diastolic dysfunction heart failure

Diastolic Heart Diastolic Heart FailureFailure

A Disorder of the Elderly A Disorder of the Elderly PatientPatient

M Chadi Alraies, MDM Chadi Alraies, MDChief Medical ResidentChief Medical Resident

St. Vincent Charity Hospital/Case Western Reserve St. Vincent Charity Hospital/Case Western Reserve UniversityUniversity

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Diastolic Heart Failure Diastolic Heart Failure DefinedDefined11: :

Clinical presentation and symptoms Clinical presentation and symptoms of heart failure with preserved LV of heart failure with preserved LV systolic functionsystolic function

Stiff ventricle equals decreased Stiff ventricle equals decreased compliance and impaired relaxation compliance and impaired relaxation leading to leading to LVEDP LVEDP

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Background: Background: Prevalence:Prevalence: as of 2004, 4.8 million as of 2004, 4.8 million

Americans are affected by diastolic heart Americans are affected by diastolic heart failure (HF)failure (HF)1,2,31,2,3

Diastolic HF prevalence increases with Diastolic HF prevalence increases with ageage4,5,6,74,5,6,7: :

< 50 years old: 15%< 50 years old: 15%

50-70 years old: 33%50-70 years old: 33%

> 70 years old: 50%> 70 years old: 50%

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Background (cont.)Background (cont.)

Incidence:Incidence: about 500,000 new cases about 500,000 new cases diagnosed per yeardiagnosed per year1,2,3,41,2,3,4

HF is the leading cause of HF is the leading cause of hospitalization in persons over the hospitalization in persons over the age of 65age of 654,84,8

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Background (cont.)Background (cont.)

More than 50% of patients with More than 50% of patients with HF have preserved LV functionHF have preserved LV function4,94,9

Mortality rates for patients with Mortality rates for patients with diastolic HF: diastolic HF: Advanced disease: 30-40% mortality Advanced disease: 30-40% mortality

in 5-10 yearsin 5-10 years4,104,10

Mortality rates are comparable to Mortality rates are comparable to those seen in systolic HFthose seen in systolic HF4,94,9

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A 68-year-old woman is hospitalized with A 68-year-old woman is hospitalized with palpitations and shortness of breath. She has a palpitations and shortness of breath. She has a history of hypertension and chronic atrial fibrillation, history of hypertension and chronic atrial fibrillation, and her medications include furosemide, and her medications include furosemide, candesartan, and warfarin. On physical examination, candesartan, and warfarin. On physical examination, the heart rate is 120/min with an irregularly the heart rate is 120/min with an irregularly irregular rhythm, and blood pressure is 130/80 mm irregular rhythm, and blood pressure is 130/80 mm Hg; she has an elevated jugular venous pulse, Hg; she has an elevated jugular venous pulse, crackles in both lungs, and marked lower extremity crackles in both lungs, and marked lower extremity edema. Echocardiography shows left ventricular edema. Echocardiography shows left ventricular hypertrophy, an ejection fraction of 70%, and no hypertrophy, an ejection fraction of 70%, and no significant valvular disease. She is treated with significant valvular disease. She is treated with intravenous diuretics, with improvement in her intravenous diuretics, with improvement in her symptoms and resolution of peripheral edema and of symptoms and resolution of peripheral edema and of crackles on lung examination. Her heart rate is now crackles on lung examination. Her heart rate is now 99/min and her blood pressure is 120/75 mm Hg. 99/min and her blood pressure is 120/75 mm Hg.

Which of the following would be the most Which of the following would be the most appropriate medication to add?appropriate medication to add? A Lisinopril A Lisinopril B Spironolactone B Spironolactone C Amlodipine C Amlodipine D Metoprolol E HydrochlorothiazideD Metoprolol E Hydrochlorothiazide

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Risk Factors for Diastolic Risk Factors for Diastolic HFHF4,114,11::

1.1. ElderlyElderly

2.2. Female Female

3.3. HypertensiveHypertensive

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EtiologyEtiology44::1.1. Long-standing HTN with LVHLong-standing HTN with LVH1212::

A hypertensive hypertrophic cardiomyopathy A hypertensive hypertrophic cardiomyopathy with LVEF >75% in the elderlywith LVEF >75% in the elderly66

2.2. Aortic Stenosis with normal LVEFAortic Stenosis with normal LVEF1313

3.3. Severe aortic or mitral regurgitationSevere aortic or mitral regurgitation

4.4. Ischemic Heart DiseaseIschemic Heart Disease Regional wall motion abnormalitiesRegional wall motion abnormalities

5.5. Restrictive CardiomyopathyRestrictive Cardiomyopathy – – Idiopathic vs. Infiltrative Idiopathic vs. Infiltrative

Sarcoidosis, Amyloidosis, HemochromatosisSarcoidosis, Amyloidosis, Hemochromatosis

6.6. HOCMHOCM

7.7. HypothyroidismHypothyroidism

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Asymptomatic Diastolic Asymptomatic Diastolic HF:HF:

More common than symptomatic More common than symptomatic diastolic HFdiastolic HF

Mayo Clinic study of 2,042 subjects Mayo Clinic study of 2,042 subjects > age 45: > age 45: Prevalence of symptomatic HF: 2.2%Prevalence of symptomatic HF: 2.2% Of those, 44% had diastolic HFOf those, 44% had diastolic HF In subjects In subjects withoutwithout symptoms of HF, symptoms of HF,

28% had diastolic HF by echo 28% had diastolic HF by echo criteriacriteria4,154,15..

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PathyphysiologyPathyphysiology4,164,16::

Diastolic FunctionDiastolic Function

Myocardial Relaxation Myocardial Relaxation ElasticityElasticity

- An active process - An active process - A passive process- A passive process

- Requires energy- Requires energy - Requires no - Requires no energyenergy

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Pathophysiology Pathophysiology (cont.)(cont.)1717: :

Normally, LV relaxation during diastole Normally, LV relaxation during diastole creates a negative LA to LV pressure creates a negative LA to LV pressure gradient, thereby augmenting diastolic gradient, thereby augmenting diastolic fillingfilling

Decrease in LV relaxation and Decrease in LV relaxation and distensibility causes increased LA, LV, distensibility causes increased LA, LV, PV, and PCW pressuresPV, and PCW pressures

Increase in LV filling during late Increase in LV filling during late diastole, increase in dependence on diastole, increase in dependence on atrial contractionatrial contraction

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Cardiac CycleCardiac Cycle

Reproduced from: Gutierrez C, Blanchard DG. Diastolic Heart Failure: Challenges of Diagnosis and Reproduced from: Gutierrez C, Blanchard DG. Diastolic Heart Failure: Challenges of Diagnosis and Treatment. Treatment. Am Fam PhysicianAm Fam Physician 2004;69:2609-16. 2004;69:2609-16.

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Pathophysiology (cont.)Pathophysiology (cont.)1717

Why do patients with diastolic dysfunction Why do patients with diastolic dysfunction have poor exercise tolerance?have poor exercise tolerance?

1.1. During normal exercise, increase in HR During normal exercise, increase in HR associated with increase in SV associated with increase in SV ( CO = HR x SV ( CO = HR x SV ))

2.2. Increased HR leads to compensatory increase in Increased HR leads to compensatory increase in relaxation rate, maintaining normal LVEDP & relaxation rate, maintaining normal LVEDP & PCWPPCWP

3.3. Increased LVEDV normally leads to increased SV Increased LVEDV normally leads to increased SV due to Frank-Starling mechanismdue to Frank-Starling mechanism

4.4. Normal LV distensibility allows normal LVEDP to Normal LV distensibility allows normal LVEDP to be maintained at increased LVEDVbe maintained at increased LVEDV

5.5. Thus, Thus, LVEDV causes LVEDV causes LVEDP and PCWP in LVEDP and PCWP in response to exercise in patients with diastolic response to exercise in patients with diastolic dysfunctiondysfunction

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Increased PCWP During Increased PCWP During Exercise in Pts. With Diastolic Exercise in Pts. With Diastolic

HF HF

Data from Kitzman, DW, Higginbotham, MB, Cobb, FR, et al, J Am Coll Cardiol 1991; Data from Kitzman, DW, Higginbotham, MB, Cobb, FR, et al, J Am Coll Cardiol 1991;

17:1065.17:1065.

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Pathophysiology (cont.)Pathophysiology (cont.)

Why is diastolic dysfunction more Why is diastolic dysfunction more common in elderly persons? common in elderly persons?

Age-related changesAge-related changes18,1918,19: : Increased collagen cross-linkingIncreased collagen cross-linking Increased smooth muscle contentIncreased smooth muscle content Loss of elastic fibersLoss of elastic fibers

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Clinical ManifestationsClinical Manifestations44: : Similar to systolic HFSimilar to systolic HF AF poorly tolerated due to loss of atrial kickAF poorly tolerated due to loss of atrial kick Tachycardia poorly tolerated due to Tachycardia poorly tolerated due to

shortening of late diastolic filling timeshortening of late diastolic filling time Elevated systemic blood pressure increases Elevated systemic blood pressure increases

LV wall stress and further impairs relaxationLV wall stress and further impairs relaxation Acute-on-chronic diastolic dysfunction Acute-on-chronic diastolic dysfunction

caused by ischemia increases LA and PV caused by ischemia increases LA and PV pressures, causing dyspnea, aka “anginal pressures, causing dyspnea, aka “anginal equivalents”equivalents”

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DiagnosisDiagnosis44: :

Controversy: does clinical HF + normal Controversy: does clinical HF + normal LVEF = diagnosis of diastolic HF? LVEF = diagnosis of diastolic HF?

Most patients with overt clinical HF Most patients with overt clinical HF and normal LV systolic function have and normal LV systolic function have some element of diastolic dysfunctionsome element of diastolic dysfunction

A study of 63 HF patients with LVH and A study of 63 HF patients with LVH and normal systolic function by echo found normal systolic function by echo found that 100% of patients had at least one that 100% of patients had at least one index of diastolic dysfunctionindex of diastolic dysfunction2020..

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Diagnosis (cont.)Diagnosis (cont.)11

Gold standard for diagnosis is Gold standard for diagnosis is cardiac catheterization:cardiac catheterization: Direct measurement of LVEDPDirect measurement of LVEDP Risk outweighs benefit for routine use in Risk outweighs benefit for routine use in

diagnosing diastolic dysfunctiondiagnosing diastolic dysfunction

Doppler Echocardiography: the Doppler Echocardiography: the primary diagnostic modality for primary diagnostic modality for diagnosisdiagnosis

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Doppler Doppler EchocardiographyEchocardiography11

Tau = time constant of LV pressure Tau = time constant of LV pressure decay during isovolumetric relaxation decay during isovolumetric relaxation that correlates with LV stiffnessthat correlates with LV stiffness

Diastolic trans-mitral valve blood flow: Diastolic trans-mitral valve blood flow: Measurement of peak velocities during Measurement of peak velocities during

early diastolic filling: early diastolic filling:

1) 1) EE wave = wave = EEarly diastolic fillingarly diastolic filling

2) 2) AA wave = wave = AAtrial contractiontrial contraction

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Spectrum of Diastolic Spectrum of Diastolic DysfunctionDysfunction11

Normal:Normal: E wave > A wave E wave > A wave Ratio 1.5:1.0Ratio 1.5:1.0

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Spectrum of Diastolic Spectrum of Diastolic DysfunctionDysfunction11

1.1. Early Diastolic Dysfunction: Early Diastolic Dysfunction:

Abnormal RelaxationAbnormal Relaxation E-to-A ratio reverses to < 1.0E-to-A ratio reverses to < 1.0 Increased isovolumetric relaxation Increased isovolumetric relaxation

time (stiff heart takes longer to relax)time (stiff heart takes longer to relax) Abnormal relaxation is a nonspecific Abnormal relaxation is a nonspecific

findingfinding

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Spectrum of Diastolic Spectrum of Diastolic Dysfunction (cont.)Dysfunction (cont.)11

2.2. Advanced Diastolic Dysfunction: Advanced Diastolic Dysfunction:

Pseudonormal PatternPseudonormal Pattern Abnormal relaxation & Abnormal relaxation & LVEDP LVEDP ““Pseudonormalization” can occur with Pseudonormalization” can occur with

decompensated HF and decompensated HF and LA pressure, LA pressure, common triggers include common triggers include tachyarrhythmias, especially AF, tachyarrhythmias, especially AF, uncontrolled HTNuncontrolled HTN

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Spectrum of Diastolic Spectrum of Diastolic Dysfunction (cont.)Dysfunction (cont.)11

3.3. Severe Diastolic Dysfunction: Severe Diastolic Dysfunction:

Restrictive PatternRestrictive Pattern LVEDP LVEDP LV diastolic filling occurs LV diastolic filling occurs

mostly during early diastole because mostly during early diastole because LVEDP so high that atrial kick unable LVEDP so high that atrial kick unable to effectively contribute to LV fillingto effectively contribute to LV filling

E-to-A ratio > 2.0 E-to-A ratio > 2.0 poor prognosis poor prognosis

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Normal Trans-Mitral-Valve Spectral Doppler Normal Trans-Mitral-Valve Spectral Doppler Flow PatternFlow Pattern


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Abnormal Relaxation Abnormal Relaxation


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Severe (Restrictive) Diastolic Severe (Restrictive) Diastolic DysfunctionDysfunction


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Doppler Echocardiography Doppler Echocardiography (cont.)(cont.)

Adapted from: Zile MR. Clinical manifestations and diagnosis of diastolic heart failure. Adapted from: Zile MR. Clinical manifestations and diagnosis of diastolic heart failure. http://www.utdol.com/diastolichttp://www.utdol.com/diastolic heart failure/clinical manifestations and diagnosis of diastolic heart failure. 3/2/07heart failure/clinical manifestations and diagnosis of diastolic heart failure. 3/2/07

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Brain Natriuretic Peptide Brain Natriuretic Peptide (BNP)(BNP)44

BNP elevated in patients with both BNP elevated in patients with both systolic and diastolic HF, but cannot be systolic and diastolic HF, but cannot be used to differentiate between the twoused to differentiate between the two21-2421-24

A study of 357 patients referred for A study of 357 patients referred for echocardiography based on clinical echocardiography based on clinical suspicion for heart failure revealed the suspicion for heart failure revealed the following mean BNP levelsfollowing mean BNP levels2525: : Diastolic Dysfunction = 373 (+/- 335)Diastolic Dysfunction = 373 (+/- 335) Systolic Dysfunction = 550 (+/- 602)Systolic Dysfunction = 550 (+/- 602) Combined Dysfunction = 919 (+/- 604)Combined Dysfunction = 919 (+/- 604)

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BNP (cont.)BNP (cont.)44

A study of 400 randomly selected A study of 400 randomly selected patients referred for echo to evaluate LV patients referred for echo to evaluate LV functionfunction2121: : With normal LV function – mean BNP was 30With normal LV function – mean BNP was 30 BNP of 75: sensitivity of 85% and specificity BNP of 75: sensitivity of 85% and specificity

of 97% in detecting ventricular dysfunctionof 97% in detecting ventricular dysfunction In the patients with normal LV systolic In the patients with normal LV systolic

function, BNP of 57 detected 28 patients with function, BNP of 57 detected 28 patients with isolated diastolic dysfunction with 100% PPVisolated diastolic dysfunction with 100% PPV

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BNP (cont.)BNP (cont.)44

A study of 294 patients with A study of 294 patients with echocardiographically normal LV echocardiographically normal LV systolic functionsystolic function2323:: Mean BNPMean BNP: :

All diastolic dysfunction = 286; normals = 33All diastolic dysfunction = 286; normals = 33 Impaired relaxation = 202Impaired relaxation = 202 Pseudonormal = 294Pseudonormal = 294 Restrictive = 402Restrictive = 402

For diagnosis of diastolic dysfunction, BNP For diagnosis of diastolic dysfunction, BNP of 62: sensitivity 85%; specificity 83%of 62: sensitivity 85%; specificity 83%

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BNP (cont.)BNP (cont.)

ACE-Is, ARBs, Spironolactone, and ACE-Is, ARBs, Spironolactone, and Diuretics: Diuretics:

BNP levelsBNP levels2626

Thus, monitoring of BNP levels may Thus, monitoring of BNP levels may be a useful method of assessing be a useful method of assessing response to treatmentresponse to treatment

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TreatmentTreatment2727::

Trial data limited compared with Trial data limited compared with systolic HFsystolic HF

Aim of therapy is to prevent or Aim of therapy is to prevent or control hemodynamic stressors.control hemodynamic stressors.

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Treatment (cont.)Treatment (cont.)27,2827,28

2005 ACC/AHA Task Force 2005 ACC/AHA Task Force Guidelines on Management of Guidelines on Management of Chronic Diastolic HF:Chronic Diastolic HF:

1)1) Control of systolic and diastolic HTNControl of systolic and diastolic HTN2)2) Control of VR in patients with AFControl of VR in patients with AF3)3) Control of pulmonary edema and Control of pulmonary edema and

peripheral congestion with diureticsperipheral congestion with diuretics4)4) Coronary revascularization in CAD Coronary revascularization in CAD

patients if ischemia thought to be patients if ischemia thought to be contributing to diastolic dysfunctioncontributing to diastolic dysfunction

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Pharmacologic Therapy Pharmacologic Therapy 2727

Patients with small, stiff LV chamber are Patients with small, stiff LV chamber are sensitive to excessive preload reductionsensitive to excessive preload reduction

Diuretics, Nitrates, Dihydropyridine Diuretics, Nitrates, Dihydropyridine CCBs, ACE-IsCCBs, ACE-Is – use with caution due to – use with caution due to potential to cause LV underfillingpotential to cause LV underfilling

Frank-Starling curve has a steeper slopeFrank-Starling curve has a steeper slope

Monitor for symptoms of weakness, Monitor for symptoms of weakness, lightheadedness, syncopelightheadedness, syncope

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DigoxinDigoxin2727

No survival benefitNo survival benefit2929

DIG ancillary trial: role of digoxin in patients DIG ancillary trial: role of digoxin in patients with HF and EF >45%with HF and EF >45% At 37-month follow-up, no effect on all-cause or At 37-month follow-up, no effect on all-cause or

CV hospitalization with digoxinCV hospitalization with digoxin A study examining the effect of IV digoxin on A study examining the effect of IV digoxin on

echocardiographic diastolic parameters echocardiographic diastolic parameters demonstrated a demonstrated a significant decrease of trans-mitral peak E significant decrease of trans-mitral peak E and E-to-A ratio, and a significant and E-to-A ratio, and a significant lengthening of deceleration timelengthening of deceleration time3030

However, consensus is that digoxin should be However, consensus is that digoxin should be avoided in diastolic HFavoided in diastolic HF

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-blockers-blockers2727

Can cause regression of LVH and Can cause regression of LVH and improvement of diastolic functionimprovement of diastolic function

Can Can HR, HR, diastolic filling time, diastolic filling time, oxygen oxygen consumption, consumption, BP BP11

CarvedilolCarvedilol has been shown to improve E- has been shown to improve E-to-A ratioto-A ratio3131

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Calcium channel blockersCalcium channel blockers2727

Non-dihydropyridine CCBs (diltiazem, Non-dihydropyridine CCBs (diltiazem, verapamil) - more potent negative inotropesverapamil) - more potent negative inotropes

CCBsCCBs - can cause regression of LVH and - can cause regression of LVH and improvement of diastolic functionimprovement of diastolic function

VerapamilVerapamil May have a “lusitropic” (relaxation-enhancing) effectMay have a “lusitropic” (relaxation-enhancing) effect2727

A study on 20 patients with diastolic HF taking A study on 20 patients with diastolic HF taking verapamil:verapamil:

signs and symptoms of HFsigns and symptoms of HF LV diastolic filling rate and treadmill exercise timeLV diastolic filling rate and treadmill exercise time3232

Amlodipine - Amlodipine - a study of 59 patients with HTN, a study of 59 patients with HTN, CAD, and diastolic dysfunction showed CAD, and diastolic dysfunction showed improvement in echo parameters (improvement in echo parameters ( E wave) with E wave) with 4 weeks of therapy4 weeks of therapy3333

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ACE-InhibitorsACE-Inhibitors2727

Afterload reduction not as important as Afterload reduction not as important as with systolic HF, but some evidence of with systolic HF, but some evidence of benefitbenefit

ACE-Is – can cause regression of LVH and ACE-Is – can cause regression of LVH and improvement of diastolic functionimprovement of diastolic function

ACE-IsACE-Is – – improve NYHA functional class, improve NYHA functional class, QOL, and may prevent myocardial fibrosis QOL, and may prevent myocardial fibrosis associated with LVHassociated with LVH

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Angiotensin II Receptor Angiotensin II Receptor BlockersBlockers2727

ARBsARBs - can cause regression of LVH and - can cause regression of LVH and improvement of diastolic functionimprovement of diastolic function

CHARM-Preserved trialCHARM-Preserved trial3434:: 3023 patients with symptomatic HF and LVEF > 3023 patients with symptomatic HF and LVEF >

40%40% Randomly assigned to receive candesartan or Randomly assigned to receive candesartan or

placebo x mean 37 monthsplacebo x mean 37 months Small but almost significant reduction in Small but almost significant reduction in

incidence of primary endpoints of CV death and incidence of primary endpoints of CV death and hospitalization for HF in the candesartan grouphospitalization for HF in the candesartan group

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Antihypertensives and Antihypertensives and LVHLVH2727

Regression of LVH may improve diastolic Regression of LVH may improve diastolic functionfunction3535

2003 meta-analysis examining the efficacy of 2003 meta-analysis examining the efficacy of various antihypertensives in reversal of LVHvarious antihypertensives in reversal of LVH3636

Relative reductions in LV mass index:Relative reductions in LV mass index: ARBs – 13%ARBs – 13% CCBs – 11%CCBs – 11% ACE-Is – 10%ACE-Is – 10% Diuretics – 8%Diuretics – 8% -blockers – 6%-blockers – 6%

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Regression of LVH Regression of LVH

Reproduced from: Zile MR. Treatment and prognosis of diastolic heart failure. Reproduced from: Zile MR. Treatment and prognosis of diastolic heart failure. www.utdol.comwww.utdol.com. 3/2/07. 3/2/07

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PrognosisPrognosis2727

Varies with symptomatic vs. Varies with symptomatic vs. asymptomatic HFasymptomatic HF

Framingham Heart Study and V-Framingham Heart Study and V-HeFT trials showed better prognosis HeFT trials showed better prognosis with diastolic HF than with systolic with diastolic HF than with systolic HF, but worse than controls HF, but worse than controls 37-39 37-39

A study of 522 patients showed A study of 522 patients showed similar 5-year mortality for diastolic similar 5-year mortality for diastolic vs. systolic HF (25% vs. 42%)vs. systolic HF (25% vs. 42%)4040

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SurvivalSurvival

Reproduced from: Zile MR. Treatment and prognosis of diastolic heart failure. Reproduced from: Zile MR. Treatment and prognosis of diastolic heart failure. www.utdol.comwww.utdol.com. 3/2/07. 3/2/07

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References: References: 1. Gutierrez C, Blanchard DG. Diastolic Heart Failure: Challenges of Diagnosis and Treatment. 1. Gutierrez C, Blanchard DG. Diastolic Heart Failure: Challenges of Diagnosis and Treatment. Am Fam PhysicianAm Fam Physician 2004;69:2609-16. 2004;69:2609-16.

2. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. 2. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll CardiolJ Am Coll Cardiol 1993;22(4 suppl A):6A-13A. 1993;22(4 suppl A):6A-13A.

3. Berry C, Murdoch DR, McMurray JJ. The economics of chronic heart failure. 3. Berry C, Murdoch DR, McMurray JJ. The economics of chronic heart failure. Eur J Heart FailEur J Heart Fail 2001; 3:283-91. 2001; 3:283-91.

4. Zile MR. Clinical manifestations and diagnosis of diastolic heart failure. 4. Zile MR. Clinical manifestations and diagnosis of diastolic heart failure. www.utdol.comwww.utdol.com. 3/2/2007. 3/2/2007

5. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic 5. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. function. CirculationCirculation 2002; 105:1387. 2002; 105:1387.

6. Topol EJ; Traill TA; Fortuin NJ. Hypertensive hypertrophic cardiomyopathy of the elderly. 6. Topol EJ; Traill TA; Fortuin NJ. Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J MedN Engl J Med 1985 Jan 31;312(5):277-83. 1985 Jan 31;312(5):277-83.

7. Gottdiener JS; McClelland RL; Marshall R; Shemanski L; Furberg CD; Kitzman DW; Cushman M; Polak J; Gardin JM; Gersh BJ; Aurigemma GP; Manolio 7. Gottdiener JS; McClelland RL; Marshall R; Shemanski L; Furberg CD; Kitzman DW; Cushman M; Polak J; Gardin JM; Gersh BJ; Aurigemma GP; Manolio TA. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. TheCardiovascular Health Study. TA. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. TheCardiovascular Health Study. Ann Ann Intern MedIntern Med 2002 Oct 15;137(8):631-9. 2002 Oct 15;137(8):631-9.

8. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. 8. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung TransplantJ Heart Lung Transplant 1994;13:S107- 1994;13:S107-12. 12.

9. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. 9. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMAJAMA. 2006 Nov 8;296(18):2209-16. . 2006 Nov 8;296(18):2209-16.

10. Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease 10. Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. management. Am Heart JAm Heart J 1997;133:703-12. 1997;133:703-12.

11. Yancy CW; Lopatin M; Stevenson LW; De Marco T; Fonarow Clinical presentation, management, and in-hospital outcomes of patients admitted with 11. Yancy CW; Lopatin M; Stevenson LW; De Marco T; Fonarow Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. (ADHERE) Database. J Am Coll CardiolJ Am Coll Cardiol. 2006 Jan 3;47(1):76-84. Epub 2005 Dec 15.. 2006 Jan 3;47(1):76-84. Epub 2005 Dec 15.

12. Vasan RS; Levy D. The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. 12. Vasan RS; Levy D. The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern MedArch Intern Med 1996 Sep 1996 Sep 9;156(16):1789-96. 9;156(16):1789-96.

13. Fifer MA; Bourdillon PD; Lorell BH. Altered left ventricular diastolic properties during pacing-induced angina in patients with aortic stenosis. 13. Fifer MA; Bourdillon PD; Lorell BH. Altered left ventricular diastolic properties during pacing-induced angina in patients with aortic stenosis. CirculationCirculation 1986 Oct;74(4):675-83. 1986 Oct;74(4):675-83.

14. Chiladakis JA, Koutsogiannis N, Kalogeropoulos A, Alexopoulos D. Acute effects of VVI pacing on ventricular diastolic performance in elderly patients 14. Chiladakis JA, Koutsogiannis N, Kalogeropoulos A, Alexopoulos D. Acute effects of VVI pacing on ventricular diastolic performance in elderly patients with normal left ventricular systolic function. with normal left ventricular systolic function. Int J CardiolInt J Cardiol. 2006 Oct 16; [Epub ahead of print] . 2006 Oct 16; [Epub ahead of print]

15. Redfield MM; Jacobsen SJ; Burnett JC Jr; Mahoney DW; Bailey KR; Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the 15. Redfield MM; Jacobsen SJ; Burnett JC Jr; Mahoney DW; Bailey KR; Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. community: appreciating the scope of the heart failure epidemic. JAMAJAMA 2003 Jan 8;289(2):194-202. 2003 Jan 8;289(2):194-202.

16. Aurigemma GP, Gaasch WH. Clinical Practice. Diastolic Heart Failure. 16. Aurigemma GP, Gaasch WH. Clinical Practice. Diastolic Heart Failure. N Engl J MedN Engl J Med 2004; 351:1387. 2004; 351:1387.

17. Zile MR, Eberli FR, Wexler L. Pathophysiology of diastolic heart failure. 17. Zile MR, Eberli FR, Wexler L. Pathophysiology of diastolic heart failure. www.utdol.comwww.utdol.com 3/2/2007. 3/2/2007.

18. Wei JY. Age and the cardiovascular system. 18. Wei JY. Age and the cardiovascular system. N Engl J MedN Engl J Med 1992;327:1735-9. 1992;327:1735-9.

19. Gaasch WH. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. 19. Gaasch WH. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMAJAMA 1994;271:1276-1280. 1994;271:1276-1280.

20. Zile MR; Gaasch WH; Carroll JD; Feldman MD; Aurigemma GP; Schaer GL; Ghali JK; Liebson PR. Heart failure with a normal ejection fraction: is 20. Zile MR; Gaasch WH; Carroll JD; Feldman MD; Aurigemma GP; Schaer GL; Ghali JK; Liebson PR. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation Circulation 2001 Aug 14;104(7):779-82. 2001 Aug 14;104(7):779-82.

21. Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing 21. Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. echocardiography to determine left ventricular dysfunction. Am Heart JAm Heart J 2001; 141:367. 2001; 141:367.

22. Krishnaswamy, P, Lubien, E, Clopton, P, Koon, J. Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic 22. Krishnaswamy, P, Lubien, E, Clopton, P, Koon, J. Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. dysfunction. Am J MedAm J Med 2001; 111:274. 2001; 111:274.

23. Lubien, E, DeMaria, A, Krishnaswamy, P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity 23. Lubien, E, DeMaria, A, Krishnaswamy, P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. recordings. CirculationCirculation 2002; 105:595. 2002; 105:595.

24. Tschope, C, Kasner, M, Westermann, D, et al. The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with 24. Tschope, C, Kasner, M, Westermann, D, et al. The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements. echocardiographic and invasive measurements. Eur Heart JEur Heart J 2005; 26:2277. 2005; 26:2277.

25. Aspromonte N, Feola M, Scardovi AB, Coletta C, D’Eri A, Giovinazzo P, Carunchio A, Chiera A, Fanelli R, DiGiacomo T, Ricci R, Ceci V, Milani L, Valle 25. Aspromonte N, Feola M, Scardovi AB, Coletta C, D’Eri A, Giovinazzo P, Carunchio A, Chiera A, Fanelli R, DiGiacomo T, Ricci R, Ceci V, Milani L, Valle R. Early diagnosis of congestive heart failure: clinical utility of B-type natriuretic peptide testing associated with Doppler echocardiography. R. Early diagnosis of congestive heart failure: clinical utility of B-type natriuretic peptide testing associated with Doppler echocardiography. J J Cardiovasc Med (Hagerstown)Cardiovasc Med (Hagerstown) 2006 Jun;7(6):406-13. 2006 Jun;7(6):406-13.

Zile MR; Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic Zile MR; Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. function. Circulation Circulation 2002 Mar 19;105(11):1387-93.2002 Mar 19;105(11):1387-93.

45M Chadi Alraies

References (cont.)References (cont.)26. Doust J, Lehman R, Glasziou P. The role of BNP testing in heart failure. 26. Doust J, Lehman R, Glasziou P. The role of BNP testing in heart failure. Am Fam PhysicianAm Fam Physician 2006 Dec 1;74(11):1893-8. 2006 Dec 1;74(11):1893-8.

27. Zile MR. Treatment and prognosis of diastolic heart failure. 27. Zile MR. Treatment and prognosis of diastolic heart failure. www.utdol.comwww.utdol.com. 3/2/2007. . 3/2/2007.

28. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic 28. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. CirculationCirculation 2005; 112:e154. 2005; 112:e154.

29. Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary 29. Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. digitalis investigation group trial. CirculationCirculation 2006; 114:397. 2006; 114:397.

30. Giunta A, Maione S, Arnese MR, Giacummo A, Liucci GA, Palma M, de Campora P, Cangianiello S, Condorelli M. Effects 30. Giunta A, Maione S, Arnese MR, Giacummo A, Liucci GA, Palma M, de Campora P, Cangianiello S, Condorelli M. Effects of intravenous digoxin on pulmonary venous and transmitral flows in patients with chronic heart failure of different of intravenous digoxin on pulmonary venous and transmitral flows in patients with chronic heart failure of different degrees. degrees. Clin CardiolClin Cardiol 1995 Jan;18(1):27-33. 1995 Jan;18(1):27-33.

31. Bergstrom A, Andersson B, Edner M, et al. Effect of carvedilol on diastolic function in patients with diastolic heart failure 31. Bergstrom A, Andersson B, Edner M, et al. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart FailEur J Heart Fail 2004; 6:453.2004; 6:453.

32. Setaro JF, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated with abnormal 32. Setaro JF, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. left ventricular diastolic filling and normal left ventricular systolic performance. Am J CardiolAm J Cardiol 1990; 66:981. 1990; 66:981.

33. Zaliunas R, Bradzionyte J, Zabiela V, Jurkevicius R. Effects of amlodipine and lacidipine on heart rate variability in 33. Zaliunas R, Bradzionyte J, Zabiela V, Jurkevicius R. Effects of amlodipine and lacidipine on heart rate variability in hypertensive patients with stable angina pectoris and isolated left ventricular diastolic dysfunction. hypertensive patients with stable angina pectoris and isolated left ventricular diastolic dysfunction. Int J CardiolInt J Cardiol 2005 2005 Jun 8;101(3):347-53.Jun 8;101(3):347-53.

34. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-34. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. ventricular ejection fraction: the CHARM-Preserved trial. LancetLancet 2003; 362:777. 2003; 362:777.

35. Watchtell K, Bella JN, Rokkedal J, et al. Change in diastolic left ventricular filling after one year of antihypertensive 35. Watchtell K, Bella JN, Rokkedal J, et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. CirculationCirculation 2002; 2002; 105:1071.105:1071.

36. Klingbeil AU, Schneider M, Martus P, Messerli FH. A meta-analysis of the effects of treatment on left ventricular mass in 36. Klingbeil AU, Schneider M, Martus P, Messerli FH. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. essential hypertension. Am J MedAm J Med 2003; 115:41. 2003; 115:41.

37. Vasan, RS, Larson, MG, Benjamin, EJ, et al. Congestive heart failure in subjects with normal versus reduced left 37. Vasan, RS, Larson, MG, Benjamin, EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll CardiolJ Am Coll Cardiol 1999; 33:1948. 1999; 33:1948.

38. Cohn, JN, Johnson, G, and Veterans Administration Cooperative Study Group. Heart failure with normal ejection fraction. 38. Cohn, JN, Johnson, G, and Veterans Administration Cooperative Study Group. Heart failure with normal ejection fraction. The V-HeFT Study. The V-HeFT Study. CirculationCirculation 1990; 81:III48. 1990; 81:III48.

39. Gottdiener, JS, McClelland, RL, Marshall, R, et al. Outcome of congestive heart failure in elderly persons: influence of 39. Gottdiener, JS, McClelland, RL, Marshall, R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. left ventricular systolic function. The Cardiovascular Health Study. Ann Intern MedAnn Intern Med 2002; 137:631. 2002; 137:631.

40. MacCarthy PA, Kearney MT, Nolan J, et al. Prognosis in heart failure with preserved left ventricular systolic function: 40. MacCarthy PA, Kearney MT, Nolan J, et al. Prognosis in heart failure with preserved left ventricular systolic function: prospective cohort study. prospective cohort study. BMJBMJ 2003; 327:78. 2003; 327:78.

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