.6-9.6++8*8*

-7.8+10-7.8+10++

% NE% NE

(ng/ml)(ng/ml)

3131++7272

-7.8-7.8++7070

4444++9696

% NE% NE

(ng/ml)(ng/ml)

3131++7272

-7.8-7.8++7070

4444++9696

*p<0.001, *p<0.001, ++p<0.05p<0.05*p<0.001, *p<0.001, ++p<0.05p<0.05

% PRA% PRA

(ng/ml/hr)(ng/ml/hr)

186186++213213

192192++267267

115115++113113

% PRA% PRA

(ng/ml/hr)(ng/ml/hr)

186186++213213

192192++267267

115115++113113

% AVP% AVP

(pg/ml)(pg/ml)

236236++259259

411411++772772++

120120++336336

% AVP% AVP

(pg/ml)(pg/ml)

236236++259259

411411++772772++

120120++336336

Comparison of Spirapril Isradipine and their Combination in HTN Patients with LVH:

Effects on LVH Regression and Arrhythmogenic Propensity

Comparison of Spirapril Isradipine and their Combination in HTN Patients with LVH:

Effects on LVH Regression and Arrhythmogenic Propensity

Manolis AJ et al. Am J Hypertens 1998Manolis AJ et al. Am J Hypertens 1998Manolis AJ et al. Am J Hypertens 1998Manolis AJ et al. Am J Hypertens 1998

PCA: Periarteriolar collagen areaTIC: Total Interstitial CollagenPCA: Periarteriolar collagen areaTIC: Total Interstitial Collagen

* p < 0,04

# p < 0.001

* p < 0,04

# p < 0.001

% Morphological and Haemodynamic changes before and after treatment.

% Morphological and Haemodynamic changes before and after treatment.

Hypertension 2000Hypertension 2000

Repair of Coronary Arterioles After Treatment with

Perindopril in Hypertensive Heart Disease

Repair of Coronary Arterioles After Treatment with

Perindopril in Hypertensive Heart Disease

LVMILVMICBFCBF CVRCVR CRCR PCAPCA TICTIC

12%12%

54%54%

33%33%

67%67%

54%

22%

7070

-70-70

##

#

##

*

**

**

0 0

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

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

Matched CohortsMatched Cohorts ACEI IRACEI IR CCB IR CCB IR ACEI Versus CCB ACEI Versus CCB Ration (95% CI)*Ration (95% CI)*

Three yearsThree years 7.77.7 11.811.8 0.65 (0.54 – 0.83)0.65 (0.54 – 0.83)

Five yearsFive years 8.88.8 11.911.9 0.74 (0.61 – 0.89)0.74 (0.61 – 0.89)

Entire follow – upEntire follow – up 8.58.5 11.911.9 0.74 (0.62 – 0.89)0.74 (0.62 – 0.89)

*Poisson regression*Poisson regression

L’Allier PL et al. J Am Coll Cardiol 2004L’Allier PL et al. J Am Coll Cardiol 2004

Incidence rate of AF-related hospitalizationsIncidence rate of AF-related hospitalizations

ACE-Inhibition in HTN Patients is Associated with a Reduction in the Occurrence of Atrial FibrillationACE-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 AFKaplan-Meir curves for the time to first occurrence of AF

L’Allier PL et al. J Am Coll Cardiol 2004L’Allier PL et al. J Am Coll Cardiol 2004

LIFE Study Change in Cornell Voltage Duration Product and Sokolow-Lyon

LIFE Study Change in Cornell Voltage Duration Product and Sokolow-Lyon

-18-18

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00Cornell ProductCornell Product Sokolow-LyonSokolow-Lyon

Ch

an

ge

fro

m b

ase

line

(%

)C

ha

ng

e f

rom

ba

selin

e (

%)

LosartanLosartanAtenololAtenolol

P<0.0001P<0.0001

P<0.0001P<0.0001

LIFE Study Primary Composite EndpointLIFE Study Primary Composite Endpoint

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

Losartan (n)Losartan (n) 46054605 45244524 44604460 43924392 43124312 42474247 41894189 41124112 40474047 38973897 18891889 901901Atenolol (n)Atenolol (n) 45884588 44944494 44144414 43494349 42894289 42054205 41354135 40664066 39923992 38213821 18541854 876876

Study MonthStudy Month

Pro

po

rtio

n o

f p

ati

ents

w

ith

fir

st e

ven

t (%

)P

rop

ort

ion

of

pa

tien

ts

wit

h f

irst

ev

ent

(%)

Intention-to-treatIntention-to-treat

LosartanLosartan

AtenololAtenolol

22

44

66

88

1010

1212

1414

1616

Adjusted risk reduction 13·0%, P=0·021Unadjusted risk reduction 14·6%, P=0·009Adjusted risk reduction 13·0%, P=0·021

Unadjusted risk reduction 14·6%, P=0·009

Effect of Losartan on Sudden Cardiac Death

in People with Diabetes: Data From the LIFE Study

Effect of Losartan on Sudden Cardiac Death

in People with Diabetes: Data From the LIFE Study

CV DeathCV Death CHD DeathCHD Death Sudden DeathSudden Death Non SDNon SD Non Coronary CV Death

Non Coronary CV Death

-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

1010

## p<0.05p<0.05

Lindholm LH, et al: Lancet 2003

Adjusted HR (95% CI)Adjusted HR (95% CI)

#: p< 0.03#: p< 0.03

##

Reduction in Risk of Stroke in Patients with AFReduction in Risk of Stroke in Patients with AF

00 66 424230301212 1818 2424 3636 4848 5454 6060 6666

2020

2525

1515

1010

55

00

Fatal and nonfatal strokeFatal and nonfatal stroke

Adjusted risk reduction 49%, p = 0.018 Adjusted risk reduction 49%, p = 0.018

Pro

po

rtio

n o

f p

atie

nts

wit

h

firs

t ev

ent

(%)

Pro

po

rtio

n o

f p

atie

nts

wit

h

firs

t ev

ent

(%)

Time (months)Time (months)

AtenololAtenolol

LosartanLosartan

Ischemic Stroke“Mosaic of Interacting Factors”Ischemic Stroke“Mosaic of Interacting Factors”

..

Hemodynamic factors

(central and peripheral blood

pressure)

Circulating factors(glucose, insulin, RBCs, PAI, TXA2,

uric acid)

Cardiac remodeling/enlargement

Vascular remodeling

Endothelial dysfunction

Prothrombotic state

Atheroscleroticplaques

Emboli formation

Thrombus formation

Embolic occlusion

Thrombotic occlusion

Ischemic stroke

HemorrhagicHemorrhagicstrokestroke

Vascular Vascular hemorrhagehemorrhage

Plaque fragmentsPlaque fragments

Plaque rupturePlaque rupture

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”?

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”?

Cardiac remodeling/Cardiac remodeling/enlargementenlargement

Endothelial dysfunctionEndothelial dysfunction

Prothrombotic stateProthrombotic state

Vascular remodelingVascular remodeling

Reduced ECG–LVHReduced ECG–LVH

Improved endothelial functionImproved endothelial function

Inhibition of platelet aggregationReduced proaggregatory factorsInhibition of platelet aggregationReduced proaggregatory factors

Inhibited atherosclerosis formationReduced carotid artery hypertrophy Reduced gluteal artery hypertrophy

Inhibited atherosclerosis formationReduced carotid artery hypertrophy Reduced gluteal artery hypertrophy

Please refer to notes page for reference citations.

ConclusionsConclusions

Patients with HTN suffer from an increased risk of arrhythmias.Patients with HTN suffer from an increased risk of arrhythmias.

The arrhythmogenic causes of arrhythmias in HTN concern The arrhythmogenic causes of arrhythmias in HTN concern

triggered activity with early and delayed after-triggered activity with early and delayed after- depolarizations depolarizations

and re-entry. and re-entry.

The mechanisms are associated with ischemia, myocardial The mechanisms are associated with ischemia, myocardial

fibrosis, increased wall stress and acute changes of BP.fibrosis, increased wall stress and acute changes of BP.

The predictive accuracy of non-invasive parameters is not high The predictive accuracy of non-invasive parameters is not high

enoughenough

A regression of LVH leads to a reduction of ventricular ectopic A regression of LVH leads to a reduction of ventricular ectopic

activity, sudden death and improves CV morbidity and activity, sudden death and improves CV morbidity and

mortality mortality